Targeted Immunomodulators for the Treatment of Moderate-to-Severe Plaque Psoriasis: Effectiveness and Value Final Evidence Report December 2, 2016 Prepared for ©Institute for Clinical and Economic Review, 2016 ICER Staff/Consultants University of Washington School of Pharmacy Modeling Group* Jeffrey A. Linder, MD, MPH, FACP David L. Veenstra, PharmD, PhD Associate Professor of Medicine Professor and Associate Director Division of General Medicine and Primary Care Pharmaceutical Outcomes Research and Policy Program Brigham and Women’s Hospital University of Washington Harvard Medical School Nathaniel Hendrix, PharmD Steven D. Pearson, MD, MSc Pharmaceutical Outcomes Research and Policy Program President University of Washington Institute for Clinical and Economic Review Daniel A. Ollendorf, PhD Chief Scientific Officer Institute for Clinical and Economic Review Rick Chapman, PhD, MS Director of Health Economics Institute for Clinical and Economic Review Varun Kumar, MBBS, MPH, MSc Health Economist Institute for Clinical and Economic Review Celia Segel, MPP Program Manager, New England CEPAC Institute for Clinical and Economic Review Anne M. Loos, MA Senior Research Associate Institute for Clinical and Economic Review *The role of the University of Washington (UW) School of Shanshan Liu, MS, MPH Pharmacy Modeling Group is limited to the development of Research Associate the cost-effectiveness model, and the resulting ICER reports Institute for Clinical and Economic Review do not necessarily represent the views of the UW. DATE OF PUBLICATION: December 2, 2016 We would also like to thank Margaret Webb, Erin Lawler, Matt Seidner, and Sarah Emond for their contributions to this report. ©Institute for Clinical and Economic Review, 2016 Page ii Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Disclosure Statement: Dr. Linder owns stock in Amgen, Biogen, and Eli Lily, has contingent value rights in Sanofi Genzyme (related to alemtuzumab for multiple sclerosis); in the past 3 years, Dr. Linder has received grant support from Astellas Pharma on an unrelated topic (overactive bladder) and Clintrex, which was supported by AstraZeneca on an unrelated topic (screening for dementia); and received an honorarium from the Society of Healthcare Epidemiology of America (SHEA) as part of the SHEA Antimicrobial Stewardship Research Workshop Planning Committee, an educational activity supported by Merck. No other authors have potential conflicts of interest. ©Institute for Clinical and Economic Review, 2016 Page iii Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents About ICER The Institute for Clinical and Economic Review (ICER) is an independent non-profit research organization that evaluates medical evidence and convenes public deliberative bodies to help stakeholders interpret and apply evidence to improve patient outcomes and control costs. ICER receives funding from government grants, non-profit foundations, health plans, provider groups, and health industry manufacturers. For a complete list of funders, visit http://www.icer- review.org/about/support/. Through all its work, ICER seeks to help create a future in which collaborative efforts to move evidence into action provide the foundation for a more effective, efficient, and just health care system. More information about ICER is available at http://www.icer- review.org About New England CEPAC The New England Comparative Effectiveness Public Advisory Council (New England CEPAC) – a core program of ICER – provides a public venue in which the evidence on the effectiveness and value of health care services can be discussed with the input of all stakeholders. New England CEPAC seeks to help patients, clinicians, insurers, and policymakers interpret and use evidence to improve the quality and value of health care. The New England CEPAC is an independent committee of medical evidence experts from across New England, with a mix of practicing clinicians, methodologists, and leaders in patient engagement and advocacy. All Council members meet strict conflict of interest guidelines and are convened to discuss the evidence summarized in ICER reports and vote on the comparative clinical effectiveness and value of medical interventions. More information about New England CEPAC is available at http://icer-review.org/programs/new-england-cepac/. ©Institute for Clinical and Economic Review, 2016 Page iv Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents In the development if this report, ICER’s researchers consulted with several clinical experts, patients, manufacturers and other stakeholders. The following clinical experts provided input that helped guide the ICER team as we shaped our scope and report. None of these individuals is responsible for the final contents of this report or should be assumed to support any part of this report, which is solely the work of the ICER team and its affiliated researchers. For a complete list of stakeholders from whom we requested input, please visit: http://icer-review.org/material/psoriasis-stakeholder-list/ Clinical Expert Reviewers Alexa B. Kimball, MD, MPH President and CEO Harvard Medical Faculty Physicians at Beth Israel Deaconess Medical Center, Inc Professor of Dermatology, Harvard Medical School Joseph F. Merola, MD, MMSc Director of Clinical Trials Co-Director, Center for Skin and Related Musculoskeletal Diseases Associate Program Director, Harvard Internal Medicine-Dermatology Residency Training Program Brigham and Women's Hospital Harvard Medical School Additional Clinical Expert Input Abby S. Van Voorhees, MD Professor and Chair of Dermatology Eastern Virginia Medical School ©Institute for Clinical and Economic Review, 2016 Page v Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table of Contents Executive Summary ............................................................................................................................ ES1 1. Background ........................................................................................................................................ 1 1.1 Introduction ................................................................................................................................. 1 2. The Topic in Context .......................................................................................................................... 6 2.1 Overview ...................................................................................................................................... 6 2.2 Treatments ................................................................................................................................... 7 2.3. Other Aspects of Treatment ..................................................................................................... 10 2.4 Insights Gained from Discussions with Patients and Patient Groups ........................................ 11 2.5 Definitions .................................................................................................................................. 13 3. Summary of Coverage Policies and Clinical Guidelines ................................................................... 17 4. Comparative Clinical Effectiveness .................................................................................................. 22 4.1 Overview .................................................................................................................................... 22 4.2 Methods ..................................................................................................................................... 22 4.3 Results ........................................................................................................................................ 26 5. Other Benefits or Disadvantages ..................................................................................................... 53 6. Comparative Value ........................................................................................................................... 54 6.1 Overview .................................................................................................................................... 54 6.2 Prior Published Evidence on Costs and Cost-Effectiveness of Psoriasis Treatments ................ 54 6.3 Cost-Effectiveness Model: Methods ......................................................................................... 55 6.4 Cost-Effectiveness Model: Results ............................................................................................. 66 6.5 Potential Budget Impact ............................................................................................................ 75 6.6 Value-based Benchmark Prices .................................................................................................. 79 6.7 Summary and Comments ........................................................................................................... 80 7. Summary of the Votes and Considerations for Policy ..................................................................... 84 References ........................................................................................................................................... 98 Appendices ......................................................................................................................................... 109 Appendix A. Evidence Review Methods and Results ......................................................................... 110 ©Institute for Clinical and Economic Review, 2016 Page vi Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix B. Evidence Summary Tables ............................................................................................. 114 Appendix C. Previous Systematic Reviews and Technology Assessments ........................................ 235 Appendix D. Ongoing Trials ................................................................................................................ 239 Appendix E. Comparative Clinical Effectiveness Supplemental Information .................................... 244 Appendix F. Network Meta-Analysis Methods and Results............................................................... 247 Appendix G. Comparative Value Supplemental Information ............................................................ 255 Appendix H. Public Comments........................................................................................................... 266 ©Institute for Clinical and Economic Review, 2016 Page vii Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents List of Acronyms Used in this Report AAD American Academy of Dermatology AE Adverse Event BI Budget impact BSA Body Surface Area CMS Centers for Medicare and Medicaid Services CUA Cost utility analysis DC Discontinuation DIC Deviance information criterion DLQI Dermatology Life Quality Index dPGA Dynamic Physician Global Assessment EADV European Association for Dermatology and Venereology ERG Evidence Review Group EQ-5D EuroQol five-dimension questionnaire GDP Gross domestic product HRQL Health-related quality of life ICER Incremental cost-effectiveness ratio IGA Investigator’s Global Assessment IPC International Psoriasis Council LY Life year MACE Major adverse cardiac events MCS Mental component score NHE National Health Expenditures NICE National Institute for Health and Care Excellence NMA Network meta-analysis NMSC Non-melanoma skin cancer PASI Psoriasis Area and Severity Index PCS Physical component score PDI Psoriasis Disability Index PGA Physician Global Assessment PRISMA Preferred Reporting Items for Systematic Reviews and Meta-Analyses PSD Psoriasis Symptom Diary PSI Psoriasis Symptom Inventory PSOLAR Psoriasis Longitudinal Assessment and Registry PUVA Psoralen and ultraviolet A radiation QALY Quality-adjusted life year RCT Randomized controlled trial Resdev Residual deviance SF-36 Short Form-36 sPGA Static Physician Global Assessment TB Tuberculosis TNF Tumor necrosis factor USPSTF U.S. Preventative Services Task Force UVB Ultraviolet B VAS Visual Analog Scale WAC Wholesale acquisition cost WLQ Work Limitations Questionnaire WPAI Work Productivity and Activity Impairment WPI Worker Productivity Index ©Institute for Clinical and Economic Review, 2016 Page viii Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Executive Summary Background Plaque psoriasis is a common disease that causes itchy, red, scaly, raised lesions on the skin, most commonly on the elbows, knees, scalp, and back.1 Psoriasis affects about 3% of the population and generally occurs before age 35.2,3 Risk factors for development of psoriasis include a family history of psoriasis, smoking, alcohol use, and obesity. Plaque psoriasis is associated with increased rates of cardiovascular disease and infection, and up to 30% of patients with plaque psoriasis have at least some manifestations of psoriatic arthritis.4,5,6 Psoriasis is associated with decreased health-related quality of life7-9 and patients with psoriasis have increased rates of depression, anxiety, and suicidal ideation. 10,11 There is no cure for plaque psoriasis, but it can be managed with topical therapies, phototherapy, and systemic therapies. Systemic therapies include older agents such as methotrexate and cyclosporine as well as newer “targeted immunomodulators,” which include biologic agents and the small molecule drug apremilast. Clinical interest in targeted immunomodulators is high, as many patients with chronic plaque psoriasis do not achieve adequate or durable benefit from older systemic therapies or phototherapy. The focus of this evidence review was to assess the comparative health and economic outcomes of targeted immunomodulators (biologics plus apremilast) relative to non-targeted therapy among adults with moderate-to-severe plaque psoriasis. Topic in Context Roughly 70% to 80% of patients with plaque psoriasis have mild disease that can be adequately managed with topical therapy. Definitions of “moderate-to-severe” plaque psoriasis vary, but generally consist of psoriasis that affects at least 5% to 10% of a patient's body surface, produces lesions that have significant redness, thickness, and scale, or significantly reduces quality of life (e.g., lesions on the face, palm, or soles of the feet).12,13 Moderate-to-severe plaque psoriasis is generally treated with systemic therapies. Treatments for psoriasis can be grouped within four broad categories: • Topical therapies include steroids, vitamin D analogs, retinoids, and calcineurin inhibitors. Topical treatments are usually in the forms of creams, ointments, or lotions. Topical ©Institute for Clinical and Economic Review, 2016 Page ES 1 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents treatment can be impractical for patients with psoriasis that affects a large area or for patients who have significant scalp involvement, and higher potency topical corticosteroids can cause skin atrophy. Topical calcineurin inhibitors may be associated with skin cancer. • Older systemic therapies include acitretin, cyclosporine, and methotrexate. Older systemic therapies have limitations including hepatotoxicity, fatigue, and stomatitis (methotrexate); hypertension, lymphoma, and skin cancer (cyclosporine); or birth defects and elevated triglycerides (acitretin). • Phototherapy, also known as light therapy, exposes the skin to ultraviolet light in order to slow the growth of overactive skin cells. • “Targeted immunomodulators” include biologics and apremilast Targeted immunomodulators that have been approved, or are nearing approval, for the treatment of moderate-to-severe plaque psoriasis in the United States are listed in Table ES1. Although not technically a biologic, apremilast is a novel, targeted, oral agent also approved for treatment of patients with moderate-to-severe plaque psoriasis. Table ES1. Targeted Immunomodulator Dosing for Moderate-to-Severe Plaque Psoriasis Mechanism of Action Name (generic/trade) Dosing TNFα adalimumab/Humira® 80mg subcutaneously, then 40mg every other week starting 1 week after initial dose etanercept/Enbrel® 50mg subcutaneously 2x/week for 3 months, then 50mg 1x/week infliximab/Remicade® 5mg/kg intravenously at weeks 0, 2, and 6, then every 8 weeks IL 12/23 ustekinumab/Stelara® Patients ≤100kg/>100kg: 45mg/90mg subcutaneously at week 0 and 4, then every 12 weeks IL 17-A secukinumab/Cosentyx® 300mg subcutaneously at weeks 0, 1, 2, 3, 4 then 300mg every 4 weeks ixekizumab/Taltz® 160mg subcutaneously at week 0, then 80mg at weeks 2, 4, 6, 8, 10, 12, then 80mg every 4 weeks brodalumab/Siliq™* 210mg subcutaneously, every 2 weeks* PDE-4 apremilast/Otezla® 5-day titration then 30mg orally 2x/day thereafter ©Institute for Clinical and Economic Review, 2016 Page ES 2 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *Not yet FDA-approved. Although the original PDUFA date was scheduled for November 16, 2016, the FDA’s review of brodalumab has been postponed to February 16, 2017 due to requirements for additional time to develop a Risk Evaluation and Mitigation Strategy (REMS). 14 Concerns regarding the use of targeted immunomodulators include injection or infusion site reactions and development of serious infection or malignancy from long-term immunosuppression, although serious adverse events are relatively rare. Please see the full report for details about short and long-term adverse effects of targeted immunomodulators. Other Treatment Considerations Non-standard dosing: to maintain effectiveness when psoriasis is not being controlled at FDA- approved doses, many physicians increase the dose. Physicians may also prescribe lower-than- approved doses of effective medications in an attempt to decrease out-of-pocket costs or minimize adverse effects. Two descriptive studies of dose escalation and decreases suggest that dose increases and decreases happen at roughly similar rates. Early, Aggressive Treatment: It is uncertain whether early aggressive treatment with immunosuppressive medications, phototherapy, or targeted immunomodulators can alter the natural history of psoriasis and/or mitigate the increased cardiovascular risk seen with the disease. Second-line Targeted Therapy: Although the focus of this report is first-line targeted therapy, the potential role of second-line targeted therapy in patients who do not respond to first-line targeted treatment is relevant. Unfortunately, there is no evidence from RCTs for targeted agents in the second-line setting. Combination Therapy: The role of combination therapy – for example, the use of topical therapies with targeted immunomodulators or use of methotrexate as an adjunctive systemic therapy – has not been rigorously evaluated, but might provide enhanced effectiveness. Combination therapy seems likely to be discussed in a forthcoming guideline from the American Academy of Dermatology and the National Psoriasis Foundation. Emerging Therapies: Biologic “biosimilar” medications are becoming available, including recently- approved biosimilars like Amjevita® (Amgen), Erelzi® (Sandoz, Inc.), and Inflectra® (Pfizer/Celltrion, Inc.). The equivalence of the etanercept biosimilar for moderate-to-severe plaque psoriasis has been reported in a single conference abstract.15 Briakinumab is an additional anti-IL 12/23 that has been evaluated, but it is unclear if it will come to market. Tofacitinib, a small molecule treatment already approved for the treatment of rheumatoid arthritis, has been shown to be effective for moderate-to-severe plaque psoriasis in randomized controlled trials.16 Baricitinib, a small molecule being investigated for possible use in psoriasis, has been evaluated in a phase IIIb trial. Finally, a ©Institute for Clinical and Economic Review, 2016 Page ES 3 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Biologics License Application (BLA) was submitted to the FDA in November 2016 for guselkumab, an IL-23, and currently has three ongoing Phase III clinical trials.17 Insights Gained from Discussions with Patients and Patient Groups Conversations with advocacy groups and individual patients highlighted the shortcomings associated with clinical trial outcomes, frustrations with the healthcare system, as well as the social, emotional, and financial impact of psoriasis. A full description of insights gained from discussions with patients and patient groups is presented in the full report, but some important highlights include: • Certain aspects of research into psoriasis are not patient-centered. Many of the tools developed to measure outcomes – including the Psoriasis Area and Severity Index (PASI) – do not capture the patient experience. Patients feel that outcome measures employed in clinical trials have not adequately captured the full range of social, psychological, and emotional effects of psoriasis, including, as noted above, increased rates of depression, anxiety, and suicidal ideation. • Treatments for plaque psoriasis can be challenging because topical therapies must be frequently applied to large areas. In addition, requirements for multiple injections and time and travel concerns for administration of infused therapy may place additional burdens on patients and their families. • Patients are often dissatisfied with systemic psoriasis treatments due to unpredictable effectiveness, poor tolerability, and lack of durability of response to previously effective medications. • Psoriasis affects social functioning because of limitations of activity; clothing choices that seem inappropriate to others (e.g., long sleeves and pants on hot days); and, especially for children and teens, teasing, bullying, and shunning because of the visible nature of the disease. • Patients are concerned about lack of access, the cost of treatment, and future availability of drugs to treat their disease. About half of patients with psoriasis are either undertreated or not treated,18 and one of the main reasons is the cost of therapy. Patients are frustrated at coverage decisions and changes in coverage that may seem capricious. Comparative Clinical Effectiveness To inform our analysis of the comparative clinical effectiveness of targeted immunomodulators for moderate-to-severe psoriasis, we abstracted evidence from available clinical studies. We included randomized controlled trials as well as high-quality systematic reviews. To evaluate other measures ©Institute for Clinical and Economic Review, 2016 Page ES 4 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents of potential benefit as well as adverse events, we examined higher-quality comparative cohort studies, other articles from the published medical literature, information from the grey literature, and information from patient groups. Our literature search identified 1,392 potentially relevant references. A total of 80 references met our inclusion criteria, representing 36 RCTs and 11 observational studies. Eight studies included head-to-head, comparative evaluations of targeted immunomodulators for plaque psoriasis, of which one was available only in the grey literature (IXORA-S). Characteristics of the 29 key trials for each agent are presented in Table ES2. In addition to these 29 studies, there were five placebo- controlled RCTs conducted exclusively in Asia. Trial populations included patients with moderate-to-severe plaque psoriasis despite generally having used topical treatments, older systemic treatments, phototherapy, or other targeted immunomodulators. Trials required washout and participants to not use non-trial treatments. Use of other treatments was prohibited in the interest of directly evaluating the comparative effectiveness of targeted immunomodulators to placebo or to one another. The primary outcome for all RCTs of targeted immunomodulator therapy was assessed at the end of the induction period (between 10 and 16 weeks after initiation, depending on agent), after which treatment crossover was typically allowed. Because of this, we could only confidently compare the comparative efficacy of targeted immunomodulators at the end of the induction period. Long-term effectiveness and safety data were variably reported by individual drug. For the primary outcome, clinical trials of targeted immunomodulators used the Psoriasis Area and Severity Index (PASI). The PASI is a measure of the percent body surface area with psoriatic lesions in each of four regions (head, trunk, arms, and legs) as well as the degree of erythema, induration, and scale of the lesions in each area. PASI scores can range from 0 to 72, with higher numbers indicating greater surface involvement and severity of lesions. The PASI is generally reported as the percentage reduction in the PASI score from baseline to follow-up. The most consistently reported primary outcome in clinical trials is the “PASI 75,” i.e., a 75% reduction in the PASI score. Many trials report other PASI thresholds: PASI 90 is a 90% improvement in the PASI score; PASI 100 indicates full disease clearance, or a follow-up PASI score of zero. Other outcome measures included in clinical trials were Physician or Investigator Global Assessments about disease severity in which a successful response is usually considered “clear/almost clear;” quality of life as measured by the Dermatology Life Quality Index (DLQI), which includes domains of symptoms, feelings, daily activities, leisure, work, school, social interactions, clothing choice, sexual difficulties, and treatment problems; and measures of symptom control. ©Institute for Clinical and Economic Review, 2016 Page ES 5 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table ES2: Summary of Characteristics of Key Trials Drug Trials Total # of Induction PASI, (mean) Age (years) Psoriasis duration Previous PsA (%) patients period (weeks) (years) biologics (%) Adalimumab REVEAL 1,483 16 22 43 19 6 24 CHAMPION Etanercept Papp, 2005 3,775 12 20 44 17 6 25 Leonardi, 2003 Tyring, 2006 Strober, 2011 Gottlieb, 2011 Bagel, 2012 Bachelez, 2015 Infliximab EXPRESS I 1,213 10 21 44 19 10 30 EXPRESS II Ustekinumab ACCEPT 2,899 12 30 45 20 33 29 PHOENIX 1 PHOENIX 2 Secukinumab FEATURE 3,079 12 28 45 18 25 20 CLEAR JUNCTURE ERASURE FIXTURE Ixekizumab UNCOVER 1 3,866 12 24 46 19 27 NR UNCOVER 2 UNCOVER 3 IXORA-S** Brodalumab AMAGINE 1 4,373 12 23 45 19 33 22 AMAGINE 2 AMAGINE 3 Apremilast ESTEEM 1 1,505 16 19 46 19 31 NR ESTEEM 2 LIBERATE *PASI = Psoriasis Area and Severity Index. PsA = psoriatic arthritis **Only available in the grey literature. Because the eight targeted immunomodulators of interest have not all been directly compared, we developed quantitative, indirect comparisons among all eight agents using a Bayesian network meta-analysis (NMA) for PASI outcomes. We used a random-effects approach and, for the base case analysis, adjusted for the placebo response rate in each study which, to some degree, accounts for baseline patient differences between studies (for example, given the baseline severity and the proportion of study subjects who previously used a biologic treatment) as well as possible unknown confounders. Further details on our NMA methods and findings are available in the full report and Appendix F. ©Institute for Clinical and Economic Review, 2016 Page ES 6 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents We also examined three key subgroups of patients and studies based on stakeholder feedback: 1) patients with concomitant psoriatic arthritis, who might have more severe skin disease and who might respond better or worse to targeted immunomodulators than patients without psoriatic arthritis; 2) patients who had previously used biologic therapy, who might be less likely to respond to a different targeted immunomodulator; and 3) results from the six studies conducted exclusively in Asia, which might have design (e.g., smaller sample sizes) or patient differences (e.g., younger age, briefer duration of psoriasis, lower BMI) in comparison to the worldwide studies. Results Clinical Effectiveness Psoriasis Area and Severity Index (PASI) Results All of the targeted immunomodulators showed statistically significantly higher PASI 75 (i.e., 75% or better improvement from baseline PASI) response rates in comparison to placebo at the end of the induction period (10 to 16 weeks depending on agent; Table ES3). In addition, all the targeted immunomodulators for which there were data showed statistically significantly higher PASI 50, 90, and 100 rates in comparison to placebo. Table ES3. Placebo-Controlled Trials: Ranges of PASI 50/75/90/100 Response Rates Treatment PASI 75 PASI 50 PASI 90 PASI 100 Tx Placebo Tx Placebo Tx Placebo Tx Placebo Adalimumab 71-80 7-19 88 30 45-52 2-11 17-20 1-2 Etanercept 40-59 3-7 71-85 7-21 19-32 1-2 6-7 0 Infliximab 76-80 2-3 91 8 45-57 1 NR NR Ustekinumab 45 67 3-4 84 10 16-37 1-2 11-18 0 mg Ustekinumab 90 66-76 3-4 86-89 10 42 1-2 13-18 0 mg Secukinumab 76-87 0-5 88-94 5-15 54-60 0-2 24-43 0-1 Ixekizumab 87-90 2-7 NR NR 68-71 1-3 35-41 0-1 Brodalumab 83-86 3-8 NR NR 69-70 1-3 37-44 0-2 Apremilast 29-33 5-6 56-59 17-20 9-94 0-2 NR NR ©Institute for Clinical and Economic Review, 2016 Page ES 7 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents In direct comparative trials, ustekinumab, secukinumab, and ixekizumab were superior to etanercept for PASI 90 and 100 (Table ES4). Secukinumab and brodalumab were superior to ustekinumab in PASI 90 and 100. Finally, a head-to-head comparison of ixekizumab and ustekinumab (IXORA-S) showed statistically-significant benefit on all key PASI measures for ixekizumab; this study has not yet been published, however. Table ES4. Comparative Trials: PASI Responses Trial Treatment PASI 75 PASI 90 PASI 100 ACCEPT Etanercept 57 23 NR Ustekinumab 45 mg 68 36 NR Ustekinumab 90 mg 74 45 NR FIXTURE Etanercept 44 21 4 Secukinumab 300 mg 77 54 24 UNCOVER 2&3 Etanercept 42-53 19-26 5-7 Ixekizumab 87-90 68-70 38-41 CLEAR Ustekinumab WBD 79 53 26 Secukinumab 300 mg 91 73 39 AMAGINE 2&3 Ustekinumab WBD 69-70 47-48 19-22 Brodalumab 210 mg 85-86 69-70 37-44 IXORA-S* Ixekizumab 91 75 37 Ustekinumab 69 42 15 *Only available in the grey literature WBD = weight-based dosing Another study that is currently only available in the grey literature is the LIBERATE trial, which included apremilast and etanercept treatment arms. However, the study was powered only to detect differences between both active agents and placebo, and also used a dosing schedule for etanercept that is not FDA-approved; for these reasons, it is not considered a true head-to-head trial of targeted immunomodulators. ©Institute for Clinical and Economic Review, 2016 Page ES 8 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Network Meta-Analysis: PASI Results Because there are relatively few direct head-to-head studies among the drugs of interest, we performed a network meta-analysis that allows for rigorous indirect comparisons of different drugs. The results of our analysis showed ixekizumab with the highest relative effectiveness [measured as relative risk (RR)] on initial PASI 75 response during induction, followed by brodalumab, infliximab, secukinumab, ustekinumab, adalimumab, and etanercept. Apremilast had the lowest relative effectiveness (see Table ES5). The network meta-analysis results are consistent with the results of head-to-head trials where those are available. Other Outcome Measures Physician Global Assessments (PGA) or Investigators Global Assessments (IGA), general assessments of disease activity, were largely consistent with the PASI 75 results. All immunomodulators showed statistically significantly higher proportions of patients with an assessment of ‘clear/almost clear’ than placebo at the primary endpoint of each trial. In head-to-head trials, ustekinumab, secukinumab, and ixekizumab were superior to etanercept; secukinumab, ixekizumab, and brodalumab were superior to ustekinumab. Dermatology Life Quality Index (DLQI) results were also generally consistent with the PASI 75. All targeted immunomodulators statistically significantly improved quality of life relative to placebo. Infliximab produced the overall greatest relative benefit and apremilast produced the smallest as measured at the end of the induction period. In head-to-head trials secukinumab and ixekizumab were superior to etanercept; secukinumab was superior to ustekinumab in one trial. Measures of symptom control were inconsistently reported across trials and used a variety of instruments. Using one psoriasis symptom index, brodalumab demonstrated a statistically significant benefit over placebo. Two secukinumab trials demonstrated improvement in itching, pain, and scaling relative to placebo. In head-to-head trials, ixekizumab demonstrated superiority over etanercept for skin pain. Harms Severe or serious adverse events were rare during the induction phase of treatment. Infections (e.g., nasopharyngitis, upper respiratory tract infections, etc.), injection site or infusion reactions, headache, and nausea were the most common side effects with biologics. Infliximab appears to have higher rates of these events than other drugs. Because they have been available for longer and are approved for many conditions, long-term safety data on all-cause mortality, major cardiovascular adverse effects, malignancy, and serious infections are available for TNFα agents. For psoriasis, in 1-year follow-up of pivotal trials of ©Institute for Clinical and Economic Review, 2016 Page ES 9 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents targeted immunomodulators, etanercept, ustekinumab, secukinumab, and brodalumab have comparable safety profiles. For example, they have rates of adverse effects leading to discontinuation of between 1.2 and 3.2 per 100 person years (PY); rates of serious adverse effects of between 4.0 and 13.0 per 100 PY; and rates of serious infections between 0.8 and 1.0 per 100 PY.19-21 In 5-years of follow up, ustekinumab continues to have comparable rates.22 An analysis from a registry of 11,466 psoriasis patients with 22,311 PY of follow-up focused on the rate of severe infectious complications. Infliximab had a higher rate (2.78 per 100 PY) and ustekinumab (0.95 per 100 PY) had a lower rate of serious infections than other available targeted immunomodulators and other systemic psoriasis treatments (1.26 to 1.80 per 100 PY). 23 Subgroup Analyses We examined three subgroups: patients with concomitant psoriatic arthritis, patients who had previous used biologic therapy, and results from Asian studies. For patients with psoriatic arthritis and prior biologic therapy, limitations in the evidence preclude determining whether there are clear, meaningful differences in targeted immunomodulator effectiveness. Although outcomes were statistically significantly in favor for all the agents available for review relative to placebo, data comparing subgroup results between agents were only available in one observational study. Patients with prior biologic therapy use had response rates that were roughly 10% lower than biologic-naive patients. The evidence is insufficient, but there do not appear to be differential effects of the targeted immunomodulators within patients who have previously used a biologic treatment or in patients with psoriatic arthritis. There were 6 placebo-controlled RCTs that were conducted in Asia, including the Japanese portion of one of the worldwide studies (ERASURE). As with the worldwide studies, the Asian studies demonstrated statistically significant improvement with targeted immunomodulators compared to placebo. None of the Asian studies included head-to-head comparisons. ©Institute for Clinical and Economic Review, 2016 Page ES 10 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table ES5. Network Meta-Analysis Base-Case League Table ixekizumab 1.03 brodalumab (0.91-1.25) 210 mg 1.07 1.04 infliximab (0.95-1.24) (0.85-1.23) 1.16 1.13 1.09 secukinumab (1.04-1.33) (0.92-1.32) (0.93-1.26) 300 mg 1.28 1.24 1.20 1.1 ustekinumab (1.14-1.45) (1.01-1.45) (1.02-1.38) (0.96-1.26) 45/90 mg 1.37 1.15 1.28 1.18 1.07 adalimumab (1.14-1.74) (1.02-1.34) (1.02-1.65) (0.95-1.52) (0.87-1.37) 1.37 1.33 1.29 1.18 1.08 1.00 secukinumab (1.18-1.66) (1.06-1.64) (1.07-1.56) (1.04-1.37) (0.91-1.30) (0.76-1.30) 150 mg 1.87 1.81 1.75 1.61 1.46 1.37 (1.05- 1.36 etanercept (1.62-2.19) (1.45-2.19) (1.45-2.10) (1.36-1.91) (1.25-1.73) 1.71) (1.10-1.65) 1.99 1.92 1.86 1.71 1.56 1.45 1.45 1.07 Erelzi (1.31-3.83) (1.22-3.73) (1.20-3.59) (1.11-3.30) (1.01-3.00) (0.90-2.86) (0.92-2.9) (0.71-1.99) 2.90 2.79 2.70 2.49 2.26 2.11 2.10 1.55 1.45 apremilast (2.03-4.46) (1.90-4.36) (1.86-4.22) (1.72-3.78) (1.58-3.49) (1.42-3.31) (1.42-3.31) (1.07-2.4) (0.70-2.64) 17.89 17.25 16.72 (11.75- 15.37 13.99 13.01 12.98 9.57 8.92 6.15 placebo (12.68-25.94) (11.94-25.39) 24.34) (10.93-22.17) (10.02-20.0) (8.98-19.27) (9.12-18.79) (6.94-13.54) (4.47-15.46) (3.81-9.80) ©Institute for Clinical and Economic Review, 2016 Page ES 11 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Controversies and Uncertainties Across the 28 Phase III RCTs identified for this review, only eight included head-to-head comparisons for the drugs of interest. Our network meta-analysis extended comparisons across all agents, but the results are based primarily on indirect comparisons which generally cannot provide the same level of certainty as head-to-head studies. Our results appear to have strong face validity, however, given that they are consistent with the comparative data where available, and, as described further in the full report, are consistent with the results of other meta-analyses and network meta-analyses. Although PASI 75 was reported as the primary endpoint in all studies, all other clinical outcomes, including PASI 50, 90, 100 and PGA/IGA, were inconsistently reported across trials, making many cross-drug comparisons difficult. Longer-term data on both drug effectiveness and harms were also variable; many studies reassigned patients to different groups (mostly cross-over to the intervention) and evaluated outcomes at different time periods. Observational data were only available for ustekinumab, secukinumab, and the TNF-α agents, which limited our understanding of real-world effectiveness and durability of benefits for many of these therapies.24 Assessments of real-world effectiveness also are limited by lack of comparative data on non-standard dosing, whether increased (to preserve effectiveness) or decreased (to reduce costs). Treatment durability and cost are both important factors in choosing a treatment for psoriasis. This uncertainty hinders our understanding of the relative effectiveness of these agents. Comparative Clinical Effectiveness: Summary and Comment Using the ICER evidence rating matrix, our evidence ratings for the comparisons of interest are provided in Table ES6; ratings are presented for the targeted immunomodulator listed in each row relative to the comparator listed in each column. Note that comparisons to placebo are not included in the table. As described previously, findings from placebo-controlled trials indicated substantial improvements in clinical measures for all agents, so these would all receive a letter grade of “A” (i.e., high certainty of substantial net health benefit) relative to placebo. The presence of some direct comparisons allowed us to be reasonably confident about the relative net health benefit for certain between-agent comparisons. However, because of the lack of many head-to-head comparisons, as described previously we relied on a network meta-analysis to estimate the comparative clinical effectiveness between many targeted immunomodulators (see Appendix F). Ratings based on a combination of direct and indirect evidence are highlighted in green in Table ES6 along with the number of head-to-head studies that informed the rating. There were two head-to-head trials comparing ixekizumab and etanercept, both of which found that ixekizumab was superior in the percentage of patients achieving various PASI thresholds, with a similar magnitude of benefit found when indirect evidence was included. We felt that the ©Institute for Clinical and Economic Review, 2016 Page ES 12 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents consistency of results across the two trials represented high certainty of a substantial net benefit for ixekizumab (“A”) and an inferior net health benefit (“D”) for etanercept in this comparison. Similarly, findings from two trials comparing brodalumab to ustekinumab showed consistently superior outcomes for brodalumab, albeit at a more incremental level (ratings of “B” and “D” for brodalumab and ustekinumab respectively). The remaining head-to-head comparisons were based on the results from single trials, giving us only moderate certainty in our estimates of comparative effectiveness. Both ustekinumab and secukinumab demonstrated better outcomes than etanercept, and these findings were supported by the network meta-analysis, leading us to give a rating of “B+” (incremental or better) to these comparisons. Etanercept was rated “C-” for both comparisons, reflecting our judgment of moderate certainty that net health benefit is either comparable or inferior. Findings from a single trial of secukinumab versus ustekinumab showed improved clinical outcomes at all PASI thresholds for secukinumab, but inclusion of indirect evidence yielded a nonsignificant difference in treatment effect. As such, we rated the evidence “C+” (comparable or better) for secukinumab and “C-” for ustekinumab in this comparison. We judge the evidence to be insufficient (I) to distinguish between etanercept and apremilast, given that the only available head-to-head trial was underpowered to detect differences between active agents and dosing of etanercept does not match the labeling for the product. Finally, the addition of a direct comparison between ixekizumab and ustekinumab is newly available, but only in abstract form, yielding moderate certainty of at least a small net benefit (“B+”). Ratings based on indirect evidence alone are highlighted in blue in the table. In one instance, certainty in the ratings remained high due to a “second-order” effect. Specifically, because we have high certainty from direct evidence that brodalumab provides an incremental net health benefit over ustekinumab, and moderate certainty that ustekinumab provides an incremental or better benefit over etanercept, we have high certainty that brodalumab would also provide an incremental benefit over etanercept or apremilast. For all other ratings, results of the network meta-analyses represented the only guide with which to judge the evidence. Drugs with evidence of net health benefit were judged B+ or C+ based on the observed magnitude of benefit, and their comparators received a C- rating (moderate certainty of comparable or inferior net health benefit). In situations where the credible interval (the Bayesian equivalent of the confidence interval) crossed 1.0, the evidence was rated I (insufficient) for both directions of the comparison. ©Institute for Clinical and Economic Review, 2016 Page ES 13 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table ES6: ICER Evidence Ratings for Head-to-Head Comparisons Treatment Comparator Adalimumab Apremilast Brodalumab Etanercept Infliximab Ixekizumab Secukinumab Ustekinumab 300 45/90 Adalimumab - C+ C- C+ C- C- I I Apremilast C- - D I C- C- C- C- Brodalumab C+ B - B I I I B (2) Etanercept C- I D - C- D (2) C- (1) C- (1) Infliximab C+ B+ I B+ - I I C+ Ixekizumab C+ B+ I A (2) I - C+ B+ (1) Secukinumab I B+ I B+ (1) I C- - C+ (1) 300 Ustekinumab I B+ D (2) B+ (1) C- C- (1) C- (1) - 45/90 Note: The table should be read row-to-column. For example, there is moderate certainty that adalimumab has a comparable to substantial net benefit compared to apremilast (C+). Conversely, there is moderate certainty that the point estimate for comparative net health benefit of apremilast is either comparable or inferior to adalimumab (C-). Other Benefits and Disadvantages Beyond effectiveness and safety of targeted immunomodulators, the method of administration, frequency of dosing during maintenance, and rapidity of effect may be important considerations. All of the targeted immunomodulators are administered subcutaneously except for apremilast (oral) and infliximab (intravenous). Patients may prefer the convenience of oral therapy with apremilast. In contrast, despite its efficacy, patients may wish to avoid the administration time and potential discomfort required for intravenous infusions of infliximab. The frequency of administration during maintenance is greatest for apremilast (twice a day). Other targeted immunomodulators are taken weekly (adalimumab, etanercept), every two weeks (brodalumab), every four weeks (secukinumab and ixekizumab), every eight weeks (infliximab), and every 12 weeks (ustekinumab). Patients could favor agents that need to be taken less frequently. How quickly a drug works to clear psoriasis is likely to be important for patient satisfaction and adherence. For patients who require rapid clearing of moderate-to-severe plaque psoriasis, ©Institute for Clinical and Economic Review, 2016 Page ES 14 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents cyclosporine, an older systemic agent, not a focus of this review, and infliximab appear to be superior to other treatments. Comparative Value We developed a simulation model to assess the long-term cost-effectiveness of targeted immunomodulators for patients with moderate-to-severe plaque psoriasis for whom topical therapies, older systemic therapies, or phototherapy have been ineffective, contraindicated, or not tolerated. We used as inputs for the model the results from our network meta-analyses and other results from the published literature. The outcomes of the model include total costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios. Uncertainty in the data inputs and assumptions were evaluated using sensitivity and scenario analyses. Consistent with other approaches to modeling sequential therapy in psoriasis, patients with less than 75% improvement after the initiation period (10 weeks for infliximab, 16 weeks for adalimumab and apremilast, 12 weeks for all other drugs) were assumed to discontinue the first- line therapy, and either receive second-line targeted therapy or non-targeted therapy (i.e., a mix of no treatment, topical therapy, other systemic therapy, and phototherapy). Second-line targeted therapy was defined as an average of all available targeted therapies; costs were averaged across available targeted agents as was effectiveness, with a small assumed decrease in effectiveness. Figure ES1: Markov model of psoriasis treatment and response The model required a number of assumptions which are represented in Table ES7 below along with the rationale for each assumption. ©Institute for Clinical and Economic Review, 2016 Page ES 15 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table ES7. Key model assumptions Assumption Rationale A patient cannot transition between Drug response does not show significant improvement past effectiveness (PASI improvement) levels. the trial period; discontinuation rate accounts for decline in effectiveness over time. Probability of discontinuing first-line therapy Empirical evidence indicates discontinuation rates beyond the is drug specific. initiation period differ across drugs, and differs in year 1 vs. years 2+ Probability of discontinuing newer drugs There are limited to non-existent data on discontinuation (secukinumab, ixekizumab, and brodalumab) rates for the newer agents. This assumption was evaluated in is the same as ustekinumab. a sensitivity analyses. Half of patients discontinuing first-line There are limited data on proportion of patients receiving targeted drug therapy receive second-line second-line targeted treatment, particularly in current targeted drug and remainder receive non- treatment paradigm with newer agents. This assumption was targeted drug. evaluated in sensitivity analyses. Second-line targeted therapy was assumed to There are no RCTs of second-line targeted therapy and limited be an average of all available targeted agents. data on second-line targeted therapy response in general. Non-targeted therapy was assumed to consist There is little evidence on the mix of treatments, costs, and of a mix of no treatment, topical treatment, patient outcomes over time in patients who do not receive non-targeted systemic treatment, and targeted therapy, as well as in patients who discontinue phototherapy. targeted therapy. Risk of death is based on age alone. Evidence suggesting that treatment of psoriasis improves survival is very weak. Patients remain on first-line therapy during A full trial period (10 weeks for infliximab, 16 weeks for the trial period. adalimumab and apremilast, 12 weeks for all others) is needed to determine whether the drug will produce an adequate response. Subcutaneous drugs are administered in-clinic Balance between assuming SQ drugs are always self- during the initiation period and by the patient administered vs. always administered in clinic. themselves during the maintenance period. Key cost, quality of life, and clinical data sources Feedback on the draft evidence report indicated that WAC is not representative of actual price paid in either public or private settings. To address this concern, we obtained data from SSR Health,25 which combines data on net US dollar sales with information on unit sales to derive net pricing at the unit level across all payer types.25 Data on the approved agents of interest are current through the third quarter of 2016. We estimated net prices for these agents by comparing the 4-quarter (i.e., 4Q2015 – 3Q2016) rolling averages of both net prices and WAC prices per unit to arrive at an average discount from WAC. We calculated averages at the drug class level and rounded these to the nearest 5%. Finally, we applied the drug class level average to the most current WAC price for ©Institute for Clinical and Economic Review, 2016 Page ES 16 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents each medication to arrive at an estimated net price. Drug class level average discounts were as follows: • TNF-α: 30% • IL-17A: 40% • Anti-IL 12/23: 15% • Apremilast: 20% For brodalumab, IL-17A agent currently under regulatory review, we estimated the launch price as the average of the WAC prices for the two other agents in this class, and then applied the 40% discount specific to IL-17A drugs. We used wholesale acquisition cost (WAC) in a scenario analysis.26 Utilities were obtained from an analysis of EQ-5D data in 3,231 patients enrolled in five RCTs evaluating secukinumab in moderate to severe psoriasis.27 The EQ-5D is one of the most commonly used generic health status measurement, and has good validity and reliability in various health conditions, including psoriasis. The EQ-5D includes questions across five dimensions: mobility, self- care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D was measured alongside PASI in the secukinumab RCTs, and the relationship between PASI improvement and EQ-5D was evaluated to derive the estimates. Short and long term drug discontinuation rates were estimated from long-term follow up studies for etanercept, adalimumab, infliximab, and ustekinumab, and were estimated based on class effect assumptions for the other drugs. Incremental Costs per Outcomes Achieved: Results Total costs, quality-adjusted life years, and life years for each therapy are shown in Table ES8. Additionally, we show the incremental cost-effectiveness ratio for each of the targeted therapies compared to non-targeted therapy. The base-case results indicate that treatment with targeted drugs, over a 10-year time frame that includes drug discontinuation, leads to QALY improvements ranging from 0.8 (apremilast) to 1.7 (ixekizumab, brodalumab). ©Institute for Clinical and Economic Review, 2016 Page ES 17 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table ES8. Results for the base case Cost QALYs LYs ICER vs. non-target non-targeted $88,086 5.531 8.64 adalimumab $208,881 6.649 8.64 $108,040 apremilast $161,741 6.353 8.64 $89,610 brodalumab* $240,398 7.151 8.64 $94,030 etanercept $198,519 6.469 8.64 $117,769 infliximab $203,532 6.776 8.64 $92,715 ixekizumab $254,287 7.187 8.64 $100,389 secukinumab $221,704 7.018 8.64 $89,843 ustekinumab $269,843 6.930 8.64 $129,904 *Results for brodalumab are tentative, as pricing is not currently available The base-case results shown in Table ES8 are also graphed in Figure ES2. Drugs that are farther to the right provide the greatest clinical benefit, and drugs higher on the y-axis are more expensive. This chart shows a general trend towards better results with more expensive therapies. Secukinumab is the most cost-effective agent versus non-targeted therapy. However, estimated cost-effectiveness ratios for all the drugs fall into a relatively narrow range, with IL-17A targeted drugs generally providing more QALY gains than TNF-α agents, but at higher cost. Ustekinumab appears above the slope of the line formed by more cost-effective competitors, indicating that it is estimated to provide fewer QALYs at higher cost, primarily as a result of including higher dosing (90mg) for heavier patients receiving this drug. ©Institute for Clinical and Economic Review, 2016 Page ES 18 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure ES2: Cost-effectiveness plane for all comparators (base case)* *Results for brodalumab are tentative, as pricing is not available We also calculated incremental cost-effectiveness ratios for etanercept compared to the IL-17A targeted drugs (Table ES9). We selected these comparisons because etanercept was the only TNF-α agent for which we felt we had adequate evidence to distinguish its overall effectiveness (lower) compared to all IL-17A targeted drugs. In addition, as the least expensive biologic agent, our analysis will help inform policymakers as to whether the incremental cost of IL-17A targeted drugs over etanercept represents good long-term value. The incremental cost-effectiveness ratios versus etanercept ranged from approximately $42,000/QALY for secukinumab up to approximately $78,000 for ixekizumab. Table ES9. Incremental cost-effectiveness ratios for IL-17A targeted drugs compared to etanercept Cost/QALY Versus Etanercept Brodalumab $61,396 Ixekizumab $77,686 Secukinumab $42,190 Sensitivity and Scenario Analyses We conducted one-way analyses to determine the impact on the ultimate cost-effectiveness result of varying the range for different inputs (parameters) of the model. We found that cost- effectiveness results were most sensitive to variation in targeted drug costs and utility, the cost and utility of non-targeted therapy, and drug discontinuation rates. In particular, non-targeted therapy considerations are important given the lack of data on the performance of such therapy in a setting ©Institute for Clinical and Economic Review, 2016 Page ES 19 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents where many patients have already failed prior use. However, comparisons to non-targeted therapy never exceeded $150,000 per QALY gained across the range of estimates for non-targeted therapy cost and utility. More detailed presentations of one-way sensitivity analyses, including tornado diagrams, are available in the full report. We conducted a scenario analysis in which productivity cost offsets were included in our calculations, which led to cost-effectiveness ratios approximately $20,000 lower than in the base case. Analyses conducted using WAC (i.e., non-discounted) drug prices yielded cost-effectiveness ratios that ranged from $140,000 to $187,000 per QALY gained. Finally, conducting analyses using a lifetime time horizon or using a different set of utilities for PASI 100 had little impact on results compared to the base case. Potential Budget Impacts: Results We also used the cost-effectiveness model to estimate the potential total budgetary impact of the two novel treatments for psoriasis patients, based on assumed patterns of product uptake for ixekizumab (approved in March 2016) and brodalumab (not yet approved) over their first five years in the market. We did not include the other therapies modeled above in this potential budget impact analysis, given their established presence in the market. Based on anticipated growth in the national economy, ICER has estimated a five-year annualized potential budget impact for each new drug that can serve as a threshold for triggering consideration of heightened policy actions to avoid negative consequences for patient access and overall health system budgets. For 2015-16, this threshold is calculated at $904 million per year for new drugs. The candidate population for treatment with these agents in our analysis is adults with moderate- to-severe plaque psoriasis who are taking a biologic agent for psoriasis for the first time. To estimate the size of this population, we first determined the estimated incidence of psoriasis in the US. (We used incidence rather than prevalence because we were interested only in patients who were taking a biologic for the first time.) Psoriasis incidence in the United States has been estimated at 78.9 cases per 100,000 persons.28 This incidence and the proportions of psoriasis patients with plaque psoriasis (79%)28 and with moderate-to-severe disease (18.2%)3 were applied to the projected 2016 U.S. population, resulting in an estimate of approximately 36,750 incident cases of moderate-severe plaque psoriasis in the US per year, or approximately 183,750 incident cases over five years. In this analysis, we assumed a 10% uptake pattern for ixekizumab and a 10% uptake for brodalumab in the eligible population. Over the entire five-year time horizon, we estimate that “unmanaged” uptake would lead to approximately 18,375 persons taking brodalumab and 18,375 taking ixekizumab. Across the full ©Institute for Clinical and Economic Review, 2016 Page ES 20 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents five-year time horizon, the weighted potential budgetary impact is approximately $65,200 per patient taking brodalumab, and approximately $72,400 per patient taking ixekizumab. Total potential budgetary impact of brodalumab over five years is approximately $1.2 billion, with an average budget impact per year of approximately $239.8 million. For ixekizumab, total potential budgetary impact over five years is approximately $1.3 billion, with an average budget impact per year of approximately $266 million. The annualized potential budget impact of brodalumab is 27% of the budget impact threshold of $904 million for a new drug, while the annualized potential budget impact of ixekizumab is 29% of the threshold. Table ES10. Estimated Total Potential Budget Impact (BI) of Brodalumab and Ixekizumab for Treatment of Plaque Psoriasis Analytic Horizon = 1 Year Analytic Horizon = 5 Years Eligible Number Annual BI Total BI Number Weighted BI Average BI Population Treated per Patient* (millions) Treated per Patient* per year (millions) Brodalumab 183,750 3,675 $32,700 $120.3 18,375 $65,200 $239.8 Ixekizumab 183,750 3,675 $37,400 $137.3 18,375 $72,400 $266.0 *Weighted budget impact calculated by subtracting cost offsets from drug costs for one-year horizon. For five-year horizon, drug costs and cost offsets apportioned assuming 20% of patients in uptake target initiate therapy each year. Those initiating in year 1 receive full drug costs and cost offsets, those initiating in year 2 receive 80% of drug costs and cost offsets, etc. Value-based Benchmark Prices Our value-based benchmark prices for each psoriasis treatment are provided in Table ES11. As noted in the ICER methods document, the value-based benchmark price for a drug is defined as the price range that would achieve cost-effectiveness ratios between $100,000 and $150,000 per QALY gained. As shown in the table, with the exception of adalimumab, apremilast, and infliximab, all drugs would require discounts from current WAC prices to fall within ICER’s threshold value range of $100,000 to $150,000/QALY. Importantly, however, our estimates of net prices bring all the drugs of interest either within this threshold value range or generate cost-effectiveness ratios that are already <$100,000 per QALY gained. Table ES11. Value-based price benchmarks for all psoriasis targeted treatment regimens Discount from Cost to achieve Cost to achieve Net price* WAC* WAC to reach $100k/QALY $150K/QALY WTP threshold ©Institute for Clinical and Economic Review, 2016 Page ES 21 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Adalimumab 36% to +1% $1,433.98 $2,048.54 $1,311.40 $2,073.74 (40mg) increase Apremilast 0.4% to +94% $34.48 $43.10 $42.94 $83.64 (30mg) increase Brodalumab $2,560.07** $4,266.79** $2,696.61 $3,840.28 10% to 37% (210mg) Etanercept $717.11 $1,024.44 $566.68 $989.98 3% to 45% (50mg) Infliximab 23% to +25% $779.24 $1,113.27 $857.54 $1,395.18 (100mg) increase Ixekizumab $2,681.40 $4,469 $2,672.66 $3,795.25 15% to 40% (80mg) Secukinumab $2,438.74 $4,064.57 $2,680.73 $3,872 5% to 34% (300mg) Ustekinumab $7,514.19 $8,840.22 $5,886.50 $8,608.05 3% to 33% (45mg) *Net price or WAC per vial/pill **Assumed net price/WAC Comparative Value: Summary and Comment There are three key findings from our analyses. First, all the targeted drugs had reasonably good value for money compared to non-targeted therapy, using our estimated, discounted drug costs. The value of targeted agents is driven primarily by their meaningful impact on patient quality of life, and secondarily by offsetting other costs of care such as clinic visits and use of non-targeted therapies. While there are multiple sources of uncertainty, primarily caused by data limitations, this finding is robust using our base-case drug prices. Second, despite the somewhat similar cost-effectiveness ratios versus non-targeted therapy, there were important differences in the total amount of patient benefit (measured as QALYs) that could be gained for each drug. Drugs with high first-line efficacy and low discontinuation rates provide the greatest patient benefit, despite the availability of second-line therapy for those who failed first-line treatment. There are several reasons for this. First, not all patients who fail first-line therapy will continue to second-line therapy, and potential patient benefit is lost. Second, initiating second-line therapy incurs the added drug cost of another initiation period. Finally, although there is a paucity of data, it appears that second-line therapy may be slightly less effective than first-line treatment with the same drug. Third, the newer IL-17A targeted agents provide good economic value in relation to etanercept and adalimumab, and potentially infliximab. The lower initial effectiveness of etanercept and ©Institute for Clinical and Economic Review, 2016 Page ES 22 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents adalimumab, high long-term discontinuation rates, and the need for more expensive second-line therapy decrease their overall value despite lower initial drug cost. We have attempted to model psoriasis treatment to both reflect clinical practice and accommodate the limits of available data. The latter necessity has placed some restrictions on how accurately we can model the course of psoriasis treatment. There are four major limitations of our analyses. First, the course and effects of therapy sequencing is not clear due to a lack of trials of targeted drugs in the second-line setting. We assumed that after first-line therapy, half of patients go to a second-line targeted therapy while half move to non-targeted therapy; we explored the effect of our assumptions on the results in sensitivity analyses. Second, we would have preferred direct utility elicitation data from clinical trials, rather than surmising quality of life from improvements in PASI score. Third, we utilized a novel source to estimate the general size of drug rebates at a drug class level, but there is uncertainty in the size of rebates for specific drugs within each class. Fourth, another major limitation of the analyses was uncertainty in the costs and quality of life effects of non-targeted therapy. We encourage decision makers to consider the uncertainty in results related to the cost and quality of life of non-targeted therapy, although findings of one-way sensitivity analyses suggest that cost-effectiveness of targeted versus non-targeted therapy remains below $150,000 per QALY across a range of assumptions. In summary, our analyses suggest that if health care payers are able to achieve significant drug rebates, the most effective (and most expensive) targeted drugs provide the greatest benefit to psoriasis patients at a reasonable economic value. New England Comparative Effectiveness Public Advisory Council Votes The New England Comparative Effectiveness Public Advisory Council deliberated on key questions raised by ICER’s report at a public meeting on November 18, 2016. The results of the votes are presented below. 1) Is the evidence adequate to demonstrate that the net health benefit of apremilast is as good as that provided by any of the TNFα inhibitors? Yes: 0 votes No: 14 votes 2) Is the evidence adequate to distinguish the net health benefit among the IL-17A targeted drugs secukinumab, ixekizumab, and brodalumab? ©Institute for Clinical and Economic Review, 2016 Page ES 23 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Yes: 0 votes No: 14 votes 2a) Is the evidence adequate to demonstrate that the net health benefit of IL-17A drugs as a class is better than that provided by adalimumab? Yes: 5 votes No: 9 votes 2b) Is the evidence adequate to demonstrate that the net health benefit of IL-17A drugs as a class is better than that provided by etanercept? Yes: 14 votes No: 0 votes 2c) Is the evidence adequate to demonstrate that the net health benefit of IL-17A drugs as a class is better than that provided by infliximab? Yes: 1 votes No: 13 votes 3) Is the evidence adequate to demonstrate that the net health benefit of ustekinumab is better than that provided by adalimumab? Yes: 1 votes No: 13 votes 4) Is the evidence adequate to demonstrate that the net health benefit of ustekinumab is better than that provided by etanercept? Yes: 14 votes No: 0 votes 5) Is the evidence adequate to demonstrate that the net health benefit of ustekinumab is better than that provided by infliximab? Yes: 0 votes No: 14 votes Care Value Voting Results 6) Given the available evidence on comparative effectiveness and incremental cost-effectiveness using estimated discounted prices for private insurers presented in the report, and taking into ©Institute for Clinical and Economic Review, 2016 Page ES 24 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents account other benefits, disadvantages, and contextual considerations, what is the long-term value for money of the following drugs compared to continued non-targeted therapy? Adalimumab: Low: 0 votes Intermediate: 11 votes High: 3 votes Etanercept: Low: 2 votes Intermediate: 11 votes High: 1 votes Infliximab: Low: 3 votes Intermediate: 9 votes High: 2 votes Ustekinumab: Low: 3 votes Intermediate: 9 votes High: 2 votes Secukinumab: Low: 0 votes Intermediate: 3 votes High: 11 votes Ixekizumab: Low: 0 votes Intermediate: 6 votes High: 8 votes Brodalumab: No comparative value vote was taken on brodalumab, as its anticipated approval by the FDA was delayed beyond the timeline of this review and thus no list price was available for consideration. Apremilast: Low: 0 votes Intermediate: 7 votes High: 7 votes ©Institute for Clinical and Economic Review, 2016 Page ES 25 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 7) Given the available evidence on comparative clinical effectiveness and incremental cost- effectiveness, and taking into account other benefits, disadvantages, and contextual considerations, what is the long-term value for money of treatment with ixekizumab and secukinumab versus etanercept? Low: 0 votes Intermediate: 1 votes High: 13 votes Key Policy Implications The New England CEPAC engaged in a moderated discussion about how best to apply evidence on targeted immunomodulators for plaque psoriasis in policy and practice. The roundtable included two clinical experts, two patient representatives, and two payer representatives. The discussion reflected multiple perspectives and opinions, and therefore, none of the statements below should be taken as a consensus view held by all participants. Below are the top-line policy implications; for more information please see the full report. Specialty Societies and Patient Advocacy Groups  Update outdated treatment guidelines for patients with moderate-to-severe chronic plaque psoriasis in a form that is easy to understand and easy-to-use by payers, clinicians, and patients. Purchasers and Insurers  Consider limiting or abolishing “step therapy” approaches to coverage. o Step-therapy can be appropriate for treating certain conditions, but given that all of the targeted immunomodulators have good value relative to non-targeted treatment, payers should strongly consider eliminating most step therapy requirements for patients with moderate-to-severe psoriasis. Any step therapy requiring initial use of TNFα inhibitors before other drugs should be reconsidered to allow rapid and permanent exceptions for patients with co-conditions, co- morbidities, or specific life requirements that make other drugs the best first choice among all available targeted immunomodulators.  If step therapy will be used: o Allow individuals switching insurers to bypass step therapy if they are already on an effective treatment. o Remove requirements for patients to have higher out-of-pocket expenses for “later step” treatments. ©Institute for Clinical and Economic Review, 2016 Page ES 26 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents  As alternative mechanisms to manage costs, consider developing indication-specific formulary designs and outcome-based payment contracts.  Co-payment and/or co-insurance for therapies should be based on prices net of discounts and rebates instead of list price. Manufacturers  Foster transparency in the rationale for price increases.  Release treatment-specific quality-of-life data. Researchers and Manufacturers  Conduct research that directly compares real-world treatment options and sequential treatment effectiveness for both naïve and treatment-experienced patients.  Generate additional information on the treatment durability of IL-17A agents. Patient Advocacy Groups, Clinicians, and Researchers  Patients and patient organizations should take a leadership role in the design of clinical trials and all stakeholders should advocate for rigorous study in diverse populations evaluating real-world comparative treatments.  Lead research efforts to evaluate heritability of psoriasis and the impact of managing plaque psoriasis on caregivers and families. ©Institute for Clinical and Economic Review, 2016 Page ES 27 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1. Background 1.1 Introduction Background Plaque psoriasis is a common disease that causes itchy, red, scaly, raised lesions on the skin, most commonly on the elbows, knees, scalp, and back.1 Psoriasis affects about 3% of the population and generally occurs before age 35.2,3 Risk factors for development of psoriasis include a family history of psoriasis, smoking, alcohol use, and obesity. Chronic plaque psoriasis accounts for about 80% to 90% of all patients with psoriasis.28-30 Plaque psoriasis is one of the cutaneous psoriasis types; others include guttate psoriasis, pustular psoriasis, inverse psoriasis, nail psoriasis, and erythrodermic psoriasis. Psoriasis is associated with systemic diseases including other autoimmune diseases (e.g., inflammatory bowel disease), metabolic syndrome, and cardiovascular disease.31 In addition, up to 30% of patients with plaque psoriasis have at least some manifestations of psoriatic arthritis.4,5 Symptoms of psoriatic arthritis include inflammation in multiple small or large joints, involvement of the distal joints in the hand, as well as inflammation of tendons, tendon insertions, and fingers. Figure 1. Typical psoriatic plaque on the knee Plaque psoriasis significantly decreases health-related quality of life, particularly if lesions are in areas that can affect daily functioning (e.g., the hands or soles of the feet) or social functioning (e.g., the face).7-9 Psoriasis itself is not a direct cause of increased mortality, but patients with severe psoriasis have increased mortality due to cardiovascular disease and infection.6 ©Institute for Clinical and Economic Review, 2016 Page 1 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents There is no cure for plaque psoriasis, but it can be managed with topical therapies, phototherapy, and systemic therapies. Systemic therapies include older agents such as methotrexate and cyclosporine as well as newer “targeted immunomodulators,” which include biologic agents and the small molecule apremilast. Clinical interest in targeted immunomodulators is high, as many patients with chronic plaque psoriasis do not achieve adequate or durable benefit from older systemic therapies or phototherapy. The newer targeted immunomodulators are generally more expensive than older medications and there are questions regarding how these costs align with the clinical value brought to patients. The direct medical costs of psoriasis have been estimated to cost the United States $52 billion to $63 billion and indirect costs of lost work productivity have been estimated to range between $24 billion and $35 billion.32 Scope of the Assessment This project evaluated the health and economic outcomes of targeted immunomodulators (biologics plus apremilast) for adults with moderate-to-severe plaque psoriasis. The scope for these assessments is described below using the PICOTS (Population, Intervention, Comparators, Outcomes, Timing, and Settings) framework. To evaluate comparative clinical effectiveness, we examined randomized controlled trials as well as high-quality systematic reviews. To evaluate other measures of potential benefit as well as adverse events, we examined higher-quality comparative cohort studies, other articles from the published medical literature, information from the grey literature, and information received from patient groups. Analytic Framework The analytic framework for this assessment is depicted in Figure 2. ©Institute for Clinical and Economic Review, 2016 Page 2 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 2. Analytic Framework: Adverse Events  Infectious  Neoplastic Interventions  Hematologic TNF-α, anti-IL-17A, anti IL-  Respiratory 12/23 agents, apremilast  Cardiovascular  Autoimmune  Injection site  Other AEs Key Measures of Clinical Population Intermediate Outcomes Benefit Adults with  PASI 75, 90, 100  Health-related quality of life moderate-to-  PGA  Functional outcomes severe plaque  Other patient-reported psoriasis outcomes Population The population of focus for this review was adults with moderate-to-severe chronic plaque psoriasis who generally failed topical treatments, older systemic treatments, phototherapy, or other targeted immunomodulators. Although not a focus of the review, we did not exclude evidence from patient populations with other concomitant psoriasis types or psoriatic arthritis. We evaluated psoriasis outcomes in subgroups where data were available, including patients who have and have not been previously treated with a targeted immunomodulator, and those with and without psoriatic arthritis. Interventions The interventions of interest were the targeted immunomodulators (biologics and apremilast) all but one of which has been approved for the treatment of moderate-to-severe plaque psoriasis:  Anti-TNF-α agents: adalimumab, etanercept, infliximab (approved only for severe plaque psoriasis)  Anti IL-12/23 agent: ustekinumab  IL-17A agents: secukinumab, ixekizumab, brodalumab (not yet approved)  Anti PDE-4 agent: apremilast ©Institute for Clinical and Economic Review, 2016 Page 3 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Comparators Wherever possible, we evaluated head-to-head trials of these interventions. Other comparators included placebo or other active treatments not listed above. Use of other treatments was prohibited in the interest of directly evaluating the comparative effectiveness of targeted immunomodulators to placebo or to one another. Outcomes This review examined key clinical outcomes, including outcomes common to plaque psoriasis trials. Discussions with patients, patient groups, clinicians, and industry, as well as publications from academic research groups, indicated that people with psoriasis have symptoms and burdens that are not well-captured by standard trial outcomes.8,33 Standard trial outcomes are generally not used or feasible to employ in actual clinical practice. We examined available data for evidence about the comparative effectiveness of targeted immunomodulators in affecting outcomes such as itch, scaling, pain, quality-of-life, and work productivity. Outcomes for which we were able to find evidence included: o Clinical Benefits o Trial Outcomes  Psoriasis Area and Severity Index (PASI): 50, 75, 90, 100  Physician Global Assessment (PGA) or Investigator’s Global Assessment (IGA) o Patient-Reported Outcomes  Dermatology Life Quality Index (DLQI)  Other measures of health-related quality of life (e.g., Short Form [SF]-36)  Symptom control (e.g., Visual Analog Scale [VAS], Psoriasis Symptom Inventory [PSI]) o Harms o Treatment-related adverse events (e.g., rate of infections) o Treatment tolerability (i.e., discontinuation due to adverse events) For most outcomes, we summarized results qualitatively and descriptively. For the PASI, we examined direct evidence of comparative clinical effectiveness and performed a network meta- analysis to evaluate comparative clinical effectiveness through indirect comparison. Timing Evidence on intervention effectiveness and harms was derived from studies of any duration. Because psoriasis is a chronic condition with no cure, we were particularly interested in evidence of durability of response to medications, as well as long-term safety. ©Institute for Clinical and Economic Review, 2016 Page 4 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Settings Plaque psoriasis is generally treated in outpatient and/or clinic settings, which was the focus of our review. ©Institute for Clinical and Economic Review, 2016 Page 5 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2. The Topic in Context 2.1 Overview Roughly 70% to 80% of patients with plaque psoriasis have mild disease that can be adequately managed with topical therapy. Definitions of “moderate-to-severe” plaque psoriasis vary, but generally consist of psoriasis that affects at least 5% to 10% of a patient’s body surface; produces lesions that have significant redness, thickness, and scale; or significantly reduces quality of life (e.g., lesions on the face, palm, or soles of the feet).12,13 Moderate-to-severe plaque psoriasis is generally treated with systemic therapies. Figure 3. Psoriatic involvement of the back involving about 10% of body surface area Pictures from the US Food and Drug Administration Public Meeting on Patient-Focused Drug Development for Psoriasis: An Overview of Psoriasis. March 17, 2016. Available at: http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm470608.htm ©Institute for Clinical and Economic Review, 2016 Page 6 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2.2 Treatments Treatments for psoriasis can be grouped within 4 broad categories: 1. Topical therapies such as steroids, vitamin D analogs, retinoids, and calcineurin inhibitors; 2. Older systemic therapies, such as acitretin, cyclosporine, and methotrexate; 3. Phototherapy, most commonly ultraviolet B light (UVB); and 4. “Targeted immunomodulators” including biologics and apremilast Topical Treatments include emollients; topical corticosteroids of varying strength; vitamin D analogs (e.g., calcipotriene, calcitriol); coal tar products which are usually available without a prescription; topical retinoids (tazarotene); topical calcineurin inhibitors (e.g., tacrolimus or pimecrolimus), which can be useful for treatment of the face and intertriginous areas; and anthralin. Topical treatments are usually in the forms of creams, ointments, or lotions, but can also be gels, foams, sprays, and shampoos. Topical treatment can be impractical for patients with psoriasis that affects a large area or for patients who have significant scalp involvement. Higher potency topical corticosteroids can cause skin atrophy if used on non-psoriatic skin, particularly on areas of thinner skin, such as the face. Topical calcineurin inhibitors may be associated with skin cancer. Older Systemic Therapy includes methotrexate, cyclosporine, and acitretin.  Methotrexate is a folic acid inhibitor. It is effective but is associated with hepatotoxicity, requires close, potentially invasive (i.e., liver biopsy) monitoring, cannot be used in patients with liver disease or kidney disease, and is an abortifacient. Drug interactions are common; bone marrow suppression is a possibility. Methotrexate is generally given weekly and many patients describe a post-dose fatigue that can last for several days (“methotrexate fog”). Patients often get stomatitis, nausea, and vomiting and, more rarely, can have lung complications. Methotrexate can be combined with TNF-alpha inhibitors.  Cyclosporine is a T cell inhibitor and works rapidly, but causes hypertension and may be associated with lymphoma and skin cancer (especially when combined with psoralen and ultraviolet A radiation [PUVA]). Cyclosporine is also associated with kidney disease, liver disease, hypertrichosis, gingival changes, GI symptoms, and neurologic symptoms. Drug interactions are common and there are many contraindications. Some European guidelines only recommend use for 2 years. Cyclosporine cannot be combined with other systemic treatments (other than phototherapy).  Acitretin, a retinoid, vitamin A analogue is highly teratogenic, associated with dry eyes and dry mouth, hair loss, as well as elevated triglycerides and musculoskeletal problems. Acitretin can be combined with phototherapy and, unlike many other psoriasis treatments, is not immunosuppressive. ©Institute for Clinical and Economic Review, 2016 Page 7 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Phototherapy includes sun exposure, broadband ultraviolet B (UVB), narrowband UVB, and psoralen with ultraviolet A (PUVA) treatment. Narrowband UVB is more effective than broadband UVB; both can be delivered at home. Psoralen, a photosensitizing drug, can be used orally or topically, as a bath, to the affected areas. Psoralen is associated with nausea, and PUVA is associated with increased squamous cell cancer and possibly melanoma; as such, UVB by far the most common form of phototherapy delivered in current clinical practice. A final form of phototherapy involves the use of excimer lasers for focused UVB light therapy. Targeted immunomodulators that have been approved, or are nearing approval, for the treatment of moderate-to-severe plaque psoriasis in the United States consist of medications with activity against the following targets: Table 1. Targeted immunomodulators for Plaque Psoriasis Brand Generic FDA Approval Date name name for Plaque Psoriasis TNF-α Enbrel® etanercept Apr-04 Remicade® infliximab Sep-06 Humira® adalimumab Jan-08 IL-12/23 Stelara® ustekinumab Sep-09 IL-17A Cosentyx ® secukinumab Jan-15 Taltz® ixekizumab Mar-16 Siliq™ brodalumab* Not yet approved Phosphodiesterase (PDE)-4 Otezla®** apremilast Sep-14 *Investigational **Although not technically a biologic, apremilast is a novel, targeted, oral agent also approved for treatment of patients with moderate-to-severe plaque psoriasis. [Note: Certolizumab pegol (Cimzia®) and golimumab (Simponi®, Simponi ARIA®) are TNF-α agents that have been approved for the treatment of psoriatic arthritis, but not plaque psoriasis. Alefacept (Amevive®) and efalizumab (Raptiva®) were T cell based biologics that were removed from the US market.] ©Institute for Clinical and Economic Review, 2016 Page 8 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Interventions of Interest Dosing information for each intervention of interest is provided in Table 2. As the earliest targeted therapies, TNF-α therapy still holds the majority (~60%) of the market share in plaque psoriasis.34 An exception to this is infliximab, which is rarely used because of its route of administration (infusion) as well as relatively high rates of discontinuation due to certain adverse effects as well as development of neutralizing antibodies (see “Harms” in Section 4.3 for further details). TNF-α share is eroding somewhat, however, based on the introduction of apremilast and the newer classes of biologic immunomodulators. Table 2. Targeted Immunomodulator Dosing for Moderate-to-Severe Plaque Psoriasis Mechanism of Action Name (generic/trade) Dosing TNFα adalimumab/Humira 80mg subcutaneously, then 40mg every other week starting 1 week after initial dose etanercept/Enbrel 50mg subcutaneously 2x/week for 3 months, then 50mg 1x/week infliximab/Remicade 5mg/kg intravenously at weeks 0, 2, and 6, then every 8 weeks IL 12/23 ustekinumab/Stelara Patients ≤100kg/>100kg: 45mg/90mg subcutaneously at week 0 and 4, then every 12 weeks IL 17-A secukinumab/Cosentyx 300mg subcutaneously at weeks 0, 1, 2, 3, 4 then 300mg every 4 weeks ixekizumab/Taltz 160mg subcutaneously at week 0, then 80mg at weeks 2, 4, 6, 8, 10, 12, then 80mg every 4 weeks brodalumab/Siliq* 210mg subcutaneously, every 2 weeks* PDE-4 apremilast/Otezla 5-day titration then 30mg orally 2x/day thereafter *Not yet FDA-approved. Although the original PDUFA date was scheduled for November 16, 2016, the FDA’s review of brodalumab has been postponed to February 16, 2017 due to requirements for additional time to develop a Risk Evaluation and Mitigation Strategy (REMS).14 ©Institute for Clinical and Economic Review, 2016 Page 9 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents For all the biologics, infections may require interruption of treatment, discontinuation, or there may be contraindications to starting these agents. Adverse events and concerns in use of TNF-alpha inhibitors include injection site reactions (for etanercept and adalimumab), infusion reactions (for infliximab), malignancies (especially skin cancer, lymphoma), infection (especially reactivation of tuberculosis and hepatitis B), congestive heart failure, demyelinating disease (e.g., multiple sclerosis), and autoimmune diseases, including a rare, lupus-like syndrome. TNF-alpha inhibitors are associated with an increased rate of severe infections. Because of the impaired immune response, vaccines should be given prior to initiating anti-TNF-alpha therapy. For the anti IL-17A agents, concerns have included infections and reactivation of latent TB, inflammatory bowel disease, and hypersensitivity reactions for secukinumab; infections, reactivation of TB, hypersensitivity reactions, neutropenia, candidal infection, and inflammatory bowel disease for ixekizumab (approved in March 2016); and candidal infections, neutropenia, and an increased risk of suicide for brodalumab (not yet approved although the FDA Dermatologic and Opthalmic Drugs Advisory Committee recommended its approval in July 2016). As noted in Table 2, the FDA delayed the decision date for brodalumab from November 2016 to February 2017 pending finalization of a Risk Evaluation and Mitigation Strategy (REMS).14 Ustekinumab, an IL-12/23 Agent, has been associated with skin cancer, severe infections, and concerns for lymphoma. Although there has also been concern for an increased risk of major cardiovascular events, several observational studies have not confirmed an effect.22,35 Anti- ustekinumab antibodies occur in a few patients and are of unclear clinical significance. Apremilast, an anti-phosphodiesterase-4 agent, is the only available oral targeted immunotherapy. Apremilast is associated with diarrhea, especially at initiation, that is lessened by titrating up the dose gradually. Additional possible adverse effects include depression and weight loss. 2.3. Other Aspects of Treatment Non-Standard Dosing: Many psoriatic drugs appear to have waning effectiveness with continued use. To maintain effectiveness physicians often prescribe increasing doses of psoriatic treatments. Occasionally physicians prescribe lower doses of effective medications to decrease out-of-pocket costs. A US commercial database that evaluated claims from 2007 to 2012 found that in the 12 months after the dose titration period, there were dose escalation rates with etanercept, adalimumab, and ustekinumab of 41%, 37%, and 36%;36 dose reductions of 49%, 54%, and 37%; and discontinuation rates of 15%, 10%, and 5%, respectively. Within the same 12 months, many patients discontinued, restarted, and switched biologic treatments. In an examination of infliximab use, 26% of treatment series involved use of a greater-than-initially-recommended dose.37 ©Institute for Clinical and Economic Review, 2016 Page 10 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents A more recent study also evaluated claims over 12 months for 7,527 patients receiving adalimumab, etanercept, or ustekinumab. The study found rates of dose escalation with adalimumab, etanercept, and ustekinumab of 8%, 31%, and 18%; discontinuations of 53%, 56%, and 39%; restarts of the same medication following discontinuation of 18%, 23%, and 9%; and switching to a different medication of 21%, 22%, and 15%, respectively. Among patients who continued receiving ustekinumab, only 0.5% decreased their dose (from 90 mg to 45 mg) during the study period. 38 Early, Aggressive Treatment: It is uncertain whether early aggressive treatment with anti- inflammatory agents can alter the natural history of psoriasis and/or mitigate the increased cardiovascular risk seen with the disease. Emerging Therapies: Biologic “biosimilar” medications are becoming available, including recently- approved biosimilars like Amjevita® (Amgen), Erelzi® (Sandoz, Inc.), and Inflectra® (Pfizer/Celltrion, Inc.). The equivalence of the etanercept biosimilar for moderate-to-severe plaque psoriasis has been reported in a single conference abstract.15 Briakinumab is an additional anti-IL 12/23 that has been evaluated, but it is unclear if it will come to market. Tofacitinib, a small molecule treatment already approved for the treatment of rheumatoid arthritis, has been shown to be effective for moderate-to-severe plaque psoriasis in randomized controlled trials.16 Baricitinib, a small molecule being investigated for possible use in psoriasis, has been evaluated in a phase IIIb trial but to date has not been submitted to the FDA. Finally, a Biologics License Application (BLA) was submitted to the FDA in November 2016 for guselkumab, an IL-23, and currently has three ongoing Phase III clinical trials.17 Combination Therapy: The role of combination therapy – for example, the use of topical therapies with targeted immunomodulators or use of methotrexate as an adjunctive systemic therapy – has not been rigorously evaluated, but might provide enhanced effectiveness. Combination therapy seems likely to be discussed in a forthcoming guideline from the American Academy of Dermatology and the National Psoriasis Foundation. 2.4 Insights Gained from Discussions with Patients and Patient Groups ICER had conversations with and received input from patient advocacy groups, including the National Psoriasis Foundation, and with individual patients (please see online Stakeholder document). These conversations highlighted the shortcomings associated with clinical trial outcomes in many studies of psoriasis therapies (as previously noted), frustrations with the healthcare system, as well as the social, emotional, and financial impact of psoriasis. Certain aspects of research into psoriasis are not patient-centered. Many of the tools developed to measure outcomes were not developed with patients in mind, and psoriasis-specific patient- centered outcome measures are limited (although the Psoriasis Symptom Inventory (PSI) and the ©Institute for Clinical and Economic Review, 2016 Page 11 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Psoriasis Disability Index (PDI) are being used; see below). For example, PASI is cumbersome and is not generally used in clinical practice and the DLQI is not psoriasis-specific. Patients at a recent FDA meeting rated flaking/scaling and itching as a having a more significant impact on their quality of life than the rash itself. Simple body surface area (BSA) measurements of psoriasis involvement do not consider the greater effect that lesions in particular areas, such as the nails, genitals, scalp, face, flexural areas, palms, and soles of the feet, may have on an individual’s quality of life. Patients also pointed out that average treatment responses described in clinical trials may not capture individual patient variability. Up to half of patients are dissatisfied with their psoriasis treatment.8,18 Dissatisfaction may be due to the unpredictable effectiveness of many agents to treat psoriasis, poor tolerability, lack of durable response, and lack of access to medications because of coverage restrictions or costs.8 Patients also expressed frustration with misdiagnoses and delayed diagnoses. The time from onset to diagnosis for plaque psoriasis averages two years. A psoriasis diagnosis may be delayed even further in those with darker skin tones. In addition to delayed diagnosis, racial and ethnic minorities appear to have a higher prevalence of psoriasis, more severe disease, more common misdiagnosis, more frequent non-treatment, and are less likely to be included in clinical trials. For all patients, treatments for plaque psoriasis may be challenging. It can be difficult to apply topical therapies, especially when the affected area involves the scalp or covers a large part of the body. Therapies can also be inconvenient to use; some require multiple injections on a daily or weekly basis, especially initially, during induction. Patients need to consider time and travel for administration of infused therapy. Psoriasis is a chronic disease that requires management over a lifetime, potentially during the treatment of other chronic conditions, including cancer. Psoriasis affects social functioning. Patients with psoriasis often feel the need to make different clothing choices to hide psoriatic skin; we heard that this can be particularly challenging for women. Patients with psoriasis may moderate choices of activities, such as swimming. Because of different clothing choices, the manifestations and difficulties faced by people with psoriasis may not be visible to others. Children with psoriasis, especially teens, face teasing, bullying, and shunning because of the visible effect of the disease. Many find that some people seeing the lesions conclude the patient has a communicable disease. Plaque psoriasis has both psychological and emotional effects. The psychological impact of severe psoriasis is comparable to that of diabetes or depression.39 Psoriasis is associated with a higher likelihood of having depression, anxiety, and suicidal ideation.10,11 Some patients reported somatic manifestations of psychiatric disease or emotional difficulties, including GI symptoms and hypertension. ©Institute for Clinical and Economic Review, 2016 Page 12 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Patients are concerned about lack of access to treatment because of inadequate insurance coverage, out of pocket costs, and future availability of drugs to treat their disease. About half of patients with psoriasis are either undertreated or not treated,18 and one of the main reasons is the cost of therapy. Patients are frustrated that they are being forced to start treatment with less efficacious medications due to insurance requirements for “step therapy” that mandates use of “preferred medications” first. In addition, switching insurance or within-plan coverage changes might require movement to another step therapy approach, which often requires patients to “start over” with previously-tried medications. Patients are anxious that individual drugs will stop working for them and want access to alternatives. Another source of frustration is that coverage decisions for biologics often seem to be dictated by other, non-psoriasis conditions, like rheumatoid arthritis, which is a listed indication for many of the drugs of interest for this review. 2.5 Definitions Psoriasis Area and Severity Index (PASI) The PASI is a measure of the percent body surface area with psoriatic lesions in each of 4 regions (head, trunk, arms, and legs) as well as the degree of erythema, induration, and scale of the lesions in each area. PASI scores range from 0 to 72. Higher numbers indicate more surface involvement and severity of lesions. The PASI is generally reported as the percentage reduction in the PASI score from baseline to follow-up. The most consistently reported result in clinical trials is PASI 75, i.e., a 75% reduction in the PASI score. For these outcomes, higher numbers indicate a greater percentage improvement: PASI 90 is a 90% improvement in the PASI score; PASI 100 indicates full disease clearance, or a follow-up PASI score of zero. Physician Global Assessment (PGA) The Static Physician Global Assessment (sPGA) is scored by the treating or evaluating physician and only considers the time of evaluation. Scores range from 0 to 7 with higher scores indicating worse severity. A good response in clinical trials in treatment generally requires sPGA scores of 0 (“clear”) or 1 (“almost clear”). The Dynamic Physician Global Assessment (dPGA), also scored from 0 to 7, considers a patient’s change from their baseline status, and is used less frequently. Unless otherwise noted, “PGA” in this report refers to the Static Physician Global Assessment. Investigator’s Global Assessment (IGA) The IGA is a modified version of the PGA, and has recently being touted as more valid measure of disease severity in psoriasis. It is based on a 5-point rather than a 6- or 7-point scale; the proportion of patients achieving a score of 0 or 1 (“clear/almost clear”) are often considered “responders” in clinical trials. ©Institute for Clinical and Economic Review, 2016 Page 13 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Dermatology Life Quality Index (DLQI) The DLQI is ten questions relating to symptoms, feelings, daily activities, leisure, work, school, social interactions, clothing choice, sexual difficulties, and treatment problems. DLQI scores range from 0 to 30 with lower scores representing better quality of life. A DLQI change of 5-points is the minimal amount of change needed to establish meaningful clinical significance in health-related quality of life (HRQL). The NICE Guideline defines mild disease as a PASI, BSA, and DLQI all ≤ 10 and moderate-to-severe disease as (PASI > 10 or BSA > 10) and DLQI > 10. EuroQol Five Dimensions (EQ-5D) The EQ-5D is a standardized, self-reported questionnaire for evaluating a patient’s health status across disease states, and is based on five dimensions: self-care, pain/discomfort, anxiety/depression, mobility, and usual care activities. It is often used to compute a quality- adjusted life year. Short Form-36 (SF-36) The SF-36 is a 36 item, quality of life instrument that captures eight domains and is reported as a score from 0 to 100 with higher scores indicating better functioning. The SF-36 also has summary component scores for physical functioning (physical component score, or PCS) and mental functioning (mental component score or MCS). Scores can be standardized to a population reference, such that the population mean score is 50 with a standard deviation of 10. Psoriasis Disability Index (PDI) The Psoriasis Disability Index assesses is a 15-question instrument that assesses five domains of health-related quality of life: daily activities; work or school performance; personal relationships; leisure; and treatment.40 Each question is scored from 0 to 3 and the individual items are summed to a total score of 0 to 45 with higher scores indicating greater impairment. The PDI can also be expressed as a proportion of total possible score. Visual Analog Scale (VAS)-skin pain VAS is a commonly used measure of pain, and can also be used to assess the skin pain associated with scaly plaques in psoriatic patients, which can have a serious impact on quality of life. This modified version of the VAS is based on a score of 0 (no skin pain) to 100 (severe skin pain). ©Institute for Clinical and Economic Review, 2016 Page 14 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Visual Analog Scale (VAS)-itch The VAS is also used to as a measure of pruritus assessment. Patients are asked to rate the severity of their itching on a five-point scale, from no pruritus (0 points) to severe pruritus (5 points). Psoriasis Symptom Inventory (PSI) The PSI is an 8-item in which patients rate the severity of signs and symptoms of psoriasis from the past 24 hours. Each item is scored 0 to 4. Individual scores are summed and a total score can range from 0 to 32 with higher scores indicating worse symptoms. Psoriasis Symptom Diary (PSD) The PSD measures the impact of psoriasis treatments on daily activities. Patients report disease severity on a scale of 0 to 10 on 20 psoriasis-specific signs and symptoms, including itching, pain, scaling, flaking, and changes in skin appearance. Hospital Anxiety and Depression Scale (HADS) The HADS is a 14-item scale that scores anxiety and depression. Seven items are related to anxiety and seven are related to depression. Each item is scored 0 to three to generate anxiety or depression scores of 0 to 21, with higher scores indicting more anxiety or depression. A score above eight is a generally-used cutoff indicating a possible diagnosis of anxiety or depression. The HADS is used for screening only, and does not represent a clinical diagnosis. Work Productivity and Activity Impairment (WPAI) The WPAI consists of 6 questions about current employment and, in the past 7 days, hours missed due to health problems, hours missed for other reasons, hours worked, productivity impairment at work (“presenteeism”), and productivity impairment in unpaid activities. Results are reported on a percentage scale from 0 to 100 in four domains: percent work time missed due to health; percent impairment while working; percent overall work impairment; and percent impairment due to health. Worker Productivity Index (WPI) The WPI combines an objective absenteeism measure and a subjective presenteeism (i.e., attending work while ill) measure into a measure of “total lost hours per week.” Work Limitations Questionnaire (WLQ) The WLQ is a self-administered instrument of 25 items, which measures four domains of work limitations, including physical, time management, mental-interpersonal, and output demands.41 ©Institute for Clinical and Economic Review, 2016 Page 15 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Visual Analog Scale-productivity Although more frequently used in arthritis patients, the VAS-productivity scale can also be used to measure work productivity in psoriasis. VAS-productivity is measured on a 0-10 scale, indicating no impact to severe impact on productivity at school, home, or work. ©Institute for Clinical and Economic Review, 2016 Page 16 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3. Summary of Coverage Policies and Clinical Guidelines To understand the insurance landscape for therapies for moderate to severe plaque psoriasis, we reviewed publicly available coverage policies and formularies at the six New England state Medicaid programs, Centers for Medicare and Medicaid Services (CMS) and all major insurance carriers available in New England. All public and private carriers in New England manage utilization of the seven approved medications under review through tiering, step therapy and excluding drugs from coverage (see Table 3). In nearly every plan, systemic therapies (such as phototherapy or methotrexate) are on the lowest tier or are considered the first-line of therapy before treatment with biologics or apremilast. Etanercept and adalimumab are most often the preferred second-line treatment and are commonly placed on lower tiers than other therapies in this review. Carriers often have discounting arrangements for etanercept and adalimumab that are driven by other conditions, most commonly rheumatoid arthritis. Nearly all private carriers in New England require prior authorization for all drugs under review, and require step therapy. Of the 19 plans reviewed, etanercept and adalimumab were listed as preferred agents in roughly two-thirds of the plans. Ixekizumab was excluded from roughly a quarter of the plans. Infliximab is commonly covered as a medical benefit because of its administration as an infused agent. As a medical benefit, patients may experience out of pocket costs related to their deductible or co-insurance. Ustekinumab, secukinumab and ixekizumab, and apremilast are more likely to be excluded from formularies. There are no national or local requirements for Medicare coverage of the products under review. Nationally, Medicare providers are required to cover topical therapy, ultraviolet light therapy, and coal tar in advance of PUVA therapy, which the Medicare provider must document. Aside from systemic therapies (such as methotrexate), all but one of the New England state Medicaid programs list adalimumab and etanercept as the preferred therapies. All other therapies under review require prior authorization. Massachusetts is the exception—there are no preferred agents and all therapies under review require prior authorization. ©Institute for Clinical and Economic Review, 2016 Page 17 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Clinical Guidelines American Academy of Dermatology https://www.aad.org/practice-tools/quality-care/clinical-guidelines/psoriasis The most recent clinical guidelines from the American Academy of Dermatology (AAD) were published in 2011 and precede FDA approval of ustekinumab, secukinumab, ixekizumab, and apremilast. The AAD guidelines recommend that patients with limited disease be treated with topicals and/or targeted phototherapy. They do not recommend treating patients with limited disease with systemic therapies that have higher levels of risk. Methotrexate, for instance, carries the risk of hepatotoxicity, is contraindicated for several conditions, and can have drug interactions. For extensive disease, the guidelines recommend treatment with topical treatments, phototherapy, systemic therapies, and biologics, but do not prioritize among the targeted immunomodulators (biologics) available at the time they were written. National Psoriasis Foundation/Canadian Guidelines https://www.ncbi.nlm.nih.gov/pubmed/22250239 In 2012, the National Psoriasis Foundation reviewed the Canadian Guidelines for the Management of Plaque Psoriasis.42 In their review, they recognized adalimumab, etanercept and ustekinumab as first-line systemic treatments for plaque psoriasis. They recognize infliximab as a second or third line treatment for plaque psoriasis. They did not prioritize among the then available targeted immunomodulators. No other drugs were reviewed at the time of the report. NICE Guidelines https://www.nice.org.uk/guidance/cg153?unlid=389990376201651723735 The UK National Institute for Health and Care Excellence (NICE) reviewed therapies and offered guidance for treatment. The most recent review was in 2014. NICE recommends progression from topical (mostly steroid) to systemic non-biologic therapy such as phototherapy, methotrexate or cyclosporine before moving on to treatment with a targeted immunomodulator. After failure of non-biological treatment, they recommend etanercept or adalimumab for patients with a PASI >10. NICE also recommends secukinumab if a discount is available and ustekinumab at the higher dose only if provided at the same cost as for the lower dose. Infliximab is recommended after failure of first-line treatment for those patients with a PASI >20 (“very severe psoriasis”). In October 2016, NICE released a new determination recommending apremilast for severe disease if apremilast is provided at a discount. NICE recommends switching therapies after treatment failure of infliximab after 10 weeks; etanercept and secukinumab after 12 weeks; and adalimumab, ustekinumab, and apremilast after 16 weeks. ©Institute for Clinical and Economic Review, 2016 Page 18 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents NICE is expected to release recommendations for ixekizumab in April 2017. European Guideline on Systemic Treatment of Psoriasis Vulgaris, 2015 Update https://www.ncbi.nlm.nih.gov/pubmed/26481193 An expert panel nominated by the European Dermatology Forum, the European Association for Dermatology and Venereology (EADV) and the International Psoriasis Council (IPC) stated that all treatments should be preceded by objective assessment of disease and health-related quality of life (HRQL). They stated that older treatments have many unwanted side effects and toxicity, but should be first-line systemic therapy. If phototherapy and older systemic agents are ineffective, contraindicated, or not tolerated, they recommended treatment with TNF-α inhibitors. Ustekinumab was recommended as “second-line therapy,” but there was “no strong consensus” as to where in the ordering of therapy, relative to TNF-α inhibitors, ustekinumab should fall. Secukinumab, apremilast, and brodalumab were not included in the review. Canadian Guidelines for the Management of Plaque Psoriasis http://www.dermatology.ca/media/guidelines/ The Canadian Guidelines were supported by Abbott Laboratories, Amgen Canada Inc., Astellas Pharma Canada Inc., Isotechnika Inc., Janssen-Ortho Inc., Leo Pharma, Schering-Plough Canada Inc., and Wyeth. This guideline did not prioritize among the then available biologic therapies, but stated that there was no reason to reserve biologic agents for second-line use. ©Institute for Clinical and Economic Review, 2016 Page 19 Final Evidence Report -Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 3. Representative Private Payer Policies for Plaque Psoriasis in New England Connecticut Massachusetts Maine New Hampshire Rhode Island Vermont Anthem United BCBS Harvard Tufts Anthem Aetna Anthem MVP BCBS Cigna BCBS Cigna Pilgrim Health Health Plan Methotrexate Tier 1 1 1 1 1 1 1 1 1 1 1 1 1 Step Therapy No No No No No No No No No No No No No PA No No No No No No No No No No No No No Preferred Agent Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Etanercept Tier 3 3 2 2 2 3 2 3 2 4 2 2 2 Step Therapy Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes PA Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Preferred Agent No No Yes Yes Yes No Yes No Yes No Yes Yes Yes Adalimumab Tier 3 2 2 2 2 3 4 3 2 5 2 2 2 Step Therapy Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes PA Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Preferred Agent No Yes Yes Yes Yes No No No Yes No Yes Yes Yes Infliximab Tier 3 3 2 Med Med 3 4 3 Med 5 3 3 3 Step Therapy Yes Med Yes Med Med Yes Yes Yes Med Yes Yes Yes Yes PA Yes Med Yes Med Med Yes Yes Yes Med Yes Yes Yes Yes Preferred Agent No No Yes Med Med No No No Med No No No No ©Institute for Clinical and Economic Review, 2016 Page 20 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Ustekinumab Tier 3 3 3 3 2 3 4 3 Med 5 4 3 3 Step Therapy Yes Yes Yes Yes Yes Yes Yes Yes Med Yes Yes Yes Yes PA Yes Yes Yes Yes Yes Yes Yes Yes Med Yes Yes Yes Yes Preferred Agent No No No No Yes No No No Med No No No No Secukinumab Tier NF 3 3 3 2 3 4 3 3 5 4 3 3 Step Therapy NF Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes PA NF Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Preferred Agent NF No No No Yes No No No No No No No No Ixekizumab Tier 3 3 NF 3 3 3 4 3 3 4 NF 3 NF Step Therapy Yes Yes NF Yes No Yes Yes Yes No No NF Yes NF PA Yes Yes NF Yes Yes Yes Yes Yes Yes No NF Yes NF Preferred Agent No No NF No No No No No No No NF No NF Apremilast Tier 3 3 3 3 2 3 4 3 3 4 4 3 3 Step Therapy Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes PA Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Preferred Agent No No No No Yes No No No No No No No No ©Institute for Clinical and Economic Review, 2016 Page 21 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 4. Comparative Clinical Effectiveness 4.1 Overview To inform our analysis of the comparative clinical effectiveness of targeted immunomodulators for moderate-to-severe chronic plaque psoriasis, we abstracted evidence from available clinical studies, whether in published, unpublished, or abstract form. The drugs and regimens of interest are included in Table 2. As described in the Background section, we included evidence from placebo-controlled trials, but focused on evidence about the comparative clinical effectiveness of these treatments compared to each other. Our review focused on key clinical outcomes common to plaque psoriasis trials, as well as symptoms and burdens of psoriasis that are not well-captured by standard trial outcomes. o Clinical Benefits o Trial Outcomes  Psoriasis Area and Severity Index (PASI): 50, 75, 90, 100  Physician Global Assessment (PGA) or Investigator’s Global Assessment (IGA) o Patient-Reported Outcomes  Dermatology Life Quality Index (DLQI)  Other measures of health-related quality of life (e.g., Short Form [SF]-36)  Symptom control (e.g., Visual Analog Scale [VAS], Psoriasis Symptom Inventory [PSI]) o Harms  Treatment-related adverse events (e.g., rate of infections)  Treatment tolerability (i.e., discontinuation due to adverse events) 4.2 Methods We included evidence from randomized controlled trials (RCTs), comparative observational studies, and high-quality systematic reviews where available. We excluded single-arm studies and studies from an early clinical development phase (i.e., Phase I). We included phase II studies only if they evaluated unique subpopulations or outcomes not otherwise available in Phase III data. We also excluded studies that only examined regimens not approved by the FDA. Data from studies which included other active treatments (e.g., tofacitinib) were included in the NMA to extend indirect ©Institute for Clinical and Economic Review, 2016 Page 22 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents comparisons, but these comparisons are not discussed in detail. Finally, we did not include studies that evaluated targeted immunomodulators as part of combination treatment. In recognition of the evolving evidence base for psoriasis, we supplemented our review of published studies with data from conference proceedings, regulatory documents, information submitted by manufacturers, and other grey literature that met ICER standards for review (for more information, see http://icer-review.org/methodology/icers-methods/icer-value-assessment-framework/grey- literature-policy/). We excluded abstracts which reported duplicative data available in published articles, or reported results from observational studies since it would be difficult, if not impossible, to evaluate the methodological quality of these studies. We also did not include any outcomes from conference proceedings or regulatory documents on the TNF-α therapies given that these treatments have been available for at least a decade and primarily have peer-reviewed data available. We also looked for studies evaluating biosimilar forms of the TNF-α agents. No peer-reviewed data were available, but a brief description of etanercept, infliximab, and adalimumab biosimilars is included in the Emerging Therapies section of this report. Data were abstracted and summarized into evidence tables for all outcomes. For most outcomes, we summarized comparative findings qualitatively. However, we quantitatively synthesized evidence for PASI 50, 75, and 90 measures through the conduct of a Bayesian network meta- analysis (see Appendix F). Data Sources and Searches Procedures for the systematic literature review assessing the evidence on targeted immunomodulators for moderate-to-severe plaque psoriasis followed established best methods used in systematic review research.43 We conducted the review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.44 The PRISMA guidelines include a checklist of 27 items, further details of which is available in Appendix Table A1. The timeframe for our search spanned the period from January 1996 to June 28, 2016 and focused on MEDLINE, EMBASE, and Cochrane-indexed articles. We limited each search to studies of human subjects and excluded articles indexed as guidelines, letters, editorials, narrative reviews, case reports, or news items. We did not conduct a de novo search for the TNF-α agents. Rather, data from the key comparative studies not captured in the initial survey of the literature were abstracted from recently published high-quality systematic reviews. To supplement the above searches and ensure optimal and complete literature retrieval, we performed a manual check of the references of recent relevant reviews and meta-analyses. Other grey literature sources included submissions from manufacturers of psoriasis therapies that were not otherwise publicly available, as well as ©Institute for Clinical and Economic Review, 2016 Page 23 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents data very recently presented during the European Academy of Dermatology and Venereology (EADV) conference in Vienna, Austria from September 28-October 2, 2016. Further details on the search algorithms, methods for study selection, data extraction, quality assessment, assessment for publication bias, and our approach to meta-analyses of the data are available in Appendix A. We included several articles published after our initial search date if the data appeared to inform this report. Assessment of Level of Certainty in Evidence We used the ICER Evidence Rating Matrix (see Figure 4) to evaluate the evidence for a variety of outcomes. The evidence rating reflects a joint judgment of two critical components: The magnitude of the difference between a therapeutic agent and its comparator in “net health benefit” – the balance between clinical benefits and risks and/or adverse effects AND The level of certainty in the best point estimate of net health benefit.45 ©Institute for Clinical and Economic Review, 2016 Page 24 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 4. ICER Evidence Rating Matrix Comparative Clinical Effectiveness High D C B A Level of Certainty in the Evidence Certainty B+ Moderate C+ Certainty P/I C- Low Low Certainty Certainty I I Negative Comparable Small Substantial Net Benefit Net Benefit Net Benefit Net Benefit Comparative Net Health Benefit A = “Superior” - High certainty of a substantial (moderate-large) net health benefit B = “Incremental” - High certainty of a small net health benefit C = “Comparable”- High certainty of a comparable net health benefit D = “Negative”- High certainty of an inferior net health benefit B+ = “Incremental or Better” - Moderate certainty of a small or substantial net health benefit, with high certainty of at least a small net health benefit C+ = “Comparable or Better” - Moderate certainty of a comparable, small, or substantial net health benefit, with high certainty of at least a comparable net health benefit P/I = “Promising but Inconclusive” - Moderate certainty of a comparable, small, or substantial net health benefit, and a small (but nonzero) likelihood of a negative net health benefit C- = “Comparable or Inferior” - Moderate certainty that the point estimate for comparative net health benefit is either comparable or inferior I = “Insufficient” - Any situation in which the level of certainty in the evidence is low ©Institute for Clinical and Economic Review, 2016 Page 25 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 4.3 Results Study Selection Our literature search identified 1,392 potentially relevant references. Key comparative studies of the TNF-α agents were gathered and cross-checked from six recent high-quality systematic reviews.27,46-50 A total of 80 references met our inclusion criteria; these citations related to 42 publications and 27 abstracts/conference presentations relating to 36 individual RCTs, as well as 11 observational studies. Primary reasons for study exclusion included use of regimens not approved by the FDA, study population or outcomes related specifically to patients with psoriatic arthritis or other types of psoriasis (e.g., erythrodermic), and non-comparative study design. Ustekinumab and the TNF-α therapies were the only treatments for which we found comparative observational data that met our inclusion criteria. Additional details of the included references are described in Appendix B, and the key studies are summarized in Table 4. Quality of Individual Studies We rated all 36 trials, of which 34 were Phase III, to be of good or fair quality using criteria from U.S. Preventive Services Task Force (USPSTF).51 Trials of good quality had study arms that were comparable at baseline, the authors used valid instruments to evaluate outcomes, and no differential attrition was observed. Fair quality studies typically used modified intention-to-treat (mITT) as the primary method of analysis. Of the 11 observational studies, five were judged to be good, three fair, and three poor quality. We did not assign a quality rating to references that were obtained from the grey literature. Key Studies Of the 36 individual RCTs, we identified 29 key clinical studies evaluating at least one of the eight therapies of interest for this review. Two of the remaining studies were Phase II, and five were conducted exclusively in Asia which are discussed separately in the subgroups section of this report. Eight studies included head-to-head trials of the drugs of interest for this review (etanercept vs. ustekinumab [ACCEPT], secukinumab [FIXTURE], and ixekizumab [UNCOVER 2 and 3]; and ustekinumab vs. brodalumab [AMAGINE 2 and 3], secukinumab [CLEAR], and ixekizumab [IXORA-S]). Three of these studies (ACCEPT, CLEAR, and IXORA-S) did not include a placebo arm. We also included a Phase IIIb trial, LIBERATE, which compared apremilast to placebo and a maintenance dose of etanercept to placebo that has not yet been published but was available in the grey literature (results from this trial are presented for the apremilast and placebo comparisons only). We also included five studies which evaluated one of the drugs of interest to another active comparator (1 of methotrexate vs. adalimumab, 2 of briakinumab vs. etanercept, and 1 of ©Institute for Clinical and Economic Review, 2016 Page 26 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents tofacitinib vs. etanercept); for purposes of this review, we only considered the comparisons to placebo in these trials. All the key studies were multicenter, double-blind, Phase III RCTs, though some removed blinding following the induction period for each drug. Many trials also re-randomized patients to different treatment groups and measured outcomes at various timepoints, making it difficult to evaluate the comparative durability of effect and harms across therapies. Most studies required washout of prior therapies, and prohibited concurrent use of these treatments throughout the trials. Study populations had similar inclusion criteria (≥18 years old, BSA ≥10%, PASI score ≥12, ≥6 months of plaque psoriasis diagnosis, and candidates for phototherapy or systemic therapy despite prior treatment with topicals, older systemic treatments, phototherapy, or other targeted immunomodulators) and were comparable with respect to age (range of means: 41-46 years, median: 45) and duration of psoriasis (range of means: 14-21 years, median: 19). Baseline PASI scores varied substantially across trials (range of means: 16-33, median: 23). Given potential other between-trial heterogeneity, we conducted a sensitivity analysis in our network meta-analysis adjusting for baseline variations; the details and results of this analysis are discussed in Appendix F. Subgroups Several populations were identified as being of special interest to stakeholders, and are described in the subgroups section of this report. The characteristics of these subgroups are as follows: Asian Studies: As previously mentioned, we separately considered five trials that were conducted exclusively in Asia (i.e., Japan, Korea, China, and Taiwan), plus a subgroup analysis of the ERASURE study. These trials were generally smaller (with the exception of LOTUS, n=322)52 with patients who were slightly younger (range of means: 40-50 years) had a briefer duration of psoriasis (range of means: 13-16 years), and lower BMI than the other trials. We considered the Asian trials as a subgroup because of the generally smaller study size and differences in patient characteristics from the worldwide studies. Patients with Previous Biologic Therapy Exposure: We also examined subgroups of patients who had and had not been previously treated with a targeted immunomodulator. Fewer patients were biologic-experienced in the studies of the older TNF-α drugs relative to the newer therapies. Across all studies, an average of 20% (range of means: 0% to 51%) of patients received prior biologic therapy. Patients who previously used biologic therapy might be less likely to respond to a subsequent targeted immunomodulator. Patients with Psoriatic Arthritis: Because up to a third of patients with psoriasis develop psoriatic arthritis, we evaluated subgroups of psoriasis patients with and without psoriatic arthritis. Among those studies that reported the number of patients with arthritis at baseline, 25% (range of means: ©Institute for Clinical and Economic Review, 2016 Page 27 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 15% to 34%) had psoriatic arthritis. Patients with concomitant psoriatic arthritis might have more severe skin disease and might respond better or worse to targeted immunomodulators than patients without psoriatic arthritis. Table 4. Key Studies Drug Trials Total # Induction PASI, Age Psoriasis Previous PsA of period (mean) (years) duration biologics (%) patients (weeks) (years) (%) Adalimumab REVEAL 1,483 16 22 43 19 6 24 CHAMPION Etanercept Papp, 2005 3,775 12 20 44 17 6 25 Leonardi, 2003 Tyring, 2006 Strober, 2011 Gottlieb, 2011 Bagel, 2012 Bachelez, 2015 Infliximab EXPRESS I 1,213 10 21 44 19 10 30 EXPRESS II Ustekinumab ACCEPT 2,899 12 20 45 20 33 29 PHOENIX 1 PHOENIX 2 Secukinumab FEATURE 3,079 12 28 45 18 25 20 CLEAR† JUNCTURE ERASURE FIXTURE Ixekizumab UNCOVER 1 3,866 12 24 46 19 27 NR UNCOVER 2 UNCOVER 3 IXORA-S* Brodalumab AMAGINE 1 4,373 12 23 45 19 33 22 AMAGINE 2 AMAGINE 3 Apremilast ESTEEM 1 1,505 16 19 46 19 31 NR ESTEEM 2 LIBERATE* *Only available in the grey literature. †The primary outcome for the CLEAR study was week 16, but to be consistent with the other secukinumab trials we considered the primary outcome to be 12 weeks. ©Institute for Clinical and Economic Review, 2016 Page 28 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Clinical Benefits The primary outcome of all trials was the proportion of patients achieving PASI 75 at the end of the induction period. The duration of the induction period varied by agent: week 10 for infliximab; week 12 for ixekizumab, secukinumab, ustekinumab, and etanercept; and week 16 for adalimumab and apremilast. Other clinical outcomes included the proportion of patients meeting additional PASI thresholds (e.g., 50, 90, 100), or achieving a score of 0 or 1 (“cleared or minimal”) on the Physician Global Assessment (PGA) or Investigator’s Global Assessment (IGA), although these were less consistently reported. Patient-reported outcomes, including quality of life, were primarily based on mean change or proportion of patients achieving a score of 0 or 1 on the DLQI (indicating very little to no disease effect on quality of life); other quality of life instruments, such as the SF-36, were less commonly used. Measures of symptom control, such as VAS scales for itch or skin pain, as well as a recently validated tool for assessing symptom control in psoriasis patients (Psoriasis Symptom Inventory [PSI]), were infrequently employed. All data are reported based on the FDA-approved or proposed dosing at the end of the induction period for each drug with the two exceptions. First, for secukinumab, while the drug label indicates that 150mg may be appropriate for some patients, we only describe outcomes for the 300mg dose. Second, although FDA-approved dosing for ustekinumab is weight-based, neither the placebo- controlled trials nor the ACCEPT study randomized participants based on weight; other direct comparison trials (i.e., IXORA-S, AMAGINE 2 and 3, and CLEAR) assigned patients their appropriate weight-based dose. The labeling was instead based on a pooled analysis of PHOENIX 1 and 2 which found that patients weighing more than 100kg achieved a better response with the 90mg, while those weighing less than 100kg had similar efficacy with either the 45mg and 90mg doses.53 In addition, although the LIBERATE trial included the approved dose of apremilast, patients in the etanercept arm received a maintenance dose (i.e., 50 mg once weekly); the study was also not statistically powered to detect differences between the agents. As such, the PASI outcomes from the etanercept arm were not included in the NMA, and only comparison of apremilast to placebo are described in the sections that follow. Psoriasis Area Severity Index (PASI) PASI 75 All targeted immunomodulators showed statistically-significantly higher PASI 75 response rates in comparison to placebo at the end of induction (10 to 16 weeks, depending on agent). In direct comparative trials, ustekinumab, secukinumab, and ixekizumab were superior to etanercept; secukinumab, ixekizumab, and brodalumab were superior to ustekinumab. ©Institute for Clinical and Economic Review, 2016 Page 29 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents All immunomodulators showed a statistically significantly higher absolute percentage of PASI 75 responders compared to placebo. The range of PASI 75 responses in the intervention and placebo groups across trials is shown in Table 5. In individual placebo-controlled RCTs, the incremental proportion of patients achieving PASI 75 above placebo within trials was 62% to 64% for adalimumab (2 trials);54,55 33% to 54% for etanercept (7 trials);56-62 74% to 77% for infliximab (2 trials);63,64 80-88% for ixekizumab (3 trials);65-67 63%-64% for ustekinumab 45 mg (2 trials);68,69 63% to 72% for ustekinumab 90 mg (2 trials);68,69 72% to 84% for secukinumab at 12 weeks (4 trials);21,70,71 78% to 80% for brodalumab (3 trials);19,72 and 13% to 18% for apremilast (2 trials).73,74) Additionally, a newly approved biosimilar to etanercept, Erelzi, had a PASI 75 response very similar to etanercept (73.4% with Erelzi vs. 75% with etanercept).15 Because this study is currently only available in the grey literature, it is unclear why response rates were higher than in other clinical trials of etanercept. Table 5. Placebo-Controlled Trials: Ranges of PASI 50/75/90/100 Response Rates across Trials Treatment PASI 75 PASI 50 PASI 90 PASI 100 Tx Placebo Tx Placebo Tx Placebo Tx Placebo Adalimumab 71-80 7-19 88 30 45-52 2-11 17-20 1-2 Etanercept 40-59 3-7 71-85 7-21 19-32 1-2 6-7 0 Infliximab 76-80 2-3 91 8 45-57 1 NR NR Ustekinumab 67 3-4 84 10 16-37 1-2 11-18 0 45 mg Ustekinumab 66-76 3-4 86-89 10 42 1-2 13-18 0 90 mg Secukinumab 76-87 0-5 88-94 5-15 54-60 0-2 24-43 0-1 Ixekizumab 87-90 2-7 NR NR 68-71 1-3 35-41 0-1 Brodalumab 83-86 3-8 NR NR 69-70 1-3 37-44 0-2 Apremilast 29-33 5-6 56-59 17-20 9-94 0-2 NR NR We identified nine head-to-head RCTs, all, but one of which showed statistically-significant differences between treatments in PASI 75 response (Table 6). In four trials, three agents were superior to etanercept: ustekinumab (57% vs. 68% and 74% for ustekinumab 45 mg and 90 mg, respectively);75 secukinumab 300 mg (44% vs. 77%);21 and ixekizumab (42% vs. 90% in UNCOVER 276 and 53% vs. 87% in UNCOVER 3).67 In four trials, two agents were superior to ustekinumab: ©Institute for Clinical and Economic Review, 2016 Page 30 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents secukinumab (79% vs. 91% for secukinumab 300 mg at 12 weeks; 83% vs. 93% at 16 weeks),77 ixekizumab (69% vs. 91% in IXORA-S),78 and brodalumab (70% vs. 86% in AMAGINE 2 and 69% vs. 85% in AMAGINE 3).19 Note that the IXORA-S study is currently only available in abstract form, and so was not included in our network meta-analysis or economic model (see below). In a recently published report of 52-week data from the CLEAR study the rate of achieving PASI 75 for secukinumab and ustekinumab was 93% vs. 80%, respectively.20,79 Table 6. Comparative Trials: PASI Responses Trial Treatment PASI 75 PASI 90 PASI 100 ACCEPT Etanercept 57 23 NR Ustekinumab 45 mg 68 36 NR Ustekinumab 90 mg 74 45 NR FIXTURE Etanercept 44 21 4 Secukinumab 300 77 54 24 mg UNCOVER 2&3 Etanercept 42-53 19-26 5-7 Ixekizumab 87-90 68-70 38-41 CLEAR Ustekinumab WBD 79 53 26 Secukinumab 300 91 73 39 mg AMAGINE 2&3 Ustekinumab WBD 69-70 47-48 19-22 Brodalumab 210 mg 85-86 69-70 37-44 IXORA-S* Ixekizumab 91 75 37 Ustekinumab 69 42 15 *Only available in the grey literature as of October 10, 2016. Not included in the NMA or economic model (see evidence summary). WBD = weight-based dosing ©Institute for Clinical and Economic Review, 2016 Page 31 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents An additional three observational studies directly comparing TNFα agents either reported non- significant findings 80 or did not conduct statistical tests on PASI 75 between groups.81,82 Network Meta-Analysis of PASI 75 Results Given the paucity of head-to-head data comparing treatments, we performed indirect comparisons of PASI response using Bayesian network meta-analyses (NMAs). NMA was felt to be appropriate, as the populations of the individual trials were sufficiently similar. Detailed descriptions of methods and results can be found in Appendix F. Briefly, we used a random-effects approach. For the primary analysis, we also adjusted for the placebo response rate in each study which, to some degree, accounts for baseline patient differences between studies (for example, given the baseline severity and the proportion of study subjects who previously used a biologic treatment) as well as possible unknown confounders. Our network meta-analysis showed that all immunomodulators had a statistically significantly higher efficacy on PASI 75 than placebo. In head-to-head comparisons, ixekizumab had the highest relative effectiveness [measured as relative risk (RR)] of achieving initial PASI 75 response during induction, followed by brodalumab, infliximab, secukinumab 300 mg, and ustekinumab 45/90 mg, and other TNFα agents (in the order of adalimumab, etanercept, and Erelzi). Apremilast had the lowest RR. (see Table 7 and Appendix F5) ©Institute for Clinical and Economic Review, 2016 Page 32 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 7. Base case NMA: league table of PASI 75 response ixekizumab 1.03 brodalumab (0.91-1.25) 210 mg 1.07 1.04 infliximab (0.95-1.24) (0.85-1.23) 1.16 1.13 1.09 secukinumab (1.04-1.33) (0.92-1.32) (0.93-1.26) 300 mg 1.28 1.24 1.20 1.1 ustekinumab (1.14-1.45) (1.01-1.45) (1.02-1.38) (0.96-1.26) 45/90 mg 1.37 1.15 1.28 1.18 1.07 adalimumab (1.14-1.74) (1.02-1.34) (1.02-1.65) (0.95-1.52) (0.87-1.37) 1.37 1.33 1.29 1.18 1.08 1.00 secukinumab (1.18-1.66) (1.06-1.64) (1.07-1.56) (1.04-1.37) (0.91-1.30) (0.76-1.30) 150 mg 1.87 1.81 1.75 1.61 1.46 1.37 (1.05- 1.36 etanercept (1.62-2.19) (1.45-2.19) (1.45-2.10) (1.36-1.91) (1.25-1.73) 1.71) (1.10-1.65) 1.99 1.92 1.86 1.71 1.56 1.45 1.45 1.07 Erelzi (1.31-3.83) (1.22-3.73) (1.20-3.59) (1.11-3.30) (1.01-3.00) (0.90-2.86) (0.92-2.9) (0.71-1.99) 2.90 2.79 2.70 2.49 2.26 2.11 2.10 1.55 1.45 apremilast (2.03-4.46) (1.90-4.36) (1.86-4.22) (1.72-3.78) (1.58-3.49) (1.42-3.31) (1.42-3.31) (1.07-2.4) (0.70-2.64) 17.89 17.25 16.72 (11.75- 15.37 13.99 13.01 12.98 9.57 8.92 6.15 placebo (12.68-25.94) (11.94-25.39) 24.34) (10.93-22.17) (10.02-20.0) (8.98-19.27) (9.12-18.79) (6.94-13.54) (4.47-15.46) (3.81-9.80) ©Institute for Clinical and Economic Review, 2016 Page 33 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Other PASI Thresholds Results for other PASI thresholds were generally consistent with results for the PASI 75. All target immunomodulators showed statistically significantly higher PASI 50, 90, and 100 rates than placebo (except that no published PASI 50 results were found for ixekizumab). In direct comparative trials, ustekinumab, secukinumab, and ixekizumab were superior to etanercept for PASI 90 and 100. Secukinumab and brodalumab were superior to ustekinumab in PASI 90 and 100. Similar to PASI 75 results, all targeted immunomodulators showed a statistically significantly higher percentage of patients achieving PASI 50, 90, and 100 compared to placebo, except for ixekizumab, which did not include PASI 50 in available trials (Table 5). Absolute rates were higher given the lower threshold for improvement with PASI 50, but generally ranged between 7% to 21% for placebo, 70% to 90% for biologics, and 55% to 60% for apremilast. PASI 90 response rates ranged between 0% to 11% for placebo, 16% to 70% for biologics, and 9% to 10% for apremilast. PASI 100 response rates ranged between 0% to 2% for placebo, 6% to 43% for biologics, and were not reported for apremilast. Eight head-to-head RCTs showed statistically significant differences between treatments on PASI 90 and PASI 100. For PASI 90, four trials showed that ustekinumab, secukinumab, and ixekizumab were superior to etanercept. For PASI 100, three trials found that ustekinumab, secukinumab and ixekizumab were superior to etanercept. For both PASI 90 and 100, secukinumab, ixekizumab, and brodalumab were superior to ustekinumab. Table 6 summarizes the comparisons and Appendix F provides more details. In addition, the recently reported 52-week results of a comparison of secukinumab and ustekinumab reported results for PASI 90 (76% vs. 61%; p < .0001) and PASI 100 (46% vs. 36%, respectively; p = .01).83 The direct comparative trials did not report PASI 50. However, we did identify two observational studies that compared PASI 50 response between treatments. One of them was a prospective, multi-center study in 162 patients (mean age 47, 68% male, mean duration of psoriasis 18 years, mean PASI 17.5) who received either infliximab or ustekinumab that found no statistically significant between-group difference in PASI 50 at seven months (96% vs. 82%).80 The other was a retrospective analysis in 89 elderly patients (mean age 70, 55% male, mean duration of psoriasis 28 years, mean PASI 11) treated with etanercept or adalimumab, finding that adalimumab had higher response rates at 12 weeks (86% vs. 82%) but lower at 24 weeks (82% vs. 90%), one year (79% vs. 90%), two years (82% vs. 92%), and three years (82% vs. 92%). However, the statistical significance of these differences was not tested.82 ©Institute for Clinical and Economic Review, 2016 Page 34 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Our network meta-analysis showed that all targeted immunomodulators were statistically significantly better than placebo on PASI 50. The effect sizes were similar among treatments, with RR ranging from 3.4 to 6.9. Pair-wise comparisons showed no difference between treatments (see Appendix F). Similarly, all immunomodulators had a statistically significantly higher efficacy on PASI 90 and 100. In head-to-head comparisons for initial PASI 90 and PASI 100, infliximab had the highest initial RR, followed by anti-interleukin agents (in the order of brodalumab, ixekizumab, secukinumab 300 mg, ustekinumab 45/90 mg combined), and other TNFα agents (in the order of adalimumab, etanercept, and Erelzi). Apremilast had the lowest RR (Appendix F). Physician Global Assessment or Investigator Global Assessment “Clear/Almost Clear” Physician Global Assessment (PGA) or Investigators Global Assessment (IGA) were generally consistent with the PASI 75 results. All immunomodulators showed statistically significantly higher proportions of patients with Physician Global Assessment (PGA) or Investigator’s Global Assessment (IGA) of ‘clear/almost clear’ than placebo at the primary end point of each trial. In head-to-head trials, ustekinumab, secukinumab, and ixekizumab were superior to etanercept; secukinumab, ixekizumab, and brodalumab were superior to ustekinumab. All immunomodulators showed statistically significantly higher efficacy on PGA/IGA compared to placebo. Across trials, the ranges of PGA/IGA response rates were 1% to 18% for placebo, 60% to 73% for adalimumab,54,55 40% to 66% for etanercept,56,57,59-62 76% to 83% for infliximab,63,64 60% to 74% for ustekinumab,68,69 65% to 74% for secukinumab,21,70,71 76-85% for brodalumab,19,72 and 20% to 22% for apremilast.73,74 Eight of nine head-to-head RCTs reported PGA response. All found statistically significant differences between treatments. The pattern response rates and differences between treatments were similar to those of PASI 75 response. In four trials, three agents had a higher proportion of patients achieve PGA scores of 0/1 than etanercept: ustekinumab (49% vs. 65% and 71% for ustekinumab 45 mg and 90 mg, respectively);75 secukinumab (27% vs. 63%);21 and ixekizumab (36% vs. 83% in UNCOVER 276 and 42% vs. 81% in UNCOVER 3;67 both p<0.0001). In four trials, three agents had a significantly higher proportion of patients with PGA scores of 0/1 than ustekinumab: secukinumab (65% vs. 81% at 12 weeks; 68% vs. 83% at 16 weeks),77 ixekizumab (18% vs. 43% for sPGA score of 0),78 and brodalumab (61% vs. 79% in AMAGINE 2 and 69% vs. 85% in AMAGINE319). Recently reported 52-week results of the CLEAR trial showed that secukinumab had a higher proportion of subjects with IGA scores of 0/1 than ustekinumab (80% vs. 65%; p < .0001).20 Two observational studies, adjusted for clinical and sociodemographic factors, compared PGA among drugs. One cross-sectional study in the U.S. with a sample size of 713 (mean age 49, 51% male, mean duration of psoriasis 19 years) showed that adalimumab had better adjusted PGA ©Institute for Clinical and Economic Review, 2016 Page 35 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents response compared to etanercept and ustekinumab (48% vs. 34% and 36%, p<0.00184). The PSOLAR registry (N=2076, mean age 47, 57% male, mean duration of psoriasis 17 years) found ustekinumab had better PGA response than infliximab (60% vs. 42%) at 12 months, but found no difference compared with etanercept or adalimumab.85 Dermatology Life Quality Index (DLQI) DLQI results were generally consistent with PASI 75 results. All targeted immunomodulators statistically significantly improved quality of life relative to placebo, with infliximab producing the overall greatest benefit and apremilast producing the smallest. In head-to-head trials, secukinumab and ixekizumab were superior to both etanercept and ustekinumab. Quality of life was measured in the majority of studies we identified in our search, primarily using the DLQI instrument. Overall, 18 of the 29 key studies evaluated mean DLQI change, while nine evaluated the proportion of patients achieving a DLQI score of 0 or 1 (indicating very little to no effect on quality of life); six included both measures. The 13 placebo-controlled trials reporting the mean DLQI change also showed a statistically significantly greater improvement for all therapies. Mean absolute difference between the intervention and placebo group improvement compared to placebo across the available studies for to each drug were as follows: adalimumab (-5.7),86 etanercept (-5.5 to -5.6),57,58 infliximab (-9.0),64 ustekinumab (-7.4 to -8.8 and -8.1 to -9.5 for 45 or 90mg, respectively),68,69 ixekizumab (-8.4),67 secukinumab (-8.8),21 and apremilast (-3.9 to -4.5)74,87,88(all outcomes, p<0.01). Brodalumab was the only agent for which no study measured mean DLQI change, though an abstract based on the AMAGINE 1 trial did report the proportion of patients achieving a DLQI score of 0/1, which was statistically significant in favor of brodalumab (absolute difference: 50.9%, p<0.001).89 Among those three placebo-controlled trials that also reported the proportion of patients with a score of 0/1, secukinumab (absolute difference: 48.3%, p<0.001)21 and ustekinumab (absolute difference: 45.3-49.3%/49.2-53.2% for 45/90mg, p<0.0001)68,69 were statistically significantly greater than placebo. Among the eight head-to-head trials, four studies evaluated improvements on the DLQI: CLEAR, FIXTURE, UNCOVER 2 and 3, and IXORA-S. Both secukinumab and ixekizumab achieved a statistically significantly greater improvement on the DLQI than etanercept and ustekinumab. Table 8 presents the data from these trials. ©Institute for Clinical and Economic Review, 2016 Page 36 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 8. DLQI Outcomes Across Direct Comparative Trials Trial Drug Mean p-value DLQI p-value change 0/1 (%) CLEAR ustekinumab NR NR 56.5 p=0.0109 secukinumab NR 66.2 FIXTURE etanercept -7.9 p<0.001 34.5 p<0.001 secukinumab -10.4 56.7 UNCOVER 2 etanercept -7.7 p<0.0001 33.8 p<0.0001 ixekizumab -10.4 64.1 UNCOVER 3 etanercept -8.0 p<0.0001 43.7 p<0.0001 ixekizumab -10.2 64.7 IXORA-S* ixekizumab NR NR 63 p<0.001 ustekinumab NR 45 *Only available in the grey literature Data on minimum clinically-important differences (MCID) DLQI changes (defined as at least a 5- point reduction) were statistically significantly in favor of apremilast, ustekinumab (both 45/90mg doses), and brodalumab compared to placebo (absolute differences: 27.9%, 54.6/59.4%, and 66.0%, respectively; all outcomes, p<0.001).74,89,90 Other Quality of Life and Mental Health Measures Few studies used other instruments to measure quality of life. One Phase II publication each for brodalumab and apremilast reported SF-36 scores. Brodalumab was associated with statistically significant improvement compared to placebo in the SF-36 PCS (+4.0 vs. +1.5) and MCS (+5.0 vs. +1.7).91 Apremilast failed to demonstrate any significant improvement relative to placebo, although improvement from baseline on the MCS was statistically significant (+2.9, p=0.0045) and numerically higher than the placebo group, which worsened (-0.8).92 Both brodalumab (+0.25 vs. - 0.01, for placebo, p<0.001)93 and adalimumab (+0.20 vs. +0.10 for placebo, p<0.01)86 demonstrated statistically significant improvements compared to placebo on the EQ-5D, though only the former was available in the peer-reviewed literature. For associated mental health outcomes, one trial of brodalumab and one trial of ustekinumab measured improvements in anxiety and depression on the HADS scale relative to placebo. In the publication of the AMAGINE 1 study, brodalumab improved both anxiety (-2.3) and depression (- 2.0) relative to placebo (-0.7 and -0.4, respectively, treatment difference: -1.5 and -2.1, p<0.001 for both outcomes).72 In a secondary analysis of PHOENIX 2, Langley and colleagues also reported a statistically significant improvement of both doses (45/90mg) of ustekinumab for anxiety (-1.6/-1/7 vs. -0.11) and depression (-1.7/-2.1 vs. -0.21) over placebo (both outcomes, p<0.001).94 ©Institute for Clinical and Economic Review, 2016 Page 37 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Symptom Control Measures of symptom control were inconsistently reported across trials and used a variety of instruments. Brodalumab was the only agent to measure PSI outcomes, and demonstrated a statistically significant benefit over placebo. Three secukinumab trials measured improvements on the PSD, and improved itching, pain, and scaling better than placebo or ustekinumab. Apremilast was also statistically significantly better than placebo on VAS-itch, while ixekizumab demonstrated superiority over etanercept for VAS-skin pain. Across the two ESTEEM RCTs and the LIBERATE trial, apremilast demonstrated a statistically significant absolute improvement over placebo for pruritus VAS of 21.0mm-35.6mm (p<0.01).74,87,88 On the PSI, significantly more patients in the brodalumab group were PSI responders (defined as a total score ≤8, with each item rated as 0 [not at all] or 1 [mild]) compared to placebo in the AMAGINE 1 study (absolute difference: 57%, p<0.001).72 The proportion of responders (defined as a minimum of 2.2 reduction for all symptoms) receiving secukinumab was statistically significantly greater than placebo on the PSD for itching (83.0% vs. 16.9%), pain (72.8% vs. 15.6%), and scaling (83.0% vs. 13.8%) in the ERASURE and FIXTURE studies (p<0.05).95 Compared to ustekinumab, statistically significantly more secukinumab patients achieved complete relief of itching (25% vs. 44%), pain (35% vs. 59%), and scaling (21% vs. 42%) (all outcomes, p<0.05), and remained statistically significantly better at week 52.96,97 In direct comparison trials, an abstract reported that ixekizumab was statistically significantly better than etanercept for VAS-skin pain (least-squares mean change from baseline: -42.2 vs. -29.0, p<0.001).98 A single publication reporting results from the AMAGINE 2 and 3 trials found that numerically more patients were PSI responders (defined as PSI score ≤8, with no item having a score >1) in the brodalumab group compared to ustekinumab group (68% vs. 55% [AMAGINE 2] and 61% vs. 52% [AMAGINE 3], respectively); groups were not compared statistically for this particular outcome in either trial, however.19 Worker Productivity Positive effects on productivity were seen in analyses of several RCTs. Four targeted immunomodulators (adalimumab, infliximab, ustekinumab, and apremilast) showed significant improvements compared to placebo. In direct comparisons, there was a greater relative benefit of ixekizumab over etanercept and secukinumab over ustekinumab. However, tools used to measure productivity outcomes (i.e., WPAI, WLQ, VAS productivity) were variably employed across studies, which hinders our ability to make inferences about the potential benefit of one drug over another based on the reported data. ©Institute for Clinical and Economic Review, 2016 Page 38 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents We identified three publications that were secondary analyses of Phase III placebo-controlled RCTs, including REVEAL, EXPRESS, PHOENIX 2, as well as an abstract pooling data from the ESTEEM trials. See the Definitions section of the report for details about the productivity instruments mentioned below. The secondary analysis of the REVEAL trial99 demonstrated a statistically significant improvement for adalimumab relative to placebo on the WPAI for total work productivity impairment (15.1%, p<0.001); the data for the placebo group were not reported, however. In the EXPRESS trial, infliximab was statistically significantly better than placebo on VAS productivity scores, with a mean 22.5% increase in the intervention group compared to a 1.1% decrease change in the placebo group; a similar trend was observed on the SF-36 physical component score (+12.1 vs. -5.2, p<0.001).100 The secondary analysis of PHOENIX 2 also demonstrated statistically significant improvements of ustekinumab 45/90mg over placebo based on WLQ domains for output demands (6.8/7.0 vs. -1.1), mental-interpersonal (7.8/7.5 vs. -1.1), and time management (6.6/9.1 vs. -0.7) compared to placebo (all outcomes, p<0.001).101 An abstract that pooled data from the ESTEEM trials also used the WLQ tool but found apremilast to be statistically significantly improved based on two of the four domains relative to placebo: time management (-2.1 vs. +2.8, p=0.002) and output demands (- 1.5 vs. +1.0, p=0.046).73 Finally, median percent improvements from baseline in productivity were better for ustekinumab 45/90mg (72.6%/71.4%) compared to no change for placebo, but groups were not compared statistically.101 Among head-to-head trials, a secondary analysis of the UNCOVER trials compared of ixekizumab and etanercept.102 Outcomes were evaluated based on the WPAI and demonstrated a statistically significant improvement over placebo in UNCOVER 1 (-19.8 vs. -0.8), and over etanercept and placebo in UNCOVER 2 (-19.5 vs. -13.7 and -2.0) and UNCOVER 3 (-19.3 vs. -17.4 and +0.6) for work productivity loss (least mean squares, p<0.001 for all outcomes). The 52-week results from the CLEAR study also demonstrated that secukinumab was statistically significantly better (p<0.01) than ustekinumab in reducing presenteeism (-24% vs. -18 %), work productivity loss (-23% vs. -17%), and activity impairment (-32% vs. -28%) on the WPAI in one abstract.103 Sexual Function Very few studies reported sexual function as an outcome. Two abstracts of head to head studies included data showing superiority of ixekizumab over etanercept and secukinumab over ustekinumab. ©Institute for Clinical and Economic Review, 2016 Page 39 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents A publication which pooled patients from PHOENIX 1 and 2 reported that the proportion of patients with impaired sexual function was statistically significantly lower with ustekinumab 45/90mg (2.6/2.8%) than placebo which remained unchanged from baseline (23.0%, p<0.001).104 In direct comparison trials, an abstract reported that secukinumab was superior to ustekinumab with statistically significantly fewer patients reporting no sexual difficulties at week 52 in the CLEAR study (89% vs. 74%, p<0.01).105 In addition, in a secondary analysis of the UNCOVER trials, one abstract reported that statistically significantly more patients reported improvements in sexual function with the ixekizumab compared to etanercept in both UNCOVER 2 (80% vs. 51%, p<0.001) and UNCOVER 3 (81% vs. 69%, respectively, p<0.05).106 Treatment Satisfaction Only two placebo-controlled trials, one of brodalumab and one of etanercept, reported treatment satisfaction, which was better for both interventions compared to placebo. Only two studies reported treatment satisfaction. The proportion of patients who were “satisfied” or “very satisfied” with treatment was statistically significantly higher in the etanercept group versus placebo (76% vs. 18%, p<0.0001).59 While one abstract reported that treatment satisfaction was statistically significantly higher in the brodalumab group relative to placebo (p<0.001), no additional data were reported.89 Harms Severe or serious adverse events were rare during treatment. During the induction phase of treatment, infections (e.g., nasopharyngitis, upper respiratory tract infections, etc.), injection site or infusion reactions, headache, and nausea were the most common side effects with biologics. Infliximab appears to have higher rates of these events than other drugs. Long-term safety data on all-cause mortality, MACE, malignancy, and serious infections are available for TNF-α agents and ustekinumab but not for the other drugs of interest for this review. Findings suggest an increased rate of serious infections for infliximab and other biologic agents relative to nonbiologic therapy, although not for ustekinumab. There were no material differences on other safety concerns among the biologic agents or in comparison with nonbiologic therapy. Adverse Events During Induction Adverse events (AEs) that occurred in ≥5% of patients in any treatment group as well as specific AEs of interest are shown as trial-weighted averages in Table 9. Most adverse events were mild or moderate. Severe or serious adverse events, death, and AEs leading to discontinuation were rare and comparable between the treatment and placebo groups. ©Institute for Clinical and Economic Review, 2016 Page 40 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents The most common AEs included mild infections (e.g. nasopharyngitis, upper respiratory tract infections, etc.); injection site reactions for subcutaneously administered drugs and infusion reactions for infliximab; headache; and nausea. There was no evidence of increased risk of serious infections or malignancies. There were no reports of tuberculosis, opportunistic infections, demyelinating disease, or lymphoma in these trials. We also did not find differences in risk of major adverse cardiac events (MACE). ©Institute for Clinical and Economic Review, 2016 Page 41 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 9. Adverse events during the placebo-controlled period % adalimumab etanercept infliximab ustekinumab secukinumab ixekizumab brodalumab apremilast placebo Any AE 65 57 71 53 58 58 58 69 52 Tx-related death 0 0 0 0.1 0 0 0.1 0.1 0 D/C due to AEs 2 2 7 1 1 2 1 5 2 Serious AEs 2 2 3 1 2 2 1 2 2 Serious Infections 1 0.5 6 0.6 NR 0.4 0.5 NR 0.3 ≥Grade 3 AEs 2 2 NR NR NR NR 4 4 3 common AEs, % Any Infections 32 27 36 36 29 27 NR NR 25 Nasopharyngitis 8 8 NR 12 11 10 9 7 8 Upper respiratory 7 6 14 5 3 4 6 8 5 tract infection Headache 6 7 13 7 6 4 4 6 4 Nausea 4 2 4 NR 5 NR NR 17 4 Injection site 19 14 NA 4 NR 10 1 NA 2 reactions Infusion Reaction NA NA 10 NA NA NA NA NA 7 Malignancy 0.2 0.5 1 0.2 NR 0.1 NR NR 0.2 excluding NMSC NMSC 0.5 0.3 NR 0.4 NR 0.1 NR NR 0.2 MACE NR 0.2 NR 0.2 NR 0 0 NR 0 * Values represent weighted averages across key trials; D/C=discontinuation; AEs=adverse events; NMSC=nonmelanoma skin cancer ©Institute for Clinical and Economic Review, 2016 Page 42 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Long-term Adverse Events Long term results of adverse events reported from pivotal trials of targeted immunomodulators are summarized in Table 10. In follow-up of trials of one to five years, etanercept, ustekinumab, secukinumab, and brodalumab had comparable safety profiles. Table 10. Long-Term Adverse Events from Trials of Targeted Immunomodulators Trial Agent Length Any Leading Serious Any Serious Cardiac Neoplasms of AE to D/C AE Infection Infection or Follow MACE -up Years Per 100 person-years AMAGINE 2 Brodalumab 1 409 2.6 8.3 NR 1.0 0.4 0.1 Ustekinumab 413 1.2 13.0 NR 0.8 0.8 0.8 AMAGINE 3 Brodalumab 1 388 3.2 7.9 NR 1.3 0.7 0.5 Ustekinumab 376 2.8 4.0 NR 1.2 0.0 0.8 FIXTURE Secukinumab* 1 252 NR† 6.8 105 NR 0.5 0.2 Etanercept 243 NR 7.0 91 NR 1.0 0 PHOENIX 1 Ustekinumab 5 215 2.1 5.3 83 1.0 0.3 0.9 PHOENIX 2 Ustekinumab 5 202 2.4 7.3 80 1.0 0.5 1.0 CLEAR Secukinumab 1 281 NR‡ NR 98 NR NR NR Ustekinumab 250 NR NR 96 NR NR NR D/C = discontinuation; MACE = major adverse cardiac events; NR = not reported. *Among subjects who received secukinumab 300 mg. †In the FIXTURE trial the rate of adverse events leading to discontinuation was not calculated, but the number of patients who discontinued secukinumab and etanercept due to adverse events were 14 and 12, respectively. A corrected proof of one-year efficacy and safety data from the CLEAR trial which compared secukinumab to ustekinumab was published online on September 20, 2016.20 The rates of any adverse effect per 100 PY for secukinumab and ustekinumab were 281 and 250, respectively. The rates of any infection per 100 PY for secukinumab and ustekinumab were 98 and 96, respectively. The number of patients who, over one year, discontinued the study medication due to an adverse effect was 10 of 335 subjects for secukinumab and 9 of 336 subjects for ustekinumab. ©Institute for Clinical and Economic Review, 2016 Page 43 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Long-term safety data are also available from PSOLAR (Psoriasis Longitudinal Assessment and Registry). PSOLAR is a multicenter, longitudinal, psoriasis-based registry study evaluating the risk of infection in biologics and other systemic therapies. The overall population was 55% male, with a mean age of 49 and a mean duration of disease of 18 years. We identified two publications describing PSOLAR results.22,23 Table 11: Incidence of adverse events from the PSOLAR Registry22 Adverse Ustekinumab Infliximab Other Nonbiologics Event biologics Per 100 person-years All-Cause 0.36 0.45 0.42 0.70 Mortality MACE 0.34 0.38 0.33 0.45 Malignancy 0.51 0.64 0.74 0.81 Serious 0.95 2.78 1.80 1.26 infections MACE = major adverse cardiovascular events. In one analysis including 12,095 patients and 31,818 PY of follow-up, participants were hierarchically attributed to having been exposed to ustekinumab, infliximab, other biologics, or nonbiologic medications. Nonbiologics were associated with a significantly higher rate of AE rates than biologics for all-cause mortality, MACE, and malignancy (Table 11).22 Another analysis of the PSOLAR Registry with 11,466 patients and 22,311 PY of follow-up, focused on serious infections. Infliximab had a higher rate and ustekinumab had a lower rate of serious infections than other available biologics, methotrexate, and nonmethotrexate nonbiologic treatment (systemic retinoids, psoralen plus UV-A, and UV-B).23 In descending order, the rate of serious infections per 100 patient years was 2.5 for infliximab, 2.0 for adalimumab, 1.5 for etanercept, 1.3 for methotrexate nonbiologics, 1.1 for nonmethotrexate nonbiologics, and 0.8 for ustekinumab. For newer targeted immunomodulators – ixekizumab, brodalumab, and apremilast – no long-term safety data beyond the duration of clinical trials have been published. Subgroup Analyses Limitations in the evidence base preclude determining whether there are meaningful differences in effectiveness within the subgroups of interest. Although outcomes were statistically significantly in favor for all the agents available for review relative to placebo across subgroups, data comparing subgroup results between agents were only available in one observational study. ©Institute for Clinical and Economic Review, 2016 Page 44 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents As previously mentioned, three subgroups were identified as being of particular interest to stakeholders: patients with psoriatic arthritis; patients who have or have not previously received biologic agents; and studies that were conducted in Asia. Patients with Psoriatic Arthritis We identified five secondary analyses evaluating outcomes for patients with psoriatic arthritis, four of which were from the grey literature.90,107-110 No data were available for the TNF-α agents or apremilast. One post hoc analysis of a Phase IIb study in brodalumab reported outcomes for those with and without psoriatic arthritis, but between group comparisons were not statistically evaluated. Three placebo-controlled RCTs included secukinumab, ixekizumab, and ustekinumab, and brodalumab and reported results among patients with psoriatic arthritis. All agents were statistically significantly better relative to placebo on the PASI 75 among patients with psoriatic arthritis (Table 12). One abstract reported results of the FIXTURE trial among patients with psoriatic arthritis. Patients with plaque psoriasis and psoriatic arthritis receiving secukinumab had a statistically significantly higher rate of achieving PASI 75 (72% vs. 39% and 2%) and PASI 90 (44% and 39% vs. 18% and 2%) compared to etanercept and placebo, respectively (p<0.01). These differences were similar to those observed for the overall trial population.110 Table 12. Proportion of patients with and without psoriatic arthritis reaching PASI 75 Drug (Trial) # of PsA PsA Achieving PASI 75 (%) Overall Population patients Intervention Placebo Intervention Placebo Secukinumab 175 72 2 82 5 (FIXTURE) Etanercept Same trial 39 4 44 Same trial (FIXTURE) Secukinumab 171 70 4 82 5 (ERASURE) Ustekinumab 563 63/62 4 67/66 3 45/90mg (PHOENIX 1 and 2) Ixekizumab (all 749 90 3 87-90 4 UNCOVER trials) Brodalumab 198 92 0 82 0 (Phase IIb) ©Institute for Clinical and Economic Review, 2016 Page 45 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents The secondary analysis of a Phase IIb trial of brodalumab was the only one that reported outcomes for patients with and without psoriatic arthritis. Patients with psoriatic arthritis (n=46) had numerically similar proportions of achieving PASI 75 compared to patients without psoriatic arthritis (n=152; 92% and 79% vs. no change for placebo), PASI 90 (83% and 71% vs. no change for placebo), a DLQI response (defined as a ≥5-point improvement; 100% vs. 79% vs. 0% and 42% for placebo), and a PSI response (defined as a score ≤8, with no item having a score >1; 94% and 79% vs. 14% and 13% for placebo) The authors stated that adverse events were similar between subgroups, no data were reported.109 One abstract evaluated SF-36 outcomes based on pooled data from the UNCOVER trials for ixekizumab and found that patients with psoriatic arthritis who received ixekizumab, relative to patients who received placebo, achieved statistically significantly greater improvements on the MCS (5.2 vs. 0.8) and PCS (5.4 vs. -1.1) subscales (both outcomes, p<0.001).108 Patients with Previous Biologic Therapy Exposure We identified seven studies that evaluated outcomes in patients who were and were not previously exposed to biologic therapy.23,74,111-115 Subgroup analyses from four RCTs were primarily reported in the grey literature, though we found two peer-reviewed publications: one a key clinical trial of apremilast (ESTEEM 2) and one Phase II study on brodalumab. No head-to-head data were available. Across placebo-controlled studies, a statistically significantly greater proportion of patients achieved a PASI 75 response with the intervention for patients with and without prior biologic therapy. Rates between groups were numerically similar, but not compared statistically, and other outcomes (PASI 50, 90, and sPGA score of 0/1) followed the same trend where reported. Table 13. Proportion of patients reaching PASI 75 in the bio-exposed and bio-naïve groups Drug Exposed (%) Naïve (%) Apremilast 22.8 31.9 Placebo 4.5 6.5 p-value74 =0.0069 <0.001 Brodalumab 88 79 Placebo 0 0 p-value111 <0.001 <0.001 Ixekizumab 89.5 88.4 Placebo 2.7 5.2 p-value112 <0.001 <0.001 Secukinumab 75.7 84.0 Placebo 4.1 4.6 p-value113 <0.0001 <0.0001 ©Institute for Clinical and Economic Review, 2016 Page 46 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents In addition to the above-described analyses from RCTs, we identified three observational studies. One small database study (DERMBIO) evaluated efficacy outcomes associated with subgroups of Danish patients (n=179, 51.4% male, age 43.4 years, mean PASI 10.9) taking ustekinumab who were and were not previously exposed to TNF-α agents, or who failed previous TNF-α therapy.114  There were no statistical differences in PASI 75 response for patients taking one, two, or three prior TNF- α. Although patients who had previously been exposed to TNF-αs achieved PASI 75 response 20 days sooner than those patients who were TNF-α naïve, the difference was also not statistically significant. Data for each subgroup were not reported in the publication, though 80% of all patients overall achieved PASI 75 at the end of the study period.114 Another study from the same database evaluated the three anti- TNF-αs and ustekinumab and found that patients (n=1,867, mean age 45.1, 64.5% male, mean PASI 12.8) taking adalimumab (OR: 1.8, 95% CI 1.4-2.3), etanercept (OR: 2.6, 95% CI 0-3.3), or infliximab (OR: 1.990, 95% CI 1.5-2.6) were statistically significantly more likely to terminate treatment than those on ustekinumab after adjusting for sex and previous biologic treatment at baseline (all outcomes, p<0.0001).115 The authors note, however, all patients who were previously exposed to biologic therapy had a higher probability of treatment discontinuation (primarily due to loss of efficacy) across all agents (OR: 1.24, 95% CI 1.05-1.46, p=0.011).115 The final observational study was a large database study (PSOLAR) comparing rates of serious infections among patients (n=11,466, 55.4% male, age 48.4 years, mean psoriasis diagnosis 17.6 years) taking TNF-αs or ustekinumab.23 The investigators evaluated the rate of serious infections across patients taking adalimumab, etanercept, infliximab, and ustekinumab and found that infliximab and adalimumab has the highest rates of infections (2.49 per 100 PYPY and 1.97 per 100 PYPY) while etanercept and ustekinumab had the lowest (1.47 per 100 PYPY and 0.83 per 100 PYPY). When divided into subgroups of patients who were biologic-exposed and biologic-naïve across agents, incidence rates were 1.35 per 100 PYPY and 1.12 per 100 PYPY, respectively; the trend was similar to the overall rates when evaluated according to drug but were not compared statistically23 Asian Studies We identified five placebo-controlled RCTs that were conducted in Asia, plus a subanalysis of the Japanese portion of the ERASURE study. No head-to-head Asian studies were available.52,116-120 Three distinct trials of ustekinumab included patients in Japan,117 China (LOTUS),52 and Taiwan and Korea (PEARL) patients,119 while the subgroup analysis for the secukinumab trial118 included Japanese patients, and the trial for infliximab120 included Chinese patients.104 We did not identify any trials conducted in Asia for ixekizumab, apremilast, or brodalumab. As in multinational studies, all studies demonstrated statistically significant differences on all PASI measures (where reported) for each therapy compared to placebo; these results are presented in the table below. The proportion of patients achieving a PASI 75 response across RCTs of ©Institute for Clinical and Economic Review, 2016 Page 47 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents adalimumab (71-80%), infliximab (76-80%), secukinumab (76-91%), and ustekinumab 45mg (67- 68%) and 90mg (66-76%) did not demonstrate any identifiable differences. Other commonly reported outcomes included improvements on the DLQI and the proportion of patients achieving a PGA or IGA score of 0/1, which were consistent with PASI score improvement. One of the studies evaluating ustekinumab also measured SF-36, and was the only trial that met our inclusion criteria to include PDI outcomes; these results are available in the summary evidence tables in Appendix B.117 Table 14. Proportion of patients Achieving PASI Scores across Asian Studies Study Study group PASI p- PASI p-value PASI p-value PASI p- 50 value 75 90 100 value Asahina, Adalimumab 81 <0.001 63 <0.001 40 <0.001 NR NR 2010 Placebo 20 4 0 NR Igarashi, Ustekinumab 83 <0.001 59 <0.001 33 <0.001 NR NR 2012 45mg Ustekinumab 84 68 44 NR 90mg Placebo 13 7 3 NR Tsai, Ustekinumab 84 <0.001 67 <0.001 49 <0.001 8 =0.024 2011 45mg Placebo 13 5 2 0 Zhu, Ustekinumab 91 <0.001 83 <0.001 67 <0.001 24 <0.001 2013 45mg Placebo 20 11 3 1 Yang, Infliximab 94 <0.001 81 <0.001 57 <0.001 NR NR 2012 Placebo 13 2 0 NR Ohtsuki, Secukinumab NR NR 83 <0.0001 62 <0.0001 28 <0.01 2014 Placebo NR 7 0 0 *NA=not available; NR=not reported Across the ustekinumab trials, the mean absolute difference in improvement on the DLQI ranged from -7.4 to -10.7, with all studies reporting outcomes that were statistically significantly better than placebo (p<0.001).52,117,119 Adalimumab also demonstrated a statistically significant improvement (-6.1, p<0.001),116 as did infliximab (-6.6, p<0.001).120 Rather than mean DLQI change, Ohtsuki and colleagues only reported the proportion of patients with a DLQI score of 0 or 1 which was statistically significant in favor of secukinumab in the ERASURE study (71.4% vs. 24.1% for placebo, p<0.001).118 The absolute mean proportion of patients achieving a score of 0 or 1 on the PGA across the placebo-controlled studies that reported PGSA was 48% to 64% higher with ustekinumab, 51.8% ©Institute for Clinical and Economic Review, 2016 Page 48 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents higher with apremilast, 81.4% higher with infliximab (all p<0.001). The subgroup analysis of the ERASURE trial was the only study to report outcomes based on the modified IGA measure and found that statistically significantly more patients were responders (a score of 0/1) in the secukinumab group compared to those receiving placebo (55.2% vs. 3.4%, p<0.0001).118 Two studies conducted in Japan, one of ustekinumab117 and one of adalimumab,116 reported SF-36 outcomes. For ustekinumab, both doses were statistically significantly better than placebo on the PCS of the SF-36 (7.8/5.1 vs. -0.95, p=0.0033 and p=0.0164 for 45mg and 90mg of ustekinumab, respectively). There were no significant differences for the MCS. For adalimumab compared to placebo, there were significant improvements in the PCS (4.6 vs. -0.4; p < 0.01) and MCS (2.4 vs. - 2.6; p < 0.05). The Ohtsuki study also reported outcomes for patients with and without prior exposure to biologic therapy. Patients who were biologic-exposed in the secukinumab group had a statistically significantly greater proportion of patients achieving PASI 75 (83.3%) and PASI 90 (50.0%) than the placebo group (0%), with a similar trend in the biologic-naïve secukinumab patients (82.6% and 65.2% vs. 8.7% and 0% for PASI 75 and PASI 90, respectively). The groups were not compared statistically, however. The most common treatment-related adverse events consistent with those reported in the main trials for the agents of interest, and no new safety concerns arose for any of the agents in this population. Controversies and Uncertainties Across the 29 Phase III RCTs identified for this review, only eight included head-to-head comparisons for the drugs of interest. The network meta-analysis extended comparisons to those between all agents, but is based on indirect comparisons. Our results are largely consistent with the comparative data, other meta-analyses, and other network meta-analyses. Although PASI 75 was reported as the primary endpoint in nearly all studies (the one exception being IXORA-S, in which the primary outcome was PASI 90), all other clinical outcomes, including PASI 50, 90, 100 and PGA/IGA, were inconsistently reported across trials making cross-drug comparisons difficult. Longer-term data on both drug effectiveness and harms were also variable; many studies reassigned patients to different groups (mostly cross-over to the intervention) and evaluated outcomes at different time periods. Observational data were only available for ustekinumab, secukinumab, and the TNF-α therapies, which limited our understanding of real-world effectiveness and durability of benefit for many of these therapies. Trials had washout of non-study treatments prior to initiating targeted immunomodulators and prohibited non-study treatments during the trials. Prohibition of non-trial treatments permits direct ©Institute for Clinical and Economic Review, 2016 Page 49 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents comparative evaluation of targeted immunomodulators with placebo or one another, but it does not represent actual practice in which next-best treatment would not be placebo or permit evaluation of combination therapy (e.g., topical use during targeted immunomodulator treatment). Assessments of real-world effectiveness also are limited by lack of comparative data on non- standard dosing, whether increased (to preserve effectiveness) or decreased (to reduce costs). Treatment durability and cost are both important factors in choosing a treatment for psoriasis. This uncertainty hinders our understanding of the relative effectiveness of these agents. We also did not identify any studies evaluating the potential association between early aggressive treatment and cardiovascular risk. There are also concerns with the reporting of patient-centered outcomes. DLQI was evaluated in 18 of the 29 clinical trials, not all trials used the same standard of measurement, and other scales were not uniformly employed. Additionally, many of the tools developed to measure outcomes were not developed with patients in mind, and psoriasis-specific instruments are limited. Finally, subgroup data were primarily reported in conference abstracts and the interventions were only compared statistically to placebo, thereby limiting our understanding of how outcomes may differ across population types. Summary Using the ICER evidence rating matrix, our evidence ratings for the comparisons of interest are provided in Table 15; ratings are presented for the targeted immunomodulator listed in each row relative to the comparator listed in each column. Note that comparisons to placebo are not included in the table. As described previously, findings from placebo-controlled trials indicated substantial improvements in clinical measures for all agents, so these would all receive a letter grade of “A” (i.e., high certainty of substantial net health benefit) relative to placebo. The presence of some direct comparisons allowed us to be reasonably confident about the relative net health benefit for some between-agent comparisons. However, because of the lack of many head-to-head comparisons, we relied on a network meta-analysis to estimate the comparative clinical effectiveness between many targeted immunomodulators (see Appendix F). Ratings based on a combination of direct and indirect evidence are highlighted in green in the table along with the number of head-to-head studies that informed the rating. There were two head-to-head trials comparing ixekizumab and etanercept, both of which showed substantial improvement in the percentage of patients achieving various PASI thresholds, and a similar magnitude of benefit when indirect evidence was included. We felt that the consistency of results across the two trials represented high certainty of a substantial net benefit for ixekizumab (“A”) and an inferior net health benefit (“D”) for etanercept in this comparison. Similarly, findings from two trials comparing ©Institute for Clinical and Economic Review, 2016 Page 50 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents brodalumab to ustekinumab showed consistent benefit for brodalumab, albeit at an incremental level (ratings of “B” and “D” for brodalumab and ustekinumab, respectively). The remaining head-to-head comparisons were based on the results from single trials, giving us only moderate certainty in our estimates of comparative effectiveness. Both ustekinumab and secukinumab demonstrated better outcomes than etanercept, and these findings were supported by the network meta-analysis, leading us to give a rating of “B+” (incremental or better) to these comparisons. Etanercept was rated “C-” for both comparisons, reflecting our judgment of moderate certainty that net health benefit is either comparable or inferior. Findings from a single trial of secukinumab vs. ustekinumab showed improved clinical outcomes at all PASI thresholds for secukinumab, but inclusion of indirect evidence yielded a nonsignificant difference in treatment effect. As such, we rated the evidence “C+” (comparable or better) for secukinumab and “C-” for ustekinumab in this comparison. We judge the evidence to be insufficient (I) to distinguish between etanercept and apremilast, given that the only available head-to-head trial was underpowered to detect differences between active agents and dosing of etanercept does not match the labeling for the product. Finally, the addition of a direct comparison between ixekizumab and ustekinumab is newly available, but only in abstract form, yielding moderate certainty of at least a small net benefit (“B+”). Table 15. ICER evidence ratings for available head-to-head comparisons Treatment Comparator Adalimumab Apremilast Brodalumab Etanercept Infliximab Ixekizumab Secukinumab Ustekinumab 300 45/90 Adalimumab - C+ C- C+ C- C- I I Apremilast C- - D I C- C- C- C- Brodalumab C+ B - B I I I B (2) Etanercept C- I D - C- D (2) C- (1) C- (1) Infliximab C+ B+ I B+ - I I C+ Ixekizumab C+ B+ I A (2) I - C+ B+ (1) Secukinumab I B+ I B+ (1) I C- - C+ (1) 300 Ustekinumab I B+ D (2) B+ (1) C- C- (1) C- (1) - 45/90 Note: The table should be read row-to-column. For example, there is moderate certainty that adalimumab has a comparable to substantial net benefit compared to apremilast (C+). Conversely, there is moderate certainty that the point estimate for comparative net health benefit of apremilast is either comparable or inferior to adalimumab (C-). Table key: green=direct + indirect evidence; blue=indirect evidence only Number of head-to-head studies in parentheses ©Institute for Clinical and Economic Review, 2016 Page 51 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Ratings based on indirect evidence alone are highlighted in blue in the table. In one instance, certainty in the ratings remained high due to a “second-order” effect. Specifically, because we have high certainty that brodalumab provides an incremental net health benefit over ustekinumab, and moderate certainty that ustekinumab provides an incremental or better benefit over etanercept, we conclude that there is high certainty that brodalumab would also provide an incremental benefit over etanercept or apremilast (its functional equivalent). For all other ratings, results of the network meta-analyses represented the only guide with which to judge the evidence. Drugs with evidence of net health benefit were judged B+ or C+ based on the observed magnitude of benefit, and their comparators received an I rating (moderate certainty of comparable or inferior net health benefit). In situations where the credible interval (the Bayesian equivalent of the confidence interval) crossed 1.0, the evidence was rated I* (insufficient) for both directions of the comparison. ©Institute for Clinical and Economic Review, 2016 Page 52 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 5. Other Benefits or Disadvantages Beyond effectiveness and safety of targeted immunomodulators, the method of administration, frequency of dosing during maintenance, and rapidity of effect may be important considerations. Regarding method of administration, all of the targeted immunomodulators are administered subcutaneously except for apremilast (oral) and infliximab (intravenous). Patients could favor the convenience of an oral drug like apremilast. Although infliximab is comparatively effective, patients might be disinclined to use an intravenous medication that is associated with administration time and discomfort. The frequency of administration during maintenance is greatest for apremilast (twice a day). Other targeted immunomodulators are taken weekly (adalimumab, etanercept), every 2 weeks (brodalumab), every 4 weeks (secukinumab and ixekizumab), every 8 weeks (infliximab), and every 12 weeks (ustekinumab). Patients could favor agents that need to be taken less frequently. How quickly a drug works to clear psoriasis is likely to be important for patient satisfaction and adherence. For patients who require rapid clearing of moderate-to-severe plaque psoriasis, cyclosporine, an older systemic agent, not a focus of this review, and infliximab appear to be superior to other treatments. ©Institute for Clinical and Economic Review, 2016 Page 53 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 6. Comparative Value 6.1 Overview The aim of this analysis was to estimate the cost-effectiveness of treatments for patients with moderate to severe plaque psoriasis who have failed topical treatment, older systemic treatments, and phototherapy. To conduct the cost-effectiveness analysis, we developed a simulation model to assess the clinical and economic outcomes of the targeted immunomodulators. Model parameters were estimated from the network meta-analyses described earlier in this report, as well as the published literature. The outcomes of the model include total costs, quality-adjusted life years (QALYs), life years (LYs), and incremental cost-effectiveness ratios. Uncertainty in the data inputs and assumptions were evaluated using sensitivity and scenario analyses. 6.2 Prior Published Evidence on Costs and Cost-Effectiveness of Psoriasis Treatments A review of the literature for prior economic models yielded several published cost-effectiveness models comparing psoriasis treatment regimens within and across classes. Among studies conducted in the U.S., one study121 comparing ustekinumab versus etanercept, based on the ACCEPT clinical trial,122 showed that ustekinumab 90mg had an incremental cost- effectiveness of $384,401/QALY versus etanercept 50mg, and ustekinumab 45mg dominated (more effective and less expensive) etanercept 50mg. The key differences between this study and our analysis are: 1) a three-year time horizon versus 10 years in our model; 2) societal perspective versus a health system perspective in our model; 3) cost of etanercept was significantly lower than that in our model; and 4) the model assumed partial responders (PASI 50-74) continued treatment, while we assumed first-line treatment continued only when PASI >75 was achieved. One other manufacturer-funded study123 evaluating various biologic therapies (TNF antagonists: adalimumab, etanercept, and infliximab; T-cell inhibitors: alefacept and efalizumab) found adalimumab had a favorable incremental cost-effectiveness ratio compared to etanercept, at $544/QALY. Infliximab accrued the highest QALYs gained, while etanercept was least costly. This study: 1) did not account for decrease in treatment efficacy for subsequent lines of treatment after first-line, 2) assumed that treatment response would be maintained indefinitely through the course of therapy, and 3) did not clearly state the model time horizon. Owing to the lack of transparency in the methods, a critical comparison with our model was not feasible. ©Institute for Clinical and Economic Review, 2016 Page 54 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Studies conducted in settings outside of the U.S. included a manufacturer-funded Canadian model124 comparing ustekinumab (45mg) with etanercept. This analysis found that ustekinumab had an incremental cost-effectiveness of CAN$590,870/QALY (US$442,203/QALY) compared to etanercept. The model used inputs for the initial phase (initial trial period) from the ACCEPT trial122 and extrapolated the same trial data for the maintenance phase. Additionally, resource utilization was obtained from expert opinion, although validated by a burden of illness study. The model assumed second-line treatment to be supportive care and did not include the possibility of a second biologic treatment for those who experienced treatment failure (defined as PASI ≤75). Other studies of interest from outside the U.S. were the manufacturer submissions to the U.K. National Institute for Health and Care Excellence (NICE).125-128 All of the models submitted to NICE were based on the York model,129 with a 10-year time horizon, and were from an NHS perspective. Overall summary and differences included that: 1) most of these analyses accounted for the possibility of second-line targeted therapy use (except ustekinumab and secukinumab); 2) drug costs used were vastly different than those in the U.S.; and 3) most assumed very large cost offsets related to avoided hospitalizations, an assumption which was viewed by the NICE Evidence Review Group (ERG) as being unrealistic and unsupported by data. Details on the NICE submissions can be found in Appendix C. 6.3 Cost-Effectiveness Model: Methods Model Structure We developed a Markov model with eight health states, as shown in Figure 5; patients could transition between states every month. After the initiation period of the first-line targeted therapy (defined as the point in time at which the primary trial outcome was measured, typically 12-16 weeks), patients were categorized into one of four health states: PASI 90 and higher, PASI 75-89, PASI 50-74, and PASI <50. Although no transition between PASI improvement states was allowed in the model, decreased treatment response and drug discontinuation over time could occur. Patients with response below 75% improvement after the initiation period (16 weeks for adalimumab and apremilast, 10 weeks for infliximab, and 12 weeks for all other drugs) were assumed to discontinue the first-line therapy. A proportion of these patients then begin second- line targeted therapy and the remainder receive non-targeted therapy (i.e., topical therapy, other systemic therapy, and phototherapy). Second-line therapy was defined as an average of all available targeted therapies given the complete lack of RCT data in the second-line setting. Costs and effects for second-line were averaged across therapies as described below. ©Institute for Clinical and Economic Review, 2016 Page 55 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 5: Markov model of psoriasis treatment and response Patients with a PASI improvement of at least 75% after the initiation periods continued on first-line therapy, but could discontinue therapy over time and transition to either second-line targeted therapy or non-targeted therapy. Non-targeted therapy was assumed to consist of a mix of no treatment, topical treatment, non- targeted systemic treatment, and phototherapy. Given the lack of specificity in the definition of non-targeted therapy, as well as a lack of clarity in the performance of such therapy in a population that has failed prior attempts at treatment, there obviously is uncertainty associated with the costs and outcomes (quality of life) in this health state; these uncertainties were incorporated in our analyses as described below. All health states were assumed to have an equal hazard of death, which the model treats as a function of age alone (i.e., no increased mortality from the psoriasis disease state or treatment). The health state utilities (quality of life) were based on percent improvement in PASI score for the four response strata: 90-100, 75-89, 50-74, and less than 50. These utilities are the same across therapies in the base case. The time horizon for the base case analysis was 10 years, rather than the more standard lifetime analysis, for several reasons. First, previous economic evaluations have used a 10-year timeframe, and doing so in this study will facilitate comparison with previous analyses. Second, because we have included second-line therapy, and eventually many patients will end up on second-line treatment in a lifetime analysis, second-line treatment would likely dominate the results, taking away from our focus on first-line therapy. Thus, a 10-year time horizon provides greater focus on the effects of first-line vs. second-line treatment. We evaluated a lifetime time horizon in a scenario analysis. ©Institute for Clinical and Economic Review, 2016 Page 56 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Target Population The population of focus for this review was adult patients with moderate to severe plaque psoriasis who failed topical treatment and phototherapy. Consistent with the patient populations in the key clinical trials, the mean age of patients in the base case is 45 years and mean weight is 90 kg. Treatment Strategies The interventions included for review are those assessed in the evidence review and NMA; their administration schedules are listed in Appendix G. Each of these therapies includes an initiation period. Regimens are based on labeled dosing recommendations for all currently marketed drugs;1,130-135 dosing for brodalumab is based on the approach used in the key clinical trials.136 Key model choices and assumptions The model used a health system perspective. All future psoriasis-related healthcare costs, QALYs and LYs were discounted at 3% per year. The model was informed by several assumptions, which are represented in Table 16 along with the rationale for each assumption. ©Institute for Clinical and Economic Review, 2016 Page 57 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 16. Key model assumptions Assumption Rationale A patient cannot transition between Drug response does not show significant improvement past effectiveness (PASI improvement) levels. the trial period; discontinuation rate accounts for decline in effectiveness over time. Probability of discontinuing first-line therapy Empirical evidence indicates discontinuation rates beyond the is drug specific. initiation period differ across drugs, and differs in year 1 vs. years 2+. Probability of discontinuing newer drugs There are limited to non-existent data on discontinuation (secukinumab, ixekizumab, and brodalumab) rates for the newer agents. This assumption was evaluated in is the same as ustekinumab. a sensitivity analysis. Half of patients discontinuing first-line There are limited data on proportion of patients receiving targeted drug therapy receive second-line second-line targeted treatment, particularly in current targeted drug and remainder receive non- treatment paradigm with newer agents. This assumption was targeted drug. evaluated in sensitivity analyses. Second-line targeted therapy was assumed to There are no RCTs of second-line targeted therapy and limited be an average of all available targeted agents. data on second-line targeted therapy response in general, yet second-line treatment reflects current clinical practice. Non-targeted therapy was assumed to consist There is little evidence on the mix of treatments, costs, and of a mix of no treatment, topical treatment, patient outcomes over time in patients who do not receive non-targeted systemic treatment, and targeted therapy, as well as in patients who discontinue phototherapy. targeted therapy. Risk of death is based on age alone. Evidence suggesting that treatment of psoriasis improves survival is weak. Patients remain on first-line therapy during A full initiation period (16 weeks for adalimumab and the initiation period. apremilast, 10 weeks for infliximab, 12 weeks for all others) is needed to determine whether the drug will produce an adequate response. Subcutaneous drugs are administered in-clinic Reflects usual current clinical practice at the first visit and by the patient themselves thereafter. Economic Inputs Costs Monthly costs included those of drug acquisition, administration, clinic visits, and laboratory tests for all surviving patients. Costs for adverse events were not included in the base case analysis but were explored in a sensitivity analysis. ©Institute for Clinical and Economic Review, 2016 Page 58 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Drug acquisition costs For each cycle of the model, surviving patients are assumed to receive one of the included drug therapies. Therefore, if patients discontinued first-line targeted therapy and were still alive, they would incur costs for either a second-line targeted therapy or for non-targeted therapy. Feedback on the draft evidence report indicated that WAC is not representative of actual price paid in either public or private settings. To address this concern, we obtained data from SSR Health,25 which combines data on net US dollar sales with information on unit sales to derive net pricing at the unit level across all payer types. Data on the approved agents of interest are current through the third quarter of 2016. We estimated net prices for these agents by comparing the four-quarter (i.e., 4Q2015 – 3Q2016) rolling averages of both net prices and WAC prices per unit to arrive at an average discount from WAC. We calculated averages at the drug class level and rounded these to the nearest five percent. Finally, we applied the drug class level average to the most current WAC price for each medication to arrive at an estimated net price. Drug class level average discounts were as follows:  TNF-α: 30%  IL-17A: 40%  Anti-IL 12/23: 15%  Apremilast: 20% For brodalumab, the IL-17A agent currently under regulatory review, we estimated the launch price as the average of the WAC prices for the two other agents in this class, and then applied the 40% discount specific to IL-17A drugs. We used wholesale acquisition cost (WAC) in a scenario analysis.26 ©Institute for Clinical and Economic Review, 2016 Page 59 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 17: Drug acquisition costs Treatment Unit cost Cost of initiation Monthly cost of Cost of 1st year Source period maintenance of therapy adalimumab $1,434 $14,361 (4 mo.) $2,868 $37,305 Net price calculation* (per 40mg) apremilast $34 $7,549 (4 mo.) $1,931 $22,997 Net price calculation (per 30mg) brodalumab [$2,560] [$17,969] (3 [$2,560] [$41,009] Assumed average of (per 210mg) mo.) ixekizumab and secukinumab, with IL-17A discount etanercept $717 $17,283 (3 mo.) $2,868 $43,095 Net price calculation (per 50mg) infliximab (per $779 $16,874 (10 $1,948 $35,380 Net price calculation 100mg) wks.) ixekizumab $2,681 $21,523 (3 mo.) $2,681 $45,652 Net price calculation (per 80mg) secukinumab $2,439 $14,656 (3 mo.) $2,439 $36,607 Net price calculation (per 300mg) ustekinumab $7,514 $26,072 (3 mo.) $3,256 $55,376 Net price calculation (70% 45mg/30% 90mg) 2nd line $2,569 $8,272** (1 mo.) $2,569 $36,531 Average monthly cost of targeted drug above drugs (per cycle) non-targeted $820 n/a n/a Yu, Curr Med Res Opin therapy (per $820 2009 (inflated to 2016 cycle) dollars using medical cost inflation rate)137 *Calculated using WAC and SSR **Switching cost Infliximab and ustekinumab are dosed based on body weight. We assumed that each infliximab administration used five 100 mg vials to account for incomplete vial usage (drug wastage). Based on weight distribution data from the ustekinumab trials, we assumed that 30% of patients were greater than 100kg and therefore would receive a 90 mg rather than the standard 45 mg dose. While one recent study has indicated up to approximately 50% of patients receive the 90mg dose after dose escalations, we used the more conservative 30% estimate in our base case because dose adjustments were not included in our base case analysis, as discussed below.138 ©Institute for Clinical and Economic Review, 2016 Page 60 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents The cost of second-line targeted therapy was calculated as the average of all first-line targeted therapies. As described above in our modeling approach, this assumption was necessary to reflect real-world practice of treatment switching yet accommodate the complete lack of data on the safety and effectiveness of specific second-line treatment scenarios. A switching cost was assigned to the first month of second-line therapy to reflect the additional cost of initiation above and beyond maintenance therapy, based on the average incremental cost across first-line therapies. The cost for non-targeted therapy was derived from a study by Yu et al.137 Yu and colleagues analyzed medical care costs for patients with psoriasis using 2003 claims data, and found that incremental adjusted total cost for patients with moderate to severe psoriasis vs. mild psoriasis was $9,841 per year in 2016 US dollars. This cost is likely representative of the difference in health care cost between a patient with active moderate to severe disease and a patient who has achieved response with treatment (not including cost of targeted treatment). The costs include utilization of non-topical systemic therapies and phototherapy, outpatient visits, and hospitalization costs. While some previous economic evaluations have assumed significant hospitalization cost offsets as a result of successful treatment, the adjusted difference in hospital costs between moderate to severe patients and mild patients in the Yu study was only $119 (2007 USD). In a separate study by Feldman and colleagues comparing health care costs for patients with moderate to severe psoriasis versus those without psoriasis, inpatient costs were approximately $1000 higher and outpatient costs $2100 higher in psoriasis patients, although the differences are difficult to interpret because the majority of patients (65%) received targeted treatments.139 Foster and colleagues found no difference in hospitalization cost changes before and after initiation of a targeted therapy in treatment responders vs. non-responders.140 These studies strongly suggest that significant cost savings from avoiding hospitalizations with successful treatment are unlikely. We found no data on the health care costs for patients who had undergone targeted treatment and failed. We assumed these patients were similar to those who underwent non-targeted treatment. We did not account for extensive use of newer or more intensive non-targeted treatments; doing so would require that we assume some degree of treatment benefit (utility improvement) to the non- targeted health state, which would offset the added cost. Given the uncertainty in the cost for patients in the non-targeted therapy health state, however, the cost of non-targeted therapy was varied by +/- 50% in sensitivity analyses. Although in clinical practice patients can experience dose changes in response to changes in effectiveness or adverse effects, we did not include dose decreases or increases, because a recent study indicated that dose increases were as common as dose decreases, and the majority of dose increases were followed by dose decreases or drug discontinuation.139 For example, 41.0% of etanercept patients had a dose increase in the 12 months following drug initiation, yet 48.7% had a dose decrease; analogous results for adalimumab are 36.6% and 53.%, and for ustekinumab 35.9% ©Institute for Clinical and Economic Review, 2016 Page 61 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents and 37.4%. Furthermore, while patients may experience dose increases as treatment effectiveness wanes, treatment failures are explicitly captured in the model by transitions to second-line targeted therapy, which is reflective of the current treatment era with multiple options. Administration costs All targeted therapies in this comparison other than apremilast were injectable or infused drugs. For subcutaneous drug therapies, we assumed that the injection was administered at the first clinic visit and was self-administered by the patient thereafter. Cost per subcutaneous injection administration at a clinic, obtained from the Redbook (CPT code 96372), was $25.44. 26 Infliximab, the only drug in the analysis that requires intravenous administration, is delivered over a two-hour infusion. Each administration was assumed to cost $164.54: $136.15 for the first hour (CPT code 96413) and $28.39 for the second hour (CPT code 96415). We also included the cost of one day lost from work ($193) to account for patient time cost related to IV administration.4 There were no administration costs for the only oral medication in the analysis, apremilast. The monthly cost for administration of second-line therapy was estimated by averaging the monthly administration costs for all first-line drugs during their maintenance phases. Laboratory and clinic visit costs Due to the interaction of the targeted therapies with the immune system, many psoriasis patients require monitoring for potential infection. Some also require testing of physiologic systems, such as hepatic function. The costs for each of the laboratory tests required by one or more targeted psoriasis therapies and the schedule of laboratory tests indicated for each drug are provided in Appendix G. When possible, the indicated laboratory tests were obtained from the drug’s labeling; otherwise, they were gathered by examination of the therapeutic protocol in the pivotal trials.4 In addition to these laboratory tests, each patient was assumed to receive four physician visits per year related to the disease. Adverse event costs No previous economic analyses have indicated that adverse events significantly impact the cost effectiveness of targeted therapies in psoriasis. However, the impact of the cost of one serious adverse event, pneumonia, was included to assess the potential importance of adverse events in relation to health care costs. Pneumonia incidence was taken from the prescribing information of each drug that has already entered the market, and a meta-analysis of phase III trials for brodalumab.141 Due to non-standard terminology, the figure for each drug reflected the incidence of 'pneumonia’, 'serious infection’, or 'serious respiratory infection.’ In the case of apremilast, no mention of serious infection was found in the prescribing information, and so we assumed that it ©Institute for Clinical and Economic Review, 2016 Page 62 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents did not increase risk of pneumonia. Absolute rates, rather than placebo-adjusted rates, were used. A cost of $5,873 per hospitalized case of pneumonia was used, based on Medicare reimbursement rates.142 Productivity costs Productivity cost offsets were included in a scenario analysis rather than the base-case analysis (as in the draft report), to reflect the dominant healthcare payer perspective used in US settings. Productivity costs were derived from work productivity impact measures in RCTs of adalimumab and ixekizumab.99,102 We estimated that patients achieving a PASI 75 improvement who were employed had a 15% improvement in total work productivity (primarily presenteeism vs. absenteeism). We also estimated that 60% of patients were employed full-time.143 We liberally assumed presenteeism improvements were valued equally to absenteeism improvements, and that presenteeism effects were not already captured by quality of life (EQ-5D) measurements. The cost offset per year for a patient achieving a PASI 75 improvement was thus $4,900. We estimated a $4,400 productivity cost offset for second-line treatment based on an assumed 10% lower clinical effect of targeted drugs in second-line. Clinical Inputs Utilities Utilities for the base case scenario were obtained from an analysis of EQ-5D data in 3,231 patients enrolled in five RCTs evaluating secukinumab in moderate to severe psoriasis.27 The EQ-5D is one of the most commonly used generic health status measurement, and has good validity and reliability in various health conditions, including psoriasis. The EQ-5D includes questions across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. It was measured alongside PASI in the secukinumab RCTs, and the relationship between PASI improvement and EQ-5D was evaluated to derive the estimates shown in Table 18. These scores unfortunately were averaged across both arms of the trials (i.e., targeted therapy and placebo), prohibiting separate evaluation of utility scores in each arm of the trial. These utilities were selected because they were derived from relatively recent clinical trials, were used in a recent NICE technology appraisal of secukinumab, and are representative of utility scores derived from multiple clinical trials including thousands of patients and a variety of targeted treatments.27 We assumed the utility for the non-targeted therapy health state was 0.642, equal to the baseline utility for patients enrolled in the secukinumab trials. While the utility score for patients with PASI <50 (0.751) could have been used, patients who were receiving targeted treatment were included in this group, and their treatment, albeit moderate, likely had an upward influence on the utility score. ©Institute for Clinical and Economic Review, 2016 Page 63 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 18. Utility by health state State Utility Source144 PASI 90-100 0.906 NICE secukinumab submission PASI 75-89 0.868 NICE secukinumab submission PASI 50-74 0.835 NICE secukinumab submission PASI <50 0.751 NICE secukinumab submission Second-line therapy 0.846 Estimated Non-targeted therapy 0.642 NICE secukinumab submission The utility of second-line therapy was calculated based on estimated second-line response across all available targeted therapies. We assumed second-line treatment had a 10% absolute lower probability of achieving PASI 75;113,145,146 this was applied as a 5% decrease in PASI 90 and PASI 75- 89, and a 5% increase in PASI <50 and PASI 50-74. We then calculated the utility for each drug and averaged across drugs. Due to similar adverse event profiles between drugs and the absence of their utility evaluation in other cost-effectiveness analyses in psoriasis, we did not include any adverse event-associated disutilities. It is very unlikely that inclusion of these disutilities would have any meaningful effect on results given the low rate of serious adverse events for the drugs evaluated in this study. Clinical probabilities Patient response to first-line targeted therapy was derived from the network meta-analysis (NMA) (see Appendix F). In the NMA, clinical trials of ustekinumab using 45mg and 90mg dosing were combined given the similar response rates; our analysis thus reflects this assumption. A re- evaluation of PHOENIX 1 and 2 trials by Lebwohl and colleagues found the 28-week PASI 75 response was 74.2% in patients weighing >100kg on the 90mg dose, and 76.9% in patients weighing 100kg or less on the 45mg dose.53 PASI 75 from the NMA at 12 weeks is 69.4% for both doses combined. In the PHOENIX 1 and 2 trials, PASI 75 increased by ~4% from the end-of-RCT 12-week measurement to the uncontrolled 28-week measurement; thus, the 69.4% PASI 75 12-week response used in the model is likely to be reasonably reflective of the effectiveness expected for weight-based dosing outcomes at 12 weeks. Several recent studies provide drug-specific discontinuation rates. Discontinuation rates during the first year after the initiation period were derived from a study by Feldman et al., who conducted a retrospective analysis using claims data for 4,309 psoriasis patients from 2007 through 2012.141 The majority of patients received etanercept or adalimumab, and a small number (N=195) received ustekinumab. Over the follow-up period, 35%, 27%, and 16% of etanercept, adalimumab, and ©Institute for Clinical and Economic Review, 2016 Page 64 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents ustekinumab patients discontinued therapy. We assumed the discontinuation rate for apremilast was the same as for etanercept, the rate for infliximab was between that of etanercept and adalimumab (30%), and that secukinumab, ixekizumab, and brodalumab had the same rate as ustekinumab (16%). Discontinuation rates after year one were estimated from a long term Danish cohort study (DERMBIO). 147 The study evaluates an 1867 treatment series (adalimumab n = 774, etanercept n = 449, infliximab n = 253, ustekinumab n = 391) administered in 1277 patients for up to 10 years. Based on a multivariate Cox model of treatment-naïve patients, we estimated approximately 15% of adalimumab, etanercept, and infliximab patients discontinued treatment each year, while 5% of ustekinumab patients did. We assumed secukinumab, ixekizumab, and brodalumab had the same discontinuation rates as ustekinumab. Another large long-term cohort study, the Psoriasis Longitudinal Assessment and Registry (PSOLAR), followed 4,000 patients with new starts for targeted agents. The findings were generally similar to the DERMBIO cohort study, although adjusted discontinuation curves were not provided.148 While long-term data are not available for ixekizumab and brodalumab because they are newer to market, a recent study presented in fall 2016 suggests secukinumab patients who initially respond maintain that response up to four years.24 Based on the DERMBIO study analysis of patients who had previously received a targeted treatment, we estimated the discontinuation rate from second-line therapy was 15% per year. An important question is what proportion of patients who discontinue therapy because of non- response then switch to another targeted agent rather than discontinue targeted therapy altogether. A study by Doshi et al. in the Medicare population from 2009 to 2012 (N=2,707) found that approximately 37% of patient who discontinued a targeted therapy restarted or switched.149 Foster et al., in a study of 2,146 commercially insured patients from 2010 through 2011, found that approximately 50% of patients who failed treatment did not continue with a targeted therapy.140 While the more recent availability of additional targeted agents with higher response rates may increase the rate of second-line targeted treatment, we assumed in our base case that 50% of patients who discontinued targeted treatment because of non-response would go on to second-line therapy; this estimate was varied from 25% to 75% in sensitivity analyses. Model validation We used several approaches to validate the model. First, we provided information on the preliminary model approach, inputs, and results to the manufacturers of the targeted drugs. Feedback from these companies resulted in the identification of an error in drug cost, and revisions to the model including addition of drug-specific discontinuation rates, modification of average patient weight, and inclusion of a switching cost for second-line targeted drug treatment. We also adjusted our base-case drug costs from WAC to discounts off WAC to reflect real-world pricing, ©Institute for Clinical and Economic Review, 2016 Page 65 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents based on net price data from SSR.25 We also added scenario analyses to assess the patient-centered impacts of achieving PASI 100 and improvement in work productivity. Second, we developed a simple ‘back-of-the-envelope’ model to assess one-year clinical and economic outcomes based on first-line targeted therapy only. The results of the two models were similar. Third, we compared our results with an independently developed (unpublished) model based on the York model framework.129 The results from these two models were generally similar. Lastly, we conducted various sensitivity and scenario analyses, as described below, to assess model behavior. Sensitivity analyses We conducted one-way sensitivity analyses to assess the impact of model input uncertainty on the results. Given the numerous potential comparisons, we selected four to highlight the importance of parameter (evidence) uncertainty: 1) infliximab vs. non-targeted therapy, 2) ixekizumab vs. non- targeted therapy, 3) ixekizumab vs. infliximab, and 4) ixekizumab vs. etanercept. These comparisons were selected because infliximab had a favorable cost-effectiveness ratio compared to non-targeted therapy, etanercept was a common comparator in head-to-head trials, and ixekizumab is representative of drugs with higher efficacy and cost and a relatively low discontinuation rate. Laboratory testing costs were not varied in the one-way sensitivity analyses, because their effects were extremely small in all models. Although productivity costs were not included in the base case analysis, we included a range of productivity cost offsets in the one-way sensitivity analyses. Scenario analyses We also conducted four specific scenario analyses: 1. Using WAC drug prices rather than discounted net prices 2. Including productivity costs 3. Estimating the impact of accounting for PASI 100 attainment 4. Using a lifetime horizon 6.4 Cost-Effectiveness Model: Results Base Case Results Total costs, QALYs, and LYs for each therapy accrued over the 10-year time horizon of the model are shown in Table 19 below. Additionally, we show the incremental cost-effectiveness ratio (ICER) for each of the targeted therapies compared to non-targeted therapy. ©Institute for Clinical and Economic Review, 2016 Page 66 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 19. Results for the base case Cost QALYs LYs ICER vs. non-target non-targeted $88,086 5.531 8.64 adalimumab $208,881 6.649 8.64 $108,040 apremilast $161,741 6.353 8.64 $89,610 brodalumab* $240,398 7.151 8.64 $94,030 etanercept $198,519 6.469 8.64 $117,769 infliximab $203,532 6.776 8.64 $92,715 ixekizumab $254,287 7.187 8.64 $100,389 secukinumab $221,704 7.018 8.64 $89,843 ustekinumab $269,843 6.930 8.64 $129,904 *Results for brodalumab are tentative, as pricing is not currently available The base-case results indicate that treatment with targeted drugs, over a 10-year time frame that includes drug discontinuation, leads to QALY improvements ranging from 0.8 (apremilast) to nearly 1.7 (ixekizumab, brodalumab). The base-case results shown in Table 19 are also graphed in Figure 6. Drugs that are farther to the right provide the greatest clinical benefit, and drugs higher on the y-axis are more expensive. This chart shows a general trend towards better results with more expensive therapies. Secukinumab is the most cost-effective agent versus non-targeted therapy. However, estimated cost-effectiveness ratios for all the drugs fall into a relatively narrow range, with IL-17A targeted drugs generally providing more QALY gains than TNF-α agents, but at higher cost. Ustekinumab appears above the slope of the line formed by more cost-effective competitors, indicating that it is estimated to provide fewer QALYs at higher cost, primarily as a result of including higher dosing (90mg) for heavier patients receiving this drug. ©Institute for Clinical and Economic Review, 2016 Page 67 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 6: Cost-effectiveness plane for all comparators (base case)* *Results for brodalumab are tentative, as pricing is not available We also calculated incremental cost-effectiveness ratios for etanercept compared to the IL-17A targeted drugs (Table 20). We selected these comparisons because etanercept was the only TNF-α for which we felt we had adequate evidence to distinguish its overall effectiveness (lower) compared to all IL-17A targeted drugs. In addition, as the least expensive biologic agent, our analysis will help inform policymakers as to whether the incremental cost of IL-17A targeted drugs over etanercept represents good long-term value. The incremental cost-effectiveness ratios versus etanercept ranged from approximately $42,000/QALY for secukinumab up to approximately $78,000 for ixekizumab. Table 20. Incremental cost-effectiveness ratios for IL-17A targeted drugs compared to etanercept Cost/QALY Versus Etanercept Brodalumab $61,396 Ixekizumab $77,686 Secukinumab $42,190 Sensitivity Analysis Results The impacts of varying each of the parameters in the model over ranges reflecting their uncertainty are shown in Figure 7 for infliximab compared to non-targeted therapy. The cost and utility of non- targeted therapy, drug costs, and the utility of targeted treatment were associated with the greatest uncertainty in the model. In particular, non-targeted therapy considerations are important ©Institute for Clinical and Economic Review, 2016 Page 68 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents given the lack of data on the performance of such therapy in a setting where many patients have already failed prior use. However, the incremental results for infliximab versus non-targeted therapy never exceeded the commonly-cited threshold of $150,000 per QALY gained, ranging from approximately $73,000 to $127,000/QALY gained across the range of non-targeted therapy cost and utility. Figure 7. One-way sensitivity analysis: Infliximab versus non-targeted therapy Figure 8 demonstrates the impact of varying these same parameters on the cost effectiveness of ixekizumab versus non-targeted therapy. Similar to the infliximab evaluation above, the greatest uncertainty arises from the cost and utility for non-targeted therapy, drug cost, and targeted treatment utility. The incremental cost-effectiveness ratio ranged from approximately $77,000 to $136,000/QALY gained across the range of assumed drug prices. ©Institute for Clinical and Economic Review, 2016 Page 69 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 8. One-way sensitivity analysis: Ixekizumab versus non-targeted therapy We also conducted one-way sensitivity analyses of ixekizumab versus infliximab. The results of varying both drug-specific and non-drug-specific parameters can be seen in Figure 9. Given that the outcomes (QALYs) of the two drugs are closer than between non-targeted and targeted therapies, the incremental cost-effectiveness ratio is more sensitive to parameter uncertainty. We see that a variety of parameters are influential, including the cost of each drug, the cost and utility of non- targeted therapy, each drug’s discontinuation rate, and the relative effectiveness. The incremental cost-effectiveness, which ranges from approximately $27,000 to $220,000 across the assumed range of ixekizumab prices. ©Institute for Clinical and Economic Review, 2016 Page 70 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 9. One-way sensitivity analysis: Infliximab versus ixekizumab Lastly, we evaluated ixekizumab vs. etanercept. The results were generally similar to the ixekizumab vs. infliximab comparison, but overall there was less uncertainty (Fig. 10). ©Institute for Clinical and Economic Review, 2016 Page 71 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 10. One-way sensitivity analysis: etanercept versus ixekizumab In summary, the sensitivity analyses show that, as expected, drug costs have the greatest impact on the uncertainty in the value of targeted agents because of their relative importance and uncertainty. Another important source of uncertainty is the cost and quality of life associated with non-targeted therapy. Lastly, depending on the comparison, drug discontinuation rates are important contributors to uncertainty. Scenario Analyses Results when productivity costs are taken into account Table 21 shows the results of the scenario in which productivity cost offsets, as described in the Methods above, are included. The ICERs in this scenario analysis – each roughly $20,000 lower than ©Institute for Clinical and Economic Review, 2016 Page 72 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents the base case – demonstrate the potentially significant role that productivity gains might play in the value of targeted agents for psoriasis. Table 21: Results comparing each drug to non-targeted therapy with productivity offset included Cost QALYs LYs ICER vs. non-target Non-targeted $88,086 5.531 8.64 - Adalimumab $185,883 6.649 8.64 $87,470 Apremilast $144,026 6.353 8.64 $68,057 Brodalumab $208,489 7.151 8.64 $74,331 Etanercept $178,838 6.469 8.64 $96,781 Infliximab $178,536 6.776 8.64 $72,641 Ixekizumab $221,812 7.187 8.64 $80,774 Secukinumab $191,971 7.018 8.64 $69,851 Ustekinumab $241,611 6.930 8.64 $109,726 Results when PASI 100 is taken into account We also assessed the impact of attaining PASI 100, by stratifying the PASI 90+ group into PASI 90-99 and PASI 100, which necessitated the use of utility estimates derived using a novel instrument based on the EQ-5D designed specifically for psoriasis (the EQ-PSO).150,120When we switched to using these utilities, the ratio for ixekizumab relative to non-targeted therapy, for example, increased to $170,163 per QALY gained, because the gains relative to baseline are smaller for this utility set. When we then used drug-specific utilities that accounted for the proportion of patients achieving PASI 100 (estimated for drugs without PASI 100 data), the incremental cost-effectiveness ratio for ixekizumab was $151 per QALY. We conclude from this scenario analysis that the impact of achieving PASI 100 relative to PASI 90-99 is unlikely to meaningfully impact the overall economic value of psoriasis treatments. Results when non-discounted WAC drug costs are used Our base case uses class-specific discounts from WAC rounded to the nearest 5%. Appendix G shows the results of the model when WAC is used to price each drug. As suggested by the one-way sensitivity analyses, these results and their much higher ICERs reinforce that drug prices are the largest determinant of cost-effectiveness. Lifetime time horizon results ©Institute for Clinical and Economic Review, 2016 Page 73 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Our base case and all scenarios listed above use a 10-year time horizon. Appendix Table G8 shows the results of using a lifetime time horizon. As more time is spent on second-line and non-targeted therapy in this scenario, the ICERs are more similar to each other and the contributions of the first- line agents become harder to discern compared to the 10-year base case analysis. Threshold Analyses To estimate the maximum prices that would correspond to given willingness to pay thresholds, we systematically altered the price of each drug in the base case scenario in order to match that threshold. Prices for each drug that would achieve cost-effectiveness thresholds ranging from $50,000 to $150,000 per QALY gained are presented in Table 22, along with the wholesale acquisition cost per tablet or vial. In many cases, discounts from WAC would be required to achieve cost-effectiveness thresholds of $50,000 or $100,000 per QALY, while premiums on price could be charged for some drugs and remain below $150,000 per QALY. Table 22. Threshold analysis for price per drug for psoriasis treatments $50k / $100k / $150k / WAC price per QALY QALY QALY vial* Adalimumab (per 40mg) $549.08 $1,311.40 $2,073.74 $2,048.54 Apremilast (per 30mg)*** $2.24 $42.94 $83.64 $43.10 Brodalumab (per 210mg) [$1,552.95] [$2,696.61] [$3,840.28] [$4,266.79]** Etanercept (per 50mg) $143.37 $566.68 $989.98 $1,024.22 Infliximab (per 100mg) $318.99 $857.54 $1,395.18 $1,113.27 Ixekizumab (per 80mg) $1,550.08 $2,672.66 $3,795.25 $4,469.00 Secukinumab (per 300mg) $1,489.47 $2,680.73 $3,872.00 $4,064.57 Ustekinumab (per 45mg) $3,164.93 $5,886.50 $8,608.05 $8,840.22 *Wholesale acquisition cost as of October 28, 2016 **Brodalumab pricing is assumed, as not yet available ***Pill ©Institute for Clinical and Economic Review, 2016 Page 74 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 6.5 Potential Budget Impact We also used the cost-effectiveness model to estimate the potential total budgetary impact of the two novel treatments for psoriasis patients, based on assumed patterns of product uptake: ixekizumab (approved in March 2016) and brodalumab (not yet approved). We did not include the other therapies modeled above in this potential budget impact analysis, given their established presence on the market. Potential Budget Impact Model: Methods We used results from the same model employed for the cost-effectiveness analyses to estimate total potential budget impact. Potential budget impact was defined as the total incremental cost of using the new therapy rather than non-targeted therapy for the treated population, calculated as incremental health care costs (including drug costs) minus any offsets in these costs from averted health care events. All costs were undiscounted and estimated over one- and five-year time horizons. The five-year timeframe was of primary interest, given the potential for cost offsets to accrue over time. The potential budget impact analysis included the entire candidate population for treatment, which included adults with moderate to severe plaque psoriasis who are taking a biologic agent for psoriasis for the first time. To estimate the size of the potential candidate population for treatment with brodalumab or ixekizumab, we first determined the estimated incidence of psoriasis in the US. We used incidence rather than prevalence because we were interested only in patients who were taking a biologic for the first time. Psoriasis incidence in the United States has been estimated at 78.9 cases per 100,000 persons.28 The proportion of psoriasis patients with plaque psoriasis has been estimated to be 79%.28 Helmick found that 18.2% of psoriasis patients have moderate-to- severe disease, defined as involving greater than 3% of body surface area.3 Applying these proportions to the projected 2016 U.S. population results in an estimate of approximately 36,750 incident cases of moderate-severe plaque psoriasis in the US per year, or approximately 183,750 incident cases over five years, assuming equal incidence rates for each of the five years in our analysis. This was assumed to be the candidate population for treatment with these novel agents. ICER’s methods for estimating potential budget impact and calculating value-based benchmark prices are described in detail elsewhere. Briefly, our calculations assume that the utilization of new drugs occurs without any payer, provider group, or pharmacy benefit management controls in place, to provide an estimate of “unmanaged” drug uptake by five years after launch. In general, we examine six characteristics of the drug or device and the marketplace to estimate “unmanaged” uptake. These characteristics are listed below: ©Institute for Clinical and Economic Review, 2016 Page 75 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents  Magnitude of improvement in clinical safety and/or effectiveness  Patient-level burden of illness  Patient preference (ease of administration)  Proportion of eligible patients currently being treated  Primary care versus specialty clinician prescribing/use  Presence or emergence of competing treatments of equal or superior effectiveness Based on our assessment of these criteria, we assign a new drug or device to one of four categories of unmanaged drug uptake patterns: 1) very high (75% uptake by year 5); 2) high (50% uptake by year 5); 3) intermediate (25% uptake by year 5); and 4) low (10% uptake by year 5). In this analysis, we assumed a 10% uptake pattern for ixekizumab and a 10% uptake for brodalumab in the eligible population. We assumed that uptake would be low for ixekizumab and brodalumab because they would be the second and third 1L-17 inhibitor therapies for psoriasis patients to enter what is considered “an increasingly saturated market.”152 Using this approach to estimate potential budget impact, we then compared our estimates to a budget impact threshold that represents a potential trigger for policy mechanisms to improve affordability, such as changes to pricing, payment, or patient eligibility. As described in ICER’s methods presentation, this threshold is based on an underlying assumption that health care costs should not grow much faster than growth in the overall national economy. From this foundational assumption, our potential budget impact threshold is derived using an estimate of growth in US gross domestic product (GDP) +1%, the average number of new drug approvals by the FDA each year, and the contribution of spending on retail and facility-based drugs to total health care spending. Calculations are performed as shown in Table 23. ©Institute for Clinical and Economic Review, 2016 Page 76 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 23. Calculation of Potential Budget Impact Threshold Item Parameter Estimate Source 1 Growth in US GDP, 2015-2016 (est.) +1% 3.75% World Bank, 2015 2 Total health care spending ($) $3.08 trillion CMS NHE, 2014 3 Contribution of drug spending to total health care 13.3% CMS National Health Expenditures spending (%) (NHE), Altarum Institute, 2014 4 Contribution of drug spending to total health care $410 billion Calculation spending ($) (Row 2 x Row 3) 5 Annual threshold for net health care cost growth $15.4 billion Calculation for ALL new drugs (Row 1 x Row 4) 6 Average annual number of new molecular entity 34 FDA, 2014 approvals, 2013-2014 7 Annual threshold for average cost growth per $452 million Calculation individual new molecular entity (Row 5 ÷ Row 6) 8 Annual threshold for estimated potential budget $904 million Calculation impact for each individual new molecular entity (doubling of Row 7) For 2015-16, therefore, the five-year annualized potential budget impact threshold that should trigger policy actions to manage affordability is calculated to total approximately $904 million per year for new drugs. Potential Budget Impact Model: Results Table 24 presents the potential budget impact of one year and five years of brodalumab and ixekizumab in the candidate population, assuming the uptake patterns previously described. Results are presented for both one-year and five-year time horizons. Results from the potential budget impact model showed that, with the uptake pattern assumptions mentioned above, an estimated 3,675 individuals would receive brodalumab in the first year, and an estimated 3,675 would receive ixekizumab in the first year. After one year of treatment with brodalumab, with net annual costs of approximately $32,700 per patient, one-year budget impact is estimated to be approximately $120.3 million. After one year of treatment with ixekizumab, net annual costs were estimated as approximately $37,400 per patient, and one-year budget impact as approximately $137.3 million. ©Institute for Clinical and Economic Review, 2016 Page 77 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Over the entire five-year time horizon, we estimate that “unmanaged” uptake would lead to approximately 18,375 persons taking brodalumab and 18,375 taking ixekizumab. Across the full five-year time horizon, the weighted potential budgetary impact (i.e., adjusted for differing periods of drug utilization and associated cost-offsets) is approximately $65,200 per patient taking brodalumab, and approximately $72,400 per patient taking ixekizumab. Total potential budgetary impact of brodalumab over five years is approximately $1.2 billion, with an average budget impact per year of approximately $240 million. For ixekizumab, total potential budgetary impact over five years is approximately $1.3 billion, with an average budget impact per year of approximately $266 million. The annualized potential budget impact of brodalumab is 27% of the budget impact threshold of $904 million for a new drug, while the annualized potential budget impact of ixekizumab is 29% of the threshold. Table 24. Estimated Total Potential Budget Impact (BI) of Brodalumab and Ixekizumab for Treatment of Plaque Psoriasis Analytic Horizon = 1 Year Analytic Horizon = 5 Years Eligible Number Annual BI Total BI Number Weighted BI Average BI Population Treated per Patient* (millions) Treated per Patient* per year (millions) Brodalumab 183,750 3,675 $32,700 $120.3 18,375 $65,200 $239.8 Ixekizumab 183,750 3,675 $37,400 $137.3 18,375 $72,400 $266.0 *Weighted budget impact calculated by subtracting cost offsets from drug costs for one-year horizon. For five-year horizon, drug costs and cost offsets apportioned assuming 20% of patients in uptake target initiate therapy each year. Those initiating in year 1 receive full drug costs and cost offsets, those initiating in year 2 receive 80% of drug costs and cost offsets, etc. Figure 12 shows the relationship between varying possible uptake patterns and potential budget impact for each drug. The vertical axis shows the annualized potential budget impact, and the horizontal axis represents the percentage of eligible patients treated over a five-year period. The colored lines demonstrate how quickly the annual potential budget impact increases with increasing percentages of patients treated at the net prices used in this analysis. As can be seen in Figure 12, potential budget impact of brodalumab is estimated to be below an annual threshold of $904 million until approximately 38% of eligible patients are treated. Approximately 34% of eligible patients could be treated with ixekizumab before potential budget impact reaches $904 million ©Institute for Clinical and Economic Review, 2016 Page 78 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure 12. Potential Budget Impact of brodalumab and ixekizumab treatment for psoriasis patients over different assumed product uptake patterns $3.0 $2.8 Ixekizumab $2.6 $2.4 Brodalumab Annual Budget Impact (Billions) $2.2 $2.0 $1.8 $1.6 $1.4 $1.2 $1.0 $0.8 $0.6 $0.4 $0.2 $0.0 0% 25% 50% 75% 100% % Eligible Patients Treated Note: Colored lines represent the annualized budget impact of different uptake patterns (eligible patients treated) at the net price of each 6.6 Value-based Benchmark Prices Our value-based benchmark prices for each psoriasis treatment are provided in Table 25. As noted in the ICER methods document, the value-based benchmark price for a drug is defined as the price range that would achieve cost-effectiveness ratios between $100,000 and $150,000 per QALY gained. As shown in the table, with the exception of adalimumab, apremilast, and infliximab, all drugs would require discounts from current WAC prices to fall within ICER’s threshold value range of $100,000 to $150,000/QALY. Importantly, however, our estimates of net prices bring all of the drugs of interest either within this threshold value range or generate cost-effectiveness ratios that are already <$100,000 per QALY gained. ©Institute for Clinical and Economic Review, 2016 Page 79 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table 25. Value-based price benchmarks for all psoriasis targeted treatment regimens Discount from Cost to achieve Cost to achieve Net price* WAC* WAC to reach $100k/QALY $150K/QALY WTP threshold Adalimumab 36% to +1% $1,433.98 $2,048.54 $1,311.40 $2,073.74 (40mg) increase Apremilast 0.4% to +94% $34.48 $43.10 $42.94 $83.64 (30mg) increase Brodalumab $2,560.07** $4,266.79** $2,696.61 $3,840.28 10% to 37% (210mg) Etanercept $717.11 $1,024.44 $566.68 $989.98 3% to 45% (50mg) Infliximab 23% to +25% $779.24 $1,113.27 $857.54 $1,395.18 (100mg) increase Ixekizumab $2,681.40 $4,469 $2,672.66 $3,795.25 15% to 40% (80mg) Secukinumab $2,438.74 $4,064.57 $2,680.73 $3,872 5% to 34% (300mg) Ustekinumab $7,514.19 $8,840.22 $5,886.50 $8,608.05 3% to 33% (45mg) *Net price or WAC per vial/pill **Assumed net price/WAC 6.7 Summary and Comments Limitations and Discussion We have attempted to model psoriasis treatment to both reflect clinical practice and accommodate the limits of available data. The latter necessity has placed some restrictions on how accurately we can model the course of psoriasis treatment. There are four major limitations of our analyses. First, the course and effects of therapy sequencing is not clear – we did not identify a single RCT of a targeted drug in the second-line setting. We have assumed that after first-line therapy, half of patients take up a second-line targeted therapy while half de-escalate therapy and move to non- targeted therapy. While we weighted all first-line agents equally for purposes of estimating the costs and utility of second-line therapy, there is no doubt that some agents are preferred over others as second-line treatment. Because there are limited data to understand second-line therapy choice, we explored the effect of our assumptions on the results in sensitivity analyses. Given the importance of second-line effectiveness, controlled trials of targeted agents in the second-line setting should be a high research priority for private and public research organizations. ©Institute for Clinical and Economic Review, 2016 Page 80 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents The uncertainty around course of therapy extends to the pattern of drug dose escalation and holidays. While we know that real world drug dosing varies from clinical trials, available data on the relationship between dose changes and effectiveness are limited. We have therefore built our model without the possibility of drug holidays as a conservative assumption which reports on the maximum number of doses possible under the labeled regimen. To balance this somewhat, we have not included any dose escalation—another known phenomenon that both contradicts labeled dosing recommendations and which is poorly characterized in the scientific literature. On a related note, long-term data on response maintenance for the newer agents will be needed. Second, we would have preferred direct utility elicitation data from clinical trials. Instead, we have had to surmise quality of life from improvements in PASI score. We believe that this is not an invalid method, but the uncertainty that it introduces into the model is greater than would be seen in a model that included direct patient reports of utility. In addition, more severe disease suffered by racial and ethnic minority patients may not be captured in model utilities. Third, targeted agents in the psoriasis clinical area have seen significant drug price increases recently. At the same time, rebates for these drugs are large and variable. Because drug rebates are not publicly available, yet we desired to provide analyses that were reflective of real-world decisions that healthcare payers are facing, we utilized a novel source to estimate the general size of drug rebates within drug class. There is uncertainty in the size of these rebates, and we encourage policy makers to consider the threshold prices provided in Table 25. Fourth, another major limitation of the analyses was uncertainty in the costs and quality of life effects of non-targeted therapy, which was assumed to consist of a mix of no treatment and various non-targeted treatments. We assumed patients in the non-targeted therapy health state had the same quality of life as at baseline in the clinical trials; this assumption could bias results in favor of targeted therapies by underestimating the quality of life in the non-targeted health state. We also estimated that patients in the non-targeted health state had approximately $10,000 in annual healthcare costs attributable to moderate/severe psoriasis; we believe this is a reasonable estimate given our definition of non-targeted therapy. Including specific interventions in the non-targeted arm would likely increase costs (biasing in favor of targeted agents) but also likely improve quality of life (biasing against targeted agents). We believe we have made reasonable compromises in our estimates, and findings of one-way sensitivity analyses suggest that cost-effectiveness of targeted vs. non-targeted therapy remains below $150,000 per QALY across a range of assumptions. We nevertheless encourage decision makers to consider the uncertainty in results related to the cost and quality of life of non-targeted therapy. There are a variety of other limitations that should be noted. We did not explicitly model patients with psoriatic arthritis. However, since 20%-30% of patients enrolled in the clinical trials were diagnosed with psoriatic arthritis, our results are relevant for plaque psoriasis populations with ©Institute for Clinical and Economic Review, 2016 Page 81 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents similar proportions of patients with comorbid psoriatic arthritis. Given that quality of life improvements are very likely to be greater in patients with psoriatic arthritis compared to the mixed population we modeled, the value of targeted agents in patients with psoriatic arthritis is expected to be greater on average. We included only one serious adverse event (upper respiratory tract infection/pneumonia) to explore the potential impact of adverse events on value. Similar to previous economic analyses, we found that serious adverse events play only a small role in the overall value of targeted agents, because they are relatively rare and generally similar across agents. It is worth noting that infliximab is the only IV administered drug considered here. Although we included patient time costs associated with infusions, other patient-focused considerations such as convenience and out of pocket expenses should be considered in decision making. Biosimilars have been FDA-approved for adalimumab, etanercept, and infliximab, although none are currently available on the market. We did not attempt to include the future impact of these agents on the value of targeted agents in psoriasis because clinical data is limited and, more importantly, drug pricing is not available. However, the threshold prices presented above provide a reference point for value-based pricing of biosimilars. Lastly, there were multiple public comments about the appropriateness of using QALYs to assess the value of drug therapies. It is worth noting that QALYs are a patient-centered outcome. In this study, our QALY estimates were derived from a measure (the EQ-5D) that captures the following five domains of patient quality of life: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Arguably, all of these domains are highly relevant for patients with psoriasis. And importantly, if quality of life benefits were not accounted for in psoriasis treatment, targeted agents would have little to no value based on current evidence. Conclusion There are three key findings from our analyses. First, all of the targeted drugs had reasonably good value for money compared to non-targeted therapy, using our estimated, discounted drug costs. The value of targeted agents is driven primarily by their meaningful impact on patient quality of life, and secondarily by offsetting other costs of care such as clinic visits and use of non-targeted therapies. While there are multiple sources of uncertainty, primarily caused by data limitations, this finding is robust using our base-case drug prices. Second, despite the somewhat similar cost-effectiveness ratios vs. non-targeted therapy, there were important differences in the total amount of patient benefit (measured as QALYs) that could be gained for each drug. Drugs with high first-line efficacy and low discontinuation rates provide the greatest patient benefit, despite the availability of second-line therapy for those who failed ©Institute for Clinical and Economic Review, 2016 Page 82 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents first-line treatment. There are several reasons for this. First, not all patients who fail first-line therapy will continue to second-line therapy, and potential patient benefit is lost. Second, initiating second-line therapy incurs the added drug cost of another initiation period. Finally, although there is a paucity of data, it appears that second-line therapy may be slightly less effective than first-line treatment with the same drug. Third, the newer IL-17A targeted agents provide good economic value in relation to etanercept. The lower initial effectiveness of etanercept, high long-term discontinuation rates, and the need for more expensive second-line therapy decrease its overall value despite lower initial drug cost. In summary, our analyses suggest that if health care payers are able to achieve significant drug rebates, the most effective (and most expensive) targeted drugs provide the greatest benefit to psoriasis patients at a reasonable economic value. ©Institute for Clinical and Economic Review, 2016 Page 83 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 7. Summary of the Votes and Considerations for Policy 7.1 About the New England CEPAC Process During New England CEPAC public meetings, the New England CEPAC Panel deliberates and votes on key questions related to the systematic review of the clinical evidence, an economic analysis of the applications of treatments under examination, and the supplementary information presented. Panel members are not pre-selected based on the topic being addressed and are intentionally selected to represent a range of expertise and diverse perspectives. Acknowledging that any judgment of evidence is strengthened by real-life clinical and patient perspectives, subject matter experts are recruited for each meeting topic and provide input to New England CEPAC Panel members before the meeting to help clarify their understanding of the different interventions being analyzed in the evidence review. The same clinical experts serve as a resource to the New England CEPAC Panel during their deliberation, and help to shape recommendations on ways the evidence can apply to policy and practice. At each meeting, after the New England CEPAC Panel votes, a policy roundtable discussion is held with the New England CEPAC Panel, clinical experts, and representatives from payers and patient groups. The goal of this discussion is to bring stakeholders together to apply the evidence to guide patient education, clinical practice, and coverage and public policies. Participants on policy roundtables are selected for their expertise on the specific meeting topic, are different for each meeting, and do not vote on any questions. At the November 18, 2016 meeting, the New England CEPAC Panel discussed issues regarding the application of the available evidence to help patients, clinicians, and payers address important questions related to the use of targeted immunomodulators for the treatment of patients with moderate-to-severe chronic plaque psoriasis. Following the evidence presentation and public comments (public comments from the meeting can be accessed here, starting at 1:27:14), the New England CEPAC Panel voted on key questions concerning the comparative clinical effectiveness and comparative value of treatment options for moderate-to-severe chronic plaque psoriasis. These questions are developed by the ICER research team for each assessment to ensure that the questions are framed to address the issues that are most important in applying the evidence to support clinical practice, medical policy decisions, and patient decision-making. The voting results are presented below, along with comments reflecting considerations mentioned by New England CEPAC Panel members during the voting process. In its deliberations and votes related to value, the New England CEPAC Panel made use of a value assessment framework with four different components of “long term value for money,” a concept ©Institute for Clinical and Economic Review, 2016 Page 84 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents that represents the long-term perspective, at the individual patient level, on patient benefits with a given intervention and the incremental costs to achieve those benefits. The four components of long term value for money are comparative clinical effectiveness, estimated incremental cost- effectiveness, other benefits or disadvantages, and contextual considerations regarding the illness or therapy. There are four elements to consider when deliberating on long term value for money: 1. Comparative clinical effectiveness is a judgment of the overall difference in clinical outcomes between two interventions (or between an intervention and placebo), tempered by the level of certainty possible given the strengths and weaknesses of the body of evidence. The New England CEPAC uses the ICER Evidence Rating Matrix as its conceptual framework for considering comparative clinical effectiveness. 2. Estimated incremental cost-effectiveness is the average per-patient incremental cost of one intervention compared to another to achieve a desired “health gain,” such as an additional stroke prevented, case of cancer diagnosed, or gain of a year of life. Alternative interventions are compared in terms of cost per unit of effectiveness, and the resulting comparison is presented as a cost-effectiveness ratio. Relative certainty in the cost and outcome estimates continues to be a consideration. As a measure of cost-effectiveness, ICER follows common academic and World Health Organization (WHO) standards by using cost per quality-adjusted life years (QALYs) and adopting thresholds at $100,000 per QALY and $150,000 per QALY as guides to reasonable ratios for cost-effectiveness. 3. Other benefits or disadvantages refers to any significant benefits or disadvantages offered by the intervention to the individual patient, caregivers, the delivery system, other patients, or the public that would not have been considered as part of the evidence on comparative clinical effectiveness. Examples of other benefits include better access to treatment centers, mechanisms of treatment delivery that require fewer visits to the clinician’s office, treatments that reduce disparities across various patient groups, and new potential mechanisms of action for treating clinical conditions that have demonstrated low rates of response to currently available therapies. Other disadvantages could include increased burden of treatment on patients or their caregivers. For each intervention evaluated, it will be open to discussion whether other benefits or disadvantages such as these are important enough to factor into the overall judgment of care value. There is no quantitative measure for other benefits or disadvantages. 4. Contextual considerations include ethical, legal, or other issues (but not cost) that influence the relative priority of illnesses and interventions. Examples of contextual considerations ©Institute for Clinical and Economic Review, 2016 Page 85 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents include whether there are currently any existing treatments for the condition, whether the condition severely affects quality of life or not, and whether the condition affects priority populations. There is no quantitative measure for contextual considerations. 7.2 Clinical Effectiveness Voting Results 1) Is the evidence adequate to demonstrate that the net health benefit of apremilast is as good as that provided by any of the TNFα inhibitors? Yes: 0 votes No: 14 votes Comments: Members of the New England CEPAC unanimously voted that the evidence was not adequate to demonstrate that the net health benefit of apremilast is as good as provided by any of the TNFα inhibitors because there were no direct comparisons and the results of the network meta-analysis suggested at least comparable if not better effectiveness for the TNFα inhibitors versus apremilast. 2) Is the evidence adequate to distinguish the net health benefit among the IL-17A targeted drugs secukinumab, ixekizumab, and brodalumab? Yes: 0 votes No: 14 votes Comments: Members of the New England CEPAC unanimously voted that the evidence was not adequate to distinguish the net health benefit among the IL-17A drugs given the absence of direct comparative evidence and their similar performance in the network meta- analysis. 2a) Is the evidence adequate to demonstrate that the net health benefit of IL-17A drugs as a class is better than that provided by adalimumab? Yes: 5 votes No: 9 votes Comments: In discussing the evidence, clinical experts emphasized that concomitant clinical conditions such as psoriatic arthritis (e.g., with axial disease or uveitis) might influence the ©Institute for Clinical and Economic Review, 2016 Page 86 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents choice by a clinician for adalimumab versus an anti-IL-17A agent. It was agreed that the results of this vote should be viewed as excluding important considerations of co- morbidities and co-conditions that might strongly affect the net health benefit for IL-17A drugs versus TNFα inhibitors. Members of the New England CEPAC were split in their vote. One member of the New England CEPAC who voted “no” felt the indirect comparisons left too much uncertainty of the magnitude of relative benefit of IL-17As. One member of the New England CEPAC who voted “yes” agreed that the evidence had limitations, but based on the consistency of PASI 90 and PASI 100 differences with the PASI 75 findings, the IL-17A inhibitors appeared to be more effective. Another member who voted “yes” was impressed by the lower projected discontinuation rate for the IL-17A inhibitors, a potential reason for their success. 2b) Is the evidence adequate to demonstrate that the net health benefit of IL-17A drugs as a class is better than that provided by etanercept? Yes: 14 votes No: 0 votes Comments: The unanimous vote was ascribed to the consistent results of head-to-head studies, mirrored in the findings of the network meta-analysis. 2c) Is the evidence adequate to demonstrate that the net health benefit of IL-17A drugs as a class is better than that provided by infliximab? Yes: 1 votes No: 13 votes Comments: The preponderance of “no” votes were ascribed to the results of the network meta-analysis in which the credible interval of this comparison overlapped with 1.0—in other words, the available data could not rule out the possibility of no difference between treatments. One New England CEPAC member voted “yes” because of concerns about access to infliximab, an intravenous medication, and because net health benefits appeared to trend better with the IL-17A inhibitors. 3) Is the evidence adequate to demonstrate that the net health benefit of ustekinumab is better than that provided by adalimumab? Yes: 1 votes No: 13 votes ©Institute for Clinical and Economic Review, 2016 Page 87 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Comments: Members of the New England CEPAC largely followed the “insufficient” finding from the network meta-analysis in this vote. The member of the New England CEPAC who voted “yes” argued that having a quarterly therapy instead of a monthly or bi-monthly therapy might be important for patient quality of life and adherence. 4) Is the evidence adequate to demonstrate that the net health benefit of ustekinumab is better than that provided by etanercept? Yes: 14 votes No: 0 votes Comments: The panel unanimously agreed that the evidence was adequate to demonstrate the net health benefit of ustekinumab over etanercept, based on direct comparative evidence between these agents and the similar findings from the network meta-analysis. 5) Is the evidence adequate to demonstrate that the net health benefit of ustekinumab is better than that provided by infliximab? Yes: 0 votes No: 14 votes Comments: While the panel voted unanimously, there was a discussion about patient heterogeneity. A practicing clinical expert acknowledged that individual patients’ responses are hard to predict. While there are some genetic differences between patients that are meaningful on a population basis, there are no indicators for individual patients and patients do occasionally see different responses between different TNFα inhibitors. In addition, panel members acknowledged that their votes were based on indirect evidence only. 7.3 Care Value Voting Results 6) Given the available evidence on comparative effectiveness and incremental cost-effectiveness using estimated discounted prices for private insurers presented in the report, and taking into account other benefits, disadvantages, and contextual considerations, what is the long-term value for money of the following drugs compared to continued non-targeted therapy? Adalimumab: Low: 0 votes Intermediate: 11 votes High: 3 votes ©Institute for Clinical and Economic Review, 2016 Page 88 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Etanercept: Low: 2 votes Intermediate: 11 votes High: 1 votes Comment: One of the members of the New England CEPAC who voted “low” value felt that etanercept was too expensive given the benefits seen. Infliximab: Low: 3 votes Intermediate: 9 votes High: 2 votes Comment: One member of the New England CEPAC who voted “low” was concerned that the time commitment and frequency of dosing for an IV therapy made it lower value. Ustekinumab: Low: 3 votes Intermediate: 9 votes High: 2 votes Comment: One member of the New England CEPAC who voted “high” value considered the convenience of quarterly dosing for patients who have an aversion to injections. Other panel members who voted “intermediate” and “low” value were concerned with weight- based dosing costs for overweight patients. Secukinumab: Low: 0 votes Intermediate: 3 votes High: 11 votes Comment: In general, members of the New England CEPAC who voted “high” felt that IL- 17A inhibitors showed demonstrable improvements in clinical outcomes at marginal costs that were at or sometimes below $100,000 per QALY, thus representing in their opinion a “high” value. Ixekizumab: Low: 0 votes Intermediate: 6 votes High: 8 votes Comment: Members of the New England CEPAC who voted “high” for both secukinumab and ixekizumab stated that this class of agents had the highest QALY gains and are the best options for patients with a challenging-to-treat disease. Two members of the New England CEPAC changed their vote for secukinumab and ixekizumab from “high” to “intermediate” because the incremental cost effectiveness ratios crossed the $100,000/QALY threshold. Brodalumab: ©Institute for Clinical and Economic Review, 2016 Page 89 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents No comparative value vote was taken on brodalumab, as its anticipated approval by the FDA was delayed beyond this review and thus no list price was available for consideration. Apremilast: Low: 0 votes Intermediate: 7 votes High: 7 votes Comments: Members of the New England CEPAC were split evenly between an intermediate and a high value vote for apremilast. The discussion centered on balancing the facts that apremilast had perhaps the lowest efficacy among drugs reviewed, offers the benefit of a unique route of administration—apremilast is the only oral drug—and has a low incremental cost effectiveness ratio. Panel members acknowledged the subset of patients who are pleased to have an oral option without drug monitoring so that they can drink alcohol and use birth control. Still, other members who leaned toward intermediate recognized apremilast’s lower efficacy and high discontinuation rate due to side effects (e.g. gastrointestinal distress) and non-response. 7) Given the available evidence on comparative clinical effectiveness and incremental cost- effectiveness, and taking into account other benefits, disadvantages, and contextual considerations, what is the long-term value for money of treatment with ixekizumab and secukinumab versus etanercept? Low: 0 votes Intermediate: 1 votes High: 13 votes Comments: The panel member who voted intermediate noted that while comorbidities were not reflected in the voting questions, IL-17A agents are contraindicated for patients with certain conditions (e.g., inflammatory bowel disease), which should factor into value considerations. ©Institute for Clinical and Economic Review, 2016 Page 90 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 7.4 Roundtable Discussion and Key Policy Implications Following its deliberation on the evidence, the New England CEPAC Panel engaged in a moderated discussion about use of targeted immunomodulators for the treatment of chronic plaque psoriasis with a Policy Roundtable that included 2 clinical experts, 2 patient representatives, and 2 payer representatives. The policy roundtable discussion with the New England CEPAC Panel reflected multiple perspectives and opinions, and therefore, none of the recommendations below should be taken as a consensus view held by all participants. The names of the Policy Roundtable participants are shown below. Table 26. Policy Roundtable Participants Joseph F. Merola, MD, MMSC Paul Jeffrey, PharmD Department of Dermatology |Harvard Medical School Director of Pharmacy; Office of Clinical Affairs Director of the Clinical Unit for Research Innovation & University of Massachusetts Medical School; Trials; Director of the Center for Skin & Related MassHealth (Massachusetts Medicaid) Musculoskeletal Diseases |Brigham and Women’s Hospital Leah McCormick Howard, JD Chris Pettit Vice President of Government Relations and Advocacy Patient Advocate National Psoriasis Foundation Portland, Oregon Abby S. Van Voorhees, MD Thomas Kowalski, RPh Chair, Department of Dermatology Clinical Pharmacy Director, Health and Medical Management Eastern Virginia Medical School Blue Cross Blue Shield of Massachusetts Chair, National Psoriasis Foundation The roundtable discussion was facilitated by Dr. Steven Pearson, MD, MSc, President of ICER. The main themes and recommendations from the discussion are organized by audience and summarized below. Specialty Societies and Patient Advocacy Groups Update treatment guidelines for patients with moderate-to-severe chronic plaque psoriasis in a form that is easy to understand and easy-to-use by payers, clinicians, and patients Payers base their coverage decisions and integration of utilization tools to a great extent on clinical guidelines. Payers on the policy roundtable expressed frustration with difficult-to- interpret, out-of-date clinical guidelines that precede the introduction of IL-17A agents. For example, there was discussion over whether methotrexate should represent a uniform first ©Institute for Clinical and Economic Review, 2016 Page 91 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents step in treatment or whether this was an artifact of older guidelines that included a smaller number of biologic agents than are available today. The National Psoriasis Foundation anticipates that revised treatment guidelines will be released in the spring of 2018, but payers are currently structuring coverage decisions based on the latest treatment guideline update from the American Academy of Dermatology and the American College of Rheumatology that was published in 2011, in which methotrexate and PUVA (a form of phototherapy now considered outdated) both play prominent roles.153 Payers expressed the need for updated guidelines from clinical societies with detailed guidance and understanding of clinical nuance that would allow for creation of meaningful step therapy approaches with “edits” that would represent reasonable clinical exceptions— for example, use of an agent that can address both psoriasis and psoriatic arthritis, or avoidance of an agent with suboptimal performance in patients with a certain comorbidity profile. Relatedly, the National Psoriasis Foundation has just released a “treat-to-target” consensus statement, based on input from 25 experts in plaque psoriasis.154,155 The statement is based on body surface area (BSA), which the authors felt was a commonly-used, practical, understandable measure for clinicians, patients, and payers. The statement established an initial treatment target BSA of ≤ 1% at 3 months and a continuing target of ≤ 1% BSA every 6 months. The consensus statement considers an initial BSA of ≤ 3% or a 75% improvement from baseline “acceptable”. Future guidelines and clinical studies should incorporate such treat-to-target goals in a way that is specific, interpretable, and implementable for payers to guide coverage decisions. Purchasers and Insurers Consider limiting or abolishing “step therapy” approaches to coverage. Based on the comparative value evaluation, for patients with moderate-to-severe plaque psoriasis all targeted immunomodulators represent reasonable long-term value for money compared to non-targeted treatment. Nonetheless, in part because of outdated clinical guidelines, and in part because many patients with psoriasis will respond to topical and other non-targeted treatments, the norm for both public and private insurers in the US has been to use step therapy protocols for access to targeted drugs and for selection among the targeted immunomodulators. Payers on the policy roundtable described step therapy as a practical, logical, cost-effective tool that seeks to mirror the idea of “treatment algorithms” common to clinicians. Payers also stated that step therapy protocols requiring treatment with TNFα inhibitors are also reasonable given their longer-term safety record. That being said, payers expressed willingness to consider modifying or eliminating step therapy ©Institute for Clinical and Economic Review, 2016 Page 92 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents protocols based on systematic evidence reviews, value assessments, and updated evidence- based guidelines. The importance of reconsidering step therapy policies was highlighted during the discussion of the policy roundtable. Patients and clinicians stated that step therapy protocols can seriously delay improvements to patients’ quality of life. Patients are often required to continue with less effective drugs for months or years prior to being allowed access to more effective, well-tolerated treatments. Patient representatives also said that step therapy can discourage patients from being treated at all, especially when clinicians do not have the resources to vigorously advocate on behalf of patients with payers. Expert clinicians agreed that step therapy and access to medications is the number one challenge in managing patients with severe plaque psoriasis. Clinicians expressed frustration with unyielding requirements to use topical therapies (which are challenging to apply to large proportions of the body surface, particularly the back); methotrexate (which can cause “methotrexate fog” and must be discontinued eventually due to the risk of liver toxicity); phototherapy (which requires frequent office visits, making adherence challenging for many patients, especially young students and working individuals); and combinations of methotrexate, phototherapy, and acitretin, which are complicated and lead to poor outcomes for many patients. Clinicians were concerned about patients dropping out of treatment because of frustrations with non-response and the administrative burdens of step therapy, burdens that are frequently repeated with every change of insurer. Clinicians argued that excellent clinical care required access to all targeted immunomodulators because of the unique benefits or disadvantages of some targeted immunomodulators for certain clinical scenarios (e.g., treatment of a patient with concomitant uveitis or axial arthritis); and availability of multiple routes of administration and dosing schedules that allow tailored regimens for patients who must travel, live far from home, or have other relevant considerations. Given that the targeted immunomodulators have good value relative to non-targeted treatment, payers should strongly consider eliminating most step therapy requirements for patients with moderate-to-severe psoriasis, especially for those patients who demonstrate the need for intensive, ongoing regimens. Given that the incremental clinical benefits of IL- 17A inhibitors cannot categorically be demonstrated to be superior to adalimumab, there may still be a reasonable justification for requiring a trial of adalimumab (or another TNFα inhibitor) prior to use of more expensive drugs, but, as discussed further below, any step therapy between TNFα inhibitors and other drugs should be carefully constructed to allow rapid and permanent exceptions for patients with co-conditions, co-morbidities, or specific ©Institute for Clinical and Economic Review, 2016 Page 93 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents life requirements that make other drugs the best first choice among all available targeted immunomodulators. If step therapy will be used: Allow individuals switching insurers to bypass step therapy if they are already on an effective treatment. Psoriasis is a chronic disease that patients manage for decades. It is important that patients maintain continuity of care, despite switching employers or insurers. Individuals switching insurer for any reason should be able to bypass step therapy protocols if current treatment is working, especially if they have used prior steps in the past. Some insurers, such as Blue Cross Blue Shield of Massachusetts, allow new members, with eligibility less than 90 days, to bypass step therapy to avoid interruption of therapy and treatment. Remove requirements for patients to have higher out-of-pocket expenses for “later step” treatments. For patients who follow a step therapy protocol and end up on a higher tier or “later step” medication, efforts should be taken to design the formulary so that patients are not required to pay a substantially higher co-payment or switch from co- payment to co-insurance. One patient advocate commented that when out-of- pocket costs go over $100 per month, adherence tends to drop.156 The general principle in formulary design should be that patients who are “good soldiers” and have tried but failed the first drug in a step therapy protocol should not be required to pay substantially more out of pocket for a subsequent treatment. As alternative mechanisms to manage costs, consider developing indication-specific formulary designs and outcome-based payment contracts. Payers should explore the use of mechanisms other than step therapy to help manage the outcomes and costs of care. Chief among the options to be considered are indication- specific formulary designs and outcome-based payment contracts. Indication-specific formulary design would allow payers to benefit from competition within each clinical indication for targeted immunomodulators. The general pattern has been for certain drugs with broad indications to gain formulary preference since most payers have not developed practical ways to link the use of these drugs to specific diagnoses. Payers should consider following the lead of Express Scripts, which has developed an indication-specific formulary design for the auto-immune conditions, allowing “niche” drugs to gain preference even if they could not compete across multiple indications. Further details on the Express Scripts program can be found here. ©Institute for Clinical and Economic Review, 2016 Page 94 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents A second option is to consider some form of outcome-based payment, in which rebates or refunds are linked to outcomes. As part of the Express Scripts program, plan sponsors will receive a refund of up to $6,000 if patients discontinue a preferred auto-immune medication within the first 90 days. As part of any refund program of this type it should be explored whether refunds to patients for their out-of-pocket payments can also be included. Co-payment and/or co-insurance for therapies should be based on prices net of discounts and rebates instead of list price. Higher out-of-pocket costs put patients at high risk of coverage loss, bankruptcy, and inability to access effective treatment necessary to control a chronic disease. As shown in our report, rebates and discounts are substantial for most psoriasis drugs. However, patient out-of-pocket payments are based on the list price for these medications. Insurers should seek ways to calculate patient contributions based on the negotiated price, allowing patients to share in savings from cost-effective treatment pathways, especially if part of a step therapy protocol. Manufacturers Foster transparency in the rationale for price increases. As noted in our report, some of the classes of psoriasis drugs have seen significant price increases in the past few years. Presently, discounted prices appear to be well-aligned with patient value for these drugs. If price increases continue at their current pace, however, this alignment will not continue for long. Manufacturers should seek to keep prices at a level that reflects the added benefit to patients, be mindful of the overall impact on health care costs of the growing use of targeted immunomodulators, and recognize the potential for lower prices to be linked to greater access for all patients. In addition, manufacturers should be transparent about the rationale for any future price increases, including new clinical evidence, improvements in therapy delivery or tolerability, and other considerations. Release treatment-specific quality-of-life data. Health economists are often frustrated by a lack of available data on disease-specific quality of life. When evaluated, information is often provided at the condition level, without data on the effect of treatment on quality of life measures. As an example, data from the commonly-used EuroQol (EQ)-5D was available for the psoriasis model, but was not ©Institute for Clinical and Economic Review, 2016 Page 95 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents stratified by treatment group. Quality-of-life assumptions were therefore driven primarily by model structure rather than actual, trial-based data on treatment effect. To address this concern, manufacturers should release both summarized and treatment-stratified quality- of-life information. Researchers and Manufacturers Conduct research that directly compares real-world treatment options and sequential treatment effectiveness for both naïve and treatment-experienced patients. As noted in the report, head-to-head clinical trial data were sparse and focused on only a few comparisons. There is also little information on how each targeted immunomodulator performs in early- versus later-line use. Patients, clinicians, and payers would benefit from real-world data comparing multiple treatment options, sequences, and combinations. For example, first-line use of targeted immunomodulators could be compared to other systemic therapies like methotrexate to evaluate their effectiveness and durability of benefit. In addition, within-class comparisons could be performed to identify advantages for particular agents. Finally, use of specific sequences of targeted immunomodulator therapy should be evaluated to identify the optimal treatment strategy for specific groups of patients, and to assess the possible decreased benefit for medications in early- versus later-line use. Generate additional information on the treatment durability of IL-17A agents. Since the IL-17A inhibitors are the newest class of drugs for plaque psoriasis, data on clinical benefits and potential harm are relatively short-term. There have been anecdotal reports suggesting that skin clearing wanes over time with IL-17A inhibitors. It is therefore important that manufacturers and researchers begin research on the longer-term effects of the IL-17A inhibitors including benefits, harms, and durability-of-response. Patient Advocacy Groups, Clinicians, and Researchers Patients and patient organizations should take a leadership role in the design of clinical trials and all stakeholders should advocate for rigorous study in diverse populations evaluating real-world comparative treatments. Given the evolution of new therapies for moderate-severe plaque psoriasis, patients and clinicians often lack information on comparative clinical effectiveness of different treatment options that is necessary to help them tailor care for the individual patient. Clinical experts ©Institute for Clinical and Economic Review, 2016 Page 96 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents noted, for example, that patients who have not yet taken a targeted immunomodulator are under-represented in many US-based clinical trials. Patient groups can help by encouraging patients to participate in clinical trials and by taking a leadership role in identifying treatment strategies and outcome measures that matter most to patients. Clinicians should also encourage patients to consider participating in research, and should develop the practice infrastructure needed to make that participation as seamless as possible. Researchers should work directly with patient groups and clinicians to ensure that trial design and implementation present the lowest barriers possible to participation. Lead research efforts to evaluate heritability of psoriasis and the impact of managing plaque psoriasis on caregivers and families. Patients groups describe the quality-of-life impacts of plaque psoriasis as extending well beyond the challenges and stigma faced by individual patients—there are substantial effects on family members and caregivers. 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Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). Journal of the American Academy of Dermatology. 2015;73(1):37-49. 88. Green L, Thaci D, Zhang Z, Goncalves J, Nograles K, Nikkels A. Effect of apremilast and etanercept on pruritus and health-related quality of life in patients with moderate to severe plaque psoriasis: Results from the LIBERATE study. Journal of the American Academy of Dermatology. 2016;74(5):AB245. 89. Strober B, Gordon K, Augustin M, et al. Improvements in patient-reported outcomes (PROs) among moderate to severe plaque psoriasis patients treated with brodalumab: Results from AMAGINE-1. Journal of the American Academy of Dermatology. 2016;74(5):AB256. 90. Sofen H, Wasel N, Yeilding N, Lee S, Zhao N, Mendelsohn A. 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Arthritis and Rheumatism. 2013;65(12):3322. 111. Papp K, Menter A, Strober B, et al. Improvement of psoriasis in patients with and without prior biologic experience: Subanalysis of a brodalumab (AMG 827) phase 2 study for moderate to severe plaque psoriasis. Journal of the American Academy of Dermatology. 2015;72(5 SUPPL. 1):AB238. 112. Gottlieb AB, Gerdes S, Lacour JP, et al. Efficacy of ixekizumab in moderate to severe psoriasis patients who have or have not received prior biologic therapies: An integrated analysis of 3 phase 3 studies. Journal of the American Academy of Dermatology. 2016;74(5):AB247. ©Institute for Clinical and Economic Review, 2016 Page 104 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 113. Papp K, Karpov A, Papavassilis C, Melendez E, Nakagawa H. Secukinumab efficacy in relationship with response to previous biologic psoriasis therapy: A subanalysis from the ERASURE Study. Journal of the American Academy of Dermatology. 2014;70(5 SUPPL. 1):AB186. 114. Clemmensen A, Spon M, Skov L, Zachariae C, Gniadecki R. Responses to ustekinumab in the anti- TNF agent-naive vs. anti-TNF agent-exposed patients with psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2011;25(9):1037-1040. 115. Gniadecki R, Bang B, Bryld LE, Iversen L, Lasthein S, Skov L. Comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris. British Journal of Dermatology. 2014;172(1):244-252. 116. Asahina A, Nakagawa H, Etoh T, Ohtsuki M. Adalimumab in Japanese patients with moderate to severe chronic plaque psoriasis: efficacy and safety results from a Phase II/III randomized controlled study. The Journal of dermatology. 2010;37(4):299-310. 117. Igarashi A, Kato T, Kato M, Song M, Nakagawa H, Japanese Ustekinumab Study G. 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Cost effectiveness of moderate to severe psoriasis therapy with etanercept and ustekinumab in the United States. PharmacoEconomics. 2013;31(9):823-839. 122. Griffiths CE, Strober BE, van de Kerkhof P, et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med. 2010;362(2):118-128. 123. Anis AH, Bansback N, Sizto S, Gupta SR, Willian MK, Feldman SR. Economic evaluation of biologic therapies for the treatment of moderate to severe psoriasis in the United States. The Journal of dermatological treatment. 2011;22(2):65-74. 124. Pan F, Brazier NC, Shear NH, Jivraj F, Schenkel B, Brown R. Cost utility analysis based on a head- to-head Phase 3 trial comparing ustekinumab and etanercept in patients with moderate-to- severe plaque psoriasis: a Canadian perspective. Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research. 2011;14(5):652-656. 125. Hinde S, Wade R, Palmer S, Woolacott N, Spackman E. Apremilast for the Treatment of Moderate to Severe Plaque Psoriasis: A Critique of the Evidence. PharmacoEconomics. 2016;34(6):587-596. 126. Turner D, Picot J, Cooper K, Loveman E. Adalimumab for the treatment of psoriasis. Health technology assessment (Winchester, England). 2009;13 Suppl 2:49-54. 127. Loveman E, Turner D, Hartwell D, Cooper K, Clegg A. Infliximab for the treatment of adults with psoriasis. Health technology assessment (Winchester, England). 2009;13 Suppl 1:55-60. 128. Gospodarevskaya E, Picot J, Cooper K, Loveman E, Takeda A. Ustekinumab for the treatment of moderate to severe psoriasis. Health technology assessment (Winchester, England). 2009;13 Suppl 3:61-66. ©Institute for Clinical and Economic Review, 2016 Page 105 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 129. Woolacott N, Hawkins N, Mason A, et al. Etanercept and efalizumab for the treatment of psoriasis: a systematic review. Health technology assessment (Winchester, England). 2006;10(46):1-233, i-iv. 130. Taltz(R) [package insert]. Eli Lilly and Company. 2016(Indianapolis, IN). 131. Stelara(R) [package insert]. Janssen Biotech Inc. 2016(Horsham, PA). 132. Remicade(R) [package insert]. Janssen Biotech Inc. 2015(Horsham, PA). 133. Otezla(R) [package insert]. Celgene Corporation. 2014(Summit, NJ). 134. Enbrel(R) [package insert]. Amgen. 2015(Thousand Oaks, CA). 135. Cosentyx(R) [package insert]. Novartis Pharmaceutical Corporation. 2016(East Hanover, NJ). 136. Farahnik B, Beroukhim K, Zhu TH, et al. Ixekizumab for the Treatment of Psoriasis: A Review of Phase III Trials. Dermatology and Therapy. 2016;6(1):25-37. 137. Yu AP, Tang J, Xie J, et al. Economic burden of psoriasis compared to the general population and stratified by disease severity. Current medical research and opinion. 2009;25(10):2429-2438. 138. C C, K W, D S, S L. Comparative Treatment Patterns Among Psoriasis Patients Using Adalimumab, Etanercept, or Ustekinumab. Am J Pharm Benefits. 2016;8(5):191-198. 139. Feldman SR, Zhao Y, Shi L, Tran MH. Economic and Comorbidity Burden Among Patients with Moderate-to-Severe Psoriasis. Journal of managed care & specialty pharmacy. 2015;21(10):874- 888. 140. Foster SA, Zhu B, Guo J, et al. Patient Characteristics, Health Care Resource Utilization, and Costs Associated with Treatment-Regimen Failure with Biologics in the Treatment of Psoriasis. Journal of managed care & specialty pharmacy. 2016;22(4):396-405. 141. Feldman SR, Zhao Y, Shi L, Tran MH, Lu J. Economic and comorbidity burden among moderate- to-severe psoriasis patients with comorbid psoriatic arthritis. Arthritis Care Res (Hoboken). 2015;67(5):708-717. 142. Services CfMaM. FY 2016 Final Rule, Correction Notice and Consolidated Appropriations Act of 2016 Tables. CMS.gov; 2016. 143. Bureau of Labor Statistics. May 2015 National Occupational Employment and Wage Estimates United States. Occupational Employment Statistics. http://www.bls.gov/oes/current/oes_nat.htm#00-0000. 144. Balasubramaniam P, Cheung S, Bishop-Bailey A, Williams R, Hatchard C. Evaluating the management of patients with psoriasis with biological therapies during standard U.K. Clinical care (2001-2014), using National Institute for Health and Care Excellence guidance as a benchmark (PICTURE study). British Journal of Dermatology. 2015;173:30-31. 145. E. R. Abstract 1654. European Academy of Dermatology and Venereology. 2014. 146. Griffiths C, Papp K, Zaldivar ER, et al. Secukinumab shows efficacy in subjects regardless of previous exposure to biologic therapy: A pooled subanalysis from four phase 3 clinical trials in psoriasis. Journal of the American Academy of Dermatology. 2015;72(5):AB251. 147. Gniadecki R, Bang B, Bryld LE, Iversen L, Lasthein S, Skov L. Comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris. The British journal of dermatology. 2015;172(1):244-252. 148. Menter A, Papp KA, Gooderham M, et al. Drug survival of biologic therapy in a large, disease- based registry of patients with psoriasis: results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Journal of the European Academy of Dermatology and Venereology : JEADV. 2016;30(7):1148-1158. ©Institute for Clinical and Economic Review, 2016 Page 106 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 149. Doshi JA, Takeshita J, Pinto L, et al. Biologic therapy adherence, discontinuation, switching, and restarting among patients with psoriasis in the US Medicare population. Journal of the American Academy of Dermatology. 2016;74(6):1057-1065.e1054. 150. Swinburn P, Lloyd A, Boye KS, Edson-Heredia E, Bowman L, Janssen B. Development of a disease- specific version of the EQ-5D-5L for use in patients suffering from psoriasis: lessons learned from a feasibility study in the UK. Value Health. 2013;16(8):1156-1162. 151. Pickard AS, Gooderham M, Hartz DS, Nicolay C. EQ-5D health utilities: Exploring ways to improve upon responsiveness in psoriasis. Journal of medical economics. 2016:1-31. 152. Vasiliou C. Psoriasis Forecast. Datamonitor Healthcare. 2015. 153. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. Journal of the American Academy of Dermatology. 2011;65(1):137-174. 154. Armstrong AW, et al. From the Medical Board of the National Psoriasis Foundation: Treatment targets for plaque psoriasis. . Journal of the American Academy of Dermatology. 2016. 155. Takeshita J, et al. Treat-to-target and improving outcomes in psoriasis- a report from the GRAPPA 2014 annual meeting. J Rheumatol 2015. 156. McCormick Howard L. National Psoriasis Foundation: a patient-centric approach to improve access to psoriatic disease treatment. The American journal of managed care. 2016;22(4 Suppl):s104-107. 157. National Institute for Health and Care Excellence (NICE). Secukinumab for treating moderate to severe plaque psoriasis. Vol TA350. 22 July 2015 ed: NICE; 2015. 158. Caldwell DM, Ades AE, Higgins JP. Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ (Clinical research ed). 2005;331(7521):897-900. 159. National Institute for Health and Care Excellence. A general linear modelling framework for pair- wise and network meta-analysis of randomised controlled trials Decision Support Unit, ScHARR, University of Sheffield, Regent Court, 30 Regent Street Sheffield, S1 4DA. 2016;2. 160. Institute for Clinical and Economic Review. Targeted Immunomodulators for the Treatment of Moderate-to-Severe Plaque Psoriasis: Effectiveness and Value. New England Comparative Effectiveness Public Advisory Council;2016. 161. Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the united states: Findings from the national psoriasis foundation surveys, 2003-2011. JAMA Dermatology. 2013;149(10):1180-1185. 162. Bissonnette R, Luger T, Thaçi D, et al. Secukinumab demonstrates sustained high efficacy and a favorable safety profile in moderate to severe psoriasis patients through 4 years of treatment. 25th Congress of the European Academy of Dermatology and Venereology; September 28- October 2, 2016; Vienna, Austria. 163. Langley RG, Elewski BE, Lebwohl M, et al. Secukinumab in plaque psoriasis--results of two phase 3 trials. The New England journal of medicine. 2014;371(4):326-338. 164. Bhosle MJ, Kulkarni A, Feldman SR, Balkrishnan R. Quality of life in patients with psoriasis. Health and Quality of Life Outcomes. 2006;4:35-35. 165. Puig L, Sofen H, Augustin M, et al. Secukinumab Provides Greater 52-Week Improvements in Patient-Reported Outcomes Than Ustekinumab in Patients With Moderate to Severe Psoriasis. 25th European Academy of Dermatology and Venereology Congress; 28 September - 2 October 2016, 2016; Vienna, Austria. ©Institute for Clinical and Economic Review, 2016 Page 107 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 166. Strober B, Jazayeri S, Thaçi D, et al. Secukinumab Provides Faster and More Sustained 52-Week Complete Relief From Psoriasis-Related Pain, Itching, and Scaling Than Ustekinumab in Subjects With Moderate to Severe Plaque Psoriasis. 25th European Academy of Dermatology and Venereology Congress; September 28-October 2, 2016, 2016; Vienna, Austria. 167. Strober B, Sigurgeirsson B, Popp G, et al. Secukinumab Provides Clearer Skin and Better Control on Patient-Reported Psoriasis Symptoms of Itching, Pain, and Scaling than Placebo and Etanercept. Journal of Psoriasis and Psoriatic Arthritis. 2016;1(4). 168. Bagel J, Duffin KC, Moore A, et al. Secukinumab Is Efficacious in Clearing Moderate to Severe Scalp Psoriasis: 12-Week Results of a Randomized Phase 3b Study. 25th European Academy of Dermatology and Venereology Congress; September 28-October 2, 2016, 2016; Vienna, Austria. 169. Gottlieb A, Sullivan J, Kubanov A, et al. Secukinumab is Effective in Subjects With Moderate to Severe Palmoplantar Psoriasis: 1.5 Year Results From the GESTURE Study. 25th European Academy of Dermatology and Venereology Congress; September 28-October 2, 2016, 2016; Vienna, Austria. 170. Reich K, Sullivan J, Arenberger P, et al. Secukinumab Shows Significant Efficacy in Nail Psoriasis: Week 32 Results from The TRANSFIGURE Study. Annals of the Rheumatic Diseases. 2016;75(Suppl 2):603-604. ©Institute for Clinical and Economic Review, 2016 Page 108 Final Evidence Report – Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendices ©Institute for Clinical and Economic Review, 2016 Page 109 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix A. Evidence Review Methods and Results Table A1. PRISMA 2009 Checklist # Checklist item TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). METHODS Protocol and 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration registration information including registration number. Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Data collection 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for process obtaining and confirming data from investigators. Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Risk of bias in 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the individual studies study or outcome level), and how this information is to be used in any data synthesis. ©Institute for Clinical and Economic Review, 2016 Page 110 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2) for each meta-analysis. Risk of bias across 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies studies). Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Risk of bias within 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). studies Results of individual 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group studies (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Risk of bias across 22 Present results of any assessment of risk of bias across studies (see Item 15). studies Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). DISCUSSION Summary of 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups evidence (e.g., healthcare providers, users, and policy makers). Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. From: Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi:10.1371/journal.pmed1000097 ©Institute for Clinical and Economic Review, 2016 Page 111 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table A2. Search Strategy of Medline 1996 to Present with Daily Update, EBM Reviews - Cochrane Database of Systematic Reviews, EBM Reviews - Cochrane Central Register of Controlled 1 Psoriasis/ 16220 2 psoria$.ti,ab. 24352 3 (secukinumab or cosentyx).ti,ab. 222 4 (ustekinumab or stelara).ti,ab. 649 5 (ixekizumab or taltz).ti,ab. 64 6 brodalumab.ti,ab. 77 7 (apremilast or otezla).ti,ab. 179 8 1 or 2 26043 9 3 or 4 or 5 or 6 or 7 1094 10 8 and 9 861 11 limit 10 to english language 824 12 limit 11 to humans 824 13 (guideline or practice guideline or letter or editorial or news or case reports or clinical 1931126 14 conference or congresses).pt. 12 not 13 700 15 remove duplicates from 14 601 Date of Search: June 28, 2016 Table A3. Search Strategy of Embase on June 28, 2016 #20 #19 AND [humans]/lim 1017 #19 #18 NOT 'case report' NOT 'case study' 1124 #18 #15 NOT #16 NOT #17 1184 #17 #15 AND [humans]/lim AND [animals]/lim 32 #16 #15 AND [animals]/lim 40 #15 #13 NOT #14 1224 #14 #12 AND [medline]/lim 413 #13 #12 AND [english]/lim 1622 #12 #10 NOT #11 1683 #11 #3 AND #9 AND ([editorial]/lim OR [erratum]/lim OR [letter]/lim OR [note]/lim OR 122 #10 [short survey]/lim) #3 AND #9 1805 #9 #4 OR #5 OR #6 OR #7 OR #8 2235 #8 'brodalumab':ab,ti 127 #7 'apremilast':ab,ti OR 'otezla':ab,ti 331 #6 'ixekizumab':ab,ti OR 'taltz':ab,ti 156 #5 'ustekinumab':ab,ti OR 'stelara':ab,ti 1454 #4 'secukinumab':ab,ti OR 'cosentyx':ab,ti 399 #3 #1 OR #2 58457 #2 psorias*:ab,ti OR psoriat*:ab,ti 57572 #1 'psoriasis vulgaris' 8040 ©Institute for Clinical and Economic Review, 2016 Page 112 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure A1. PRISMA Flow Chart Showing Results of Literature Search 1618 potentially relevant references screened 1266 citations excluded Population: 228 Intervention/Comparator: 10 352 references for full text Outcomes: 268 review Study Type: 534 Duplicates: 226 272 citations excluded (not an FDA-approved regimen, arthritis outcomes, non-plaque psoriasis types, and non- 80 TOTAL (36 RCTs) comparative study -42 RCT publications design) -27 abstracts -11 observational studies 6 systematic reviews ©Institute for Clinical and Economic Review, 2016 Page 113 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix B. Evidence Summary Tables Study, Study Design Intervention (n) Inclusion and Patient Outcomes Harms Dosing Schedule Exclusion Criteria Characteristics Quality rating Anti-TNF Agents Adalimumab Sauret, 2008 Phase III 1)Adalimumab: 40 mg Inclusion: Age, mean PASI 50 at 16 weeks Serious AEs at 16 every other week (%): weeks, %: RCT following an 80 mg a diagnosis of 1)42.9 dose (n=108) psoriasis for at least 1)88 1)1.9 (NCT00235820) Double-blind 12 months and stable 2)40.7 2)placebo (n=53) moderate to severe 2)30.2 2)1.9 Multicenter chronic plaque 3) Methotrexate: 7.5 psoriasis (PASI≥10 and CHAMPION Male, % to 25 mg once weekly BSA≥10%); candidate PASI 75 at 16 weeks AEs leading to (n=110) for systematic therapy 28 1)64.8 (%): discontinuation at 16 or phototherapy; For 16 weeks weeks, % Good quality study sites in Europe 2)66.0 1)79.6 publication and Canada 1)0.9 2)18.9 Exclusion: 2)1.9 Caucasian, % ITT with NRI Previous systemic anti-TNF therapy or 1)95.4 PASI 90 at 16 weeks methotrexate; (%): pregnancy 2)92.5 1)51.9 ©Institute for Clinical and Economic Review, 2016 Page 114 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Duration of PsO, yr 2)11.3 1)17.9 2)18.8 PASI 100 at 16 weeks (%): 1)16.7 (p=0.004) With PsA, % 2)1.9 1)21.3 2)20.8 PGA of ‘clear’ or ‘minimal’ at 16 weeks: Previous systemic 1) 73.1 and/or phototherapy, % 2) 11.3 1)82.2 2)90.4 *PGA ranging from 0 to 5 †P<0.001 vs. placebo PASI, mean (range) unless specified otherwise 1)20.2 (10.4-52.9) 2)19.2 (6.5-38.1) Revicki, 2008 See above See above See above See above At week 16: NR ©Institute for Clinical and Economic Review, 2016 Page 115 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents DLQI, mean change (NCT00235820) 1) -3.4 3) -9.1 CHAMPION 1 vs. 3, p<0.001 Good quality ED-5D publication 1) 0.1 3) 0.2 1 vs. 3, p<0.01 VAS pruritus 1) -1.7 3) -4.8 1 vs. 3, p<0.001 Menter, 2008 Phase III, multicenter, Period A (16 wk) Inclusion: Age, mean PASI 75, %: SAE through 16 double-blind RCT weeks,% 1)Adalimumab: 40 mg A diagnosis of 1)44.1 1)68 at wk 12, 71 at every other week psoriasis of at least 6 wk 16 1)1.8 (NCT00237887) following an 80 mg months, stable 2)45.4 dose (n=814) moderate to severe 2)1.8 plaque psoriasis for at ©Institute for Clinical and Economic Review, 2016 Page 116 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 67 centers in the 2)placebo (n=398) least 2 2)5 at wk 12, 7 at wk United States and months(PASI≥12, 16 REVEAL BSA≥10% and PGA of Male, % Serious infectious AE 14 centers in Canada at least moderate P<0.001 for both through 16 weeks, % 1)67.1 severity); 1)0.6 Good quality 2)64.6 publication ITT with NRI PASI 90, %: 2)1.0 Exclusion: 1)37 at wk 12, 45 at Caucasian, % wk 16 A history of CNS AEs leading to disease, cancer or 1)91.2 2)2 at wk 12, 2 at wk discontinuation lymphoproliferative 16 through 16 weeks, % disease 2)90.2 P<0.01 for both 1)1.7 2)2.0 Duration of PsO, yr PASI 100, %: 1)18.1 1)14 at wk 12, 20 at 2)18.4 wk 16 2)<1 a wk 12, 1 at wk 16 With hx of PsA, % P<0.01 for both 1)27.5 2)28.4 PGA of ‘clear’ or ‘minimal’ at 12 weeks, %: ©Institute for Clinical and Economic Review, 2016 Page 117 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Previous systemic 1)60 biologic, % 2)4 1)11.9 P<0.01 2)13.3 PGA of ‘clear’ at 12 weeks, %: PASI, mean (SD) 1)16 1)19.0 (7.08) 2)<1 2) 18.8 (7.09) P<0.01 *patients with missing PASI scores were considered nonresponders †PGA ranging from 0 to 5 Kimball, 2010 Work productivity See above See above See above At 16 weeks NR outcomes from REVEAL TWPI (total work productivity (NCT00237887) TWPI (%) impairment) 1) 18.5 1) -13.4 2) 17.9 REVEAL 3) -2.3 ©Institute for Clinical and Economic Review, 2016 Page 118 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Absolute difference: 11.1% Good quality Presenteeism (%) publication 1) 17.8 2) 16.8 TAI (total activity impairment) 1) -18.8 Absenteeism (%) 3) -3.3 1) 3.3 Absolute difference: 2) 2.6 15.5% p=NS Impairment while working owing to presenteeism 1) -12.9 3) -1.5 Absolute difference: 11.4% All outcomes, p<0.0001 ©Institute for Clinical and Economic Review, 2016 Page 119 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Employment and absenteeism measures = NS Asahina, 2010 Phase II/III, 1)adalimumab 40 mg Inclusion: Age, mean PASI 50 at week 16, %: Any SAE at 16 multicenter, double- eow (n=38) weeks, %: blind RCT a clinical diagnosis of 2)44.2 2)81.4 2)adalimumab 80mg moderate to severe 2) 2.3 Good quality at week 0 and 40 mg chronic plaque 4)43.9 4)19.6 publication eow starting week 2 4) 2.2 42 sites in Japan psoriasis for at least 6 P<0.001 (n=43) months, stable for at Male, % 3)adalimumab 80 mg least the recent 2 AEs leading to eow (n=42) months (PASI≥12, and ITT with NRI 2)35 PASI 75,%: discontinuation BSA≥10%) 4)placebo eow (n=46) through 16 weeks, % 4)41 2)53.3 at wk 12, 62.8 at wk 16 2)11.6 for 24 wk Exclusion: 4)2.2 at wk 12, 4.3 at 4)10.9 Caucasian, % wk 16 Previous anti-TNF therapy, other skin NR, trial in Japan P<0.001 for both diseases or infection, systemic lupus erythematosus, scleroderma or Duration of PsO, yr PASI 90,%: rheumatoid 2)14.0 2)30.2 at wk 12, 39.5 Arthritis; a history of at wk 16 CNS disease, cancer, 4)15.5 lymphoma, leukemia, 4)0 at wk 12 and wk tuberculosis, or 16 lymphoproliferative ©Institute for Clinical and Economic Review, 2016 Page 120 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents disease; positive With hx of PsA, % P<0.001 for both serology for HIV, Hep B, Hep C, infectious NR disease, PGA “clear” or immunosuppressive “minimal” at week disease or abnormal Previous systemic 16,%: hematological, non-biologic, % hepatic, or renal 2) 60.5 values 2)41.9 4) 8.7 4)37.0 P<0.001 PASI, mean (SD) Change in QoL at wk 2)30.2 (10.9) 16, mean (SD) 4)29.1 (11.8) 2) DLQI -5.1 (5.7); SF- 36 physical 4.6 (7.6);mental 2.4 (10.2) 4) DLQI 1.0 (7.0); SF- 36 physical -0.4 (7.3); mental -2.6 (10.6) P<0.001 for DLQI, p<0.01 for SF-36 physical, p<0.05 for SF-36 mental ©Institute for Clinical and Economic Review, 2016 Page 121 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *missing data were imputed by LOCF †PGA ranging from 0 to 5 Etanercept Papp, 2005 Phase III, multicenter, 1)etanercept 50 mg Inclusion: Age, median PASI 50 at week 12, %: SAE double-blind RCT BIW (203) Active and clinically 1)44.5 1)72 NR 2)etanercept 25 mg stable plaque psoriasis Fair quality BIW (204) with ≥10% BSA 3)44.0 3)9 publication 50 sites in the US, involvement; baseline Canada, and Europe 3)placebo (204) P<0.0001 Grade 3 or 4 PASI≥10; at least one laboratory previous Male, % abnormalities at week phototherapy or 24, n systemic therapy; 1)67 PASI 75 at week 12,%: mITT with LOCF adequate 1)1 hematological, renal, 3)64 1)46 and hepatic function 3)1 3)3 Caucasian, % P<0.0001 Exclusion: NR Active severe infection; other skin PASI 90 at week 12,%: conditions; active guttate, Duration of PsO, yr 1)19 erythrodermic or 1)18.1 3)<1 pustular psoriasis; ©Institute for Clinical and Economic Review, 2016 Page 122 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents previous anti-TNF 3)17.5 P<0.0001 therapy With hx of PsA, % sPGA “clear” or “almost clear” at 1)26 week 12,%: 3)26 1) 54 3) 3 Previous systemic P<0.0001 therapy, % Oral retinoids *missing data were 1)23 imputed by LOCF 3)24 †PGA ranging from 0 to 5 Oral retinoids 1)38 3)39 Oral retinoids 1)18 3)16 ©Institute for Clinical and Economic Review, 2016 Page 123 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI, median (range) 1)16.1 (7.0-57.3) 3)16.0 (7.0-62.4) Leonardi, 2003 Phase III, multicenter, 1) etanercept 25 mg Inclusion: Age, median PASI 50 at week 12, %: SAE double-blind RCT QW for 24 wk (n=160) Active but clinically 3)44.8 3)74 NR 2) etanercept 25 mg stable moderate-to- Fair quality BIW for 24 wk (n=162) severe plaque 4)45.6 4)14 publication 47 sites in the US psoriasis (PASI≥10 and 3) etanercept 50 mg P<0.001 BSA≥10%); previous BIW for 24 wk (n=164) phototherapy or Male, % systemic therapy, or mITT with LOCF 4) placebo BIW for 12 candidate for such 3)65 PASI 75 at week 12,%: wk 25 mg BIW after therapy wk 12 (n=166) 4)63 3)49 Exclusion: 4)4 guttate, erythrodermic, or White race, % P<0.001 pustular psoriasis; active skin conditions; 3)87 previous anti-TNF therapy 4)90 PASI 90 at week 12,%: 3)22 Duration of PsO, yr 4)1 3)18.6 P<0.001 ©Institute for Clinical and Economic Review, 2016 Page 124 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 4)18.4 sPGA “clear” or “almost clear” at With hx of PsA, % week 12,%: 22 3) 49 4) 5 Previous systemic P<0.001 therapy or phototherapy, % 76 %improvement DLQI, mean (SD) 3)61.0 (4.3) PASI, median (SE) 4)10.9 (4.8) 3)18.4 (0.7) P<0.001 4)18.3 (0.6) *missing data were imputed by LOCF †PGA ranging from 0 to 5 Tyring, 2006 Phase III, multicenter, 1)50 mg BIW (n=300) Inclusion: Age, median PASI 50 at week 12, %: SAE at 12 weeks,% double-blind RCT 2)placebo (n=300) Active, clinically stable 1)45.8 3)74 1)0 plaque psoriasis with ©Institute for Clinical and Economic Review, 2016 Page 125 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents (NCT00111449) For 12 wk PASI≥10 and 2)45.6 4)14 2)0.3 BSA≥10%; previous 39 sites in the US and systemic therapy or P<0.0001 Canada phototherapy, or Fair quality Male, % AEs leading to candidate for such publication discontinuation therapy; adequate 1)65 PASI 75 at week 12,%: through 12 weeks, % hematological, renal, mITT with LOCF and hepatic function 2)70 3)47 1)1.3 4)5 2)1.6 Exclusion: Duration of PsO, yr P<0.0001 History of psychiatric 1)20.1 disease; active guttate, 2)19.7 PASI 90 at week 12,%: erythrodermic, or 3)21 pustular psoriasis; previous snit-TNF With hx of PsA, % 4)1 therapy 1)35 P<0.001 2)33 %improvement DLQI, mean (SD) Previous systemic therapy or 3)69.1 phototherapy, % 4)22.1 NR P<0.0001 ©Institute for Clinical and Economic Review, 2016 Page 126 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI, median (SD) *missing data were imputed by LOCF 1)18.3 (7.6) 2)18.1 (7.4) Other outcomes reported: FACIT-F, Ham-D, and BDI Bagel, 2012 Phase III, multicenter, 1)etanercept 50 mg Inclusion: Age, median PASI 50 at week 12, %: SAE at week 12,% double-blind RCT BIW through week 12, followed by Stable moderate to 1)39 1)85 1)0 etanercept 50 mg QW severe plaque Good quality psoriasis with 2)42 2)7 2)0 and placebo QW publication Conducted in North BSA≥10% for ≥ 6 through week 24 America P<0.0001 (n=62) months; PASI ≥10 and SSA ≥ 30% with PSSI Male, % AEs leading to 2)placebo BIW ≥15; candidates for discontinuation through week 12, phototherapy or 1)53.2 PASI 75 at week 12,%: mITT with LOCF through 12 weeks, % followed by systemic therapy etanercept 50 mg BIW 2)58.1 1)59 1)3.2 (n=62) 2)5 2)0 Exclusion: White or Caucasian, % P<0.0001 guttate, 1)69.4 erythrodermic, or pustular 2)75.8 PASI 90 at week 12,%: 1)25 ©Institute for Clinical and Economic Review, 2016 Page 127 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents psoriasis; significant Duration of PsO, yr 2)2 medical 1)17.5 P<0.0001 problems; a history of tuberculosis; 2)11.9 or a history of cancer PGA 0-1 at week 12, % 5 years or less before With hx of PsA, % 1)54 enrollment NR 2)5 P<0.0001 Previous biologic therapy, % *missing data were Anti-TNF imputed by LOCF 1)6.8 2)6.5 Non-anti-TNF 1)3.2 2)4.8 PASI, median (range) 1)15.5 (8,46) ©Institute for Clinical and Economic Review, 2016 Page 128 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2)15.2 (10,41) Gottlieb, 2011 Phase III, multicenter, 1)briakinumab 200 Inclusion: Age, median PASI 75 at week 12, %: Severe AE at 12 double-blind RCT mg at week 0 and 4, weeks, % followed by 100 mg at A diagnosis of chronic 2)43.1 2)56.0 week 8 (n=138) plaque psoriasis for 2)2.1 (NCT00691964) ≥6months, stable for 3)44.0 3)7.4 33 sites in the United 2)etanercept 50 mg ≥2 months; BSA ≥ 3)4.3 States P<0.001 BIW at week 0-11 10%; PGA at least (n=141) moderate (≥3); PASI ≥ Good quality Male, % 12 publication Serious AE at 12 3)placebo (n=68) ITT with NRI 2)69.5 PASI 90 at week 12, %: weeks, % Exclusion: 3)69.1 2)23 2)0.7 Previous systemic anti-IL-12/23p40 3)1.4 3)2.9 therapy, etanercept, or inability to Caucasian, % P≤0.002 discontinue topical therapy, 2)90.1 AEs leading to phototherapies, or discontinuation systemic therapies 3)95.6 PASI 100 at week through 12 weeks, % 12, %: 2)2.8 2)6.7 Duration of PsO, yr 3)0 3)0 2)17.0 p≤0.002 3)19.1 PGA 0-1 at week 12, % ©Institute for Clinical and Economic Review, 2016 Page 129 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents With hx of PsA, % 2)39.7 2)22.7 3)2.9 3)20.6 P<0.0001 Previous biologic DLQI of 0 at week therapy, % 12, % 2)14.2 2)21.3 3)14.7 3)2.9 p≤0.008 PASI, mean (SD) 2)20 (14.2) *missing data were imputed by LOCF 3)10 (14.7) Strober, 2011 Phase III, multicenter, 1)briakinumab 200 Inclusion: Age, median PASI 75 at week 12, %: Severe AE at week double-blind RCT mg at week 0 and 4, 12, % followed by 100 mg at A diagnosis of chronic 2)45.2 2)39.6 week 8 (n=139) plaque psoriasis for 2)0.7 (NCT00710580) ≥6months, stable for 3)45.0 3)6.9 41 sites in the US 2)etanercept 50 mg ≥2 months; BSA ≥ 3)2.8 BIW at week 0-11 10%; PGA at least (n=139) moderate (≥3); PASI ≥ Good quality Male, % PASI 90 at week 12, %: 12 publication ITT with NRI Serious AE at week 3)placebo (n=72) 2)61.2 2)13.7 12, % Exclusion: ©Institute for Clinical and Economic Review, 2016 Page 130 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Previous systemic 3)63.9 3)4.2 2)0.7 anti-IL-12/23p40 therapy, etanercept, 3)2.8 or inability to Caucasian, % PASI 100 at week discontinue topical 12, %: therapy, 2)91.4 AEs leading to phototherapies, or 2)5.8 discontinuation systemic therapies 3)93.1 through 12 weeks, % 3)0 2)2.9 Duration of PsO, yr 3)2.8 PGA 0-1 at week 12, % 2)15.2 2)39.7 3)15.5 3)2.9 P<0.0001 With hx of PsA, % 2)33.1 DLQI of 0 at week 3)20.8 12, % 2)29.5 Previous biologic 3)4.2 therapy, % 2)7.9 *missing data were 3)4.2 imputed by LOCF ©Institute for Clinical and Economic Review, 2016 Page 131 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI, mean (SD) 2)18.5 (6.0) 3)18.3 (6.4) Bachelez, 2015 Phase III, multicenter, 1)tofacitinib 5 mg Inclusion: Age, median PASI 50 at week 12, %: Severe TEAEs at week double-blind RCT twice daily (n=329) 12, % Chronic stable plaque 3)42.0 3)80.3 2) tofacitinib 10 mg psoriasis for ≥ 12 2)2 (NCT01241591) twice daily (n=330) months; candidates 4)46.0 4)20.6 122 sites worldwide for systemic therapy 3)5 (not included the US 3)etanercept 50 mg or phototherapy; PASI and Canada) BIW at week 0-11 ≥12 and PGA of Good quality Male, % (n=335) moderate or severe; publication Serious TEAEs at week BSA ≥10%; failed to 3)70 PASI 75 at week 12, %: 4)placebo (n=107) 12, % respond or had a ITT with NRI contraindication to or 4)66 3)58.8 2)2 were intolerant to at least one conventional 4)5.6 3)2 systemic therapy Caucasian, % 3)87 PASI 90 at week 12, %: AEs leading to Exclusion: discontinuation 4)84 3)32.2 through 12 weeks, % Non-plaque or drug- induced forms of 4)0.9 2)3 psoriasis, could not Duration of PsO, yr continue systemic 3)4 therapies, previous or had a contraindication ©Institute for Clinical and Economic Review, 2016 Page 132 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents to etanercept, 3)18.0 previously not responded to anti-TNF 4)17.0 PGA 0-1 at week 12, % therapy, active 3)66.3 infection, previous tofacitinib With hx of PsA, % 4)15.0 3)21 4)24 PGA 0 at week 12, % 3)19.4 Previous biologic 4)1.9 therapy, % 3)11 DLQI reduction ≥5 4)11 from baseline at week 12, % 3)74.7 PASI, median (range) 4)31.8 3)19.4 (12.0-63.6) 4)19.5 (12.4-54.6) *patients with missing data were considered non-responders †PGA ranging from 0 to 4 ©Institute for Clinical and Economic Review, 2016 Page 133 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Infliximab Reich, 2005 Phase III, multicenter, 1) infusions of Inclusion: Age, median PASI 50 at week 10, % Serious AEs at week double-blind RCT infliximab 5mg/kg at 24, % weeks 0,2 and 6, then A diagnosis of 1)42.6 1)91 every 8 weeks to week moderate-to-severe 1)6 EXPRESS plaque psoriasis for ≥6 2)43.8 2)8 46 (n=301) 32 sites (countries NR) moths; candidates for 2)3 2) infusions of placebo phototherapy or at weeks 0,2 and 6, systemic therapy; Fair quality Male, % PASI 75 at week 10, % then every 8 weeks to PASI≥12 and BSA≥10% publication ITT and NRI only for AEs leading to week 46 (n=77) 1)69 1)80 PASI measures only discontinuation through 24 weeks, % Crossover at week 24 2)79 2)3 Exclusion: 1)9 A history or risk of 2)7 serious infection, White, % PASI 90 at week 10, % lymphoproliferative disease, or active NR 1)57 tuberculosis; previous anti-TNF treatment 2)1 Duration of PsO, yr 1)19.1 PGA of 0-1 at week 10, % 2)17.3 1)83 2)4 ©Institute for Clinical and Economic Review, 2016 Page 134 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents With PsA, % All p<0.0001 1)31 2)29 Change in DLQI from baseline at week 10, mean** Previous biologic 1)10.3 therapy, % 2)0.4 NR P<0.001 PASI, mean (SD) *ITT analysis results, 1)22.9 per-protocol is not presented here 2)22.8 †PGA ranging from 0 to 5 **Reported in Reich 2006 Reich, 2006 Work productivity See above See above See above At week 10 Discontinuation due outcomes from to AEs through week EXPRESS Productivity VAS 50 (%) EXPRESS Productivity VAS 1) -0.1 Placebo/INF: 10.4 ©Institute for Clinical and Economic Review, 2016 Page 135 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 5.8 2) 2.7 INF/INF: 11.3 Fair quality 2) 6.3 publication SF-RP (role physical) Discontinuation due to unsatisfactory SF-RP (role physical) 1) -5.2 therapeutic effects (%) 1) 64.8 2) 20.6 Placebo/INF: 9.7 2) 69.8 INF/INF: 4.7 SF-RE (role emotional) SF-RE (role emotional) 1) -2.2 1) 72.1 2) 18.2 2) 71.9 All outcomes, p<0.001 at week 10 and 24 Menter, 2007 Phase III, multicenter, 1)infusions of Inclusion: Age, median PASI 75 at week 10, % ≥1 SAE at week 14, % double-blind RCT infliximab 3mg/kg at weeks 0,2 and 6 A diagnosis of 2)44.5 2)75.5 2) 2.9 (n=313) moderate-to-severe EXPRESS II plaque psoriasis; 3)44.4 3)1.9 3) 2.4 63 sites in the US, 2)infusions of candidates for Canada, and Europe infliximab 5mg/kg at phototherapy or weeks 0,2 and 6 systemic therapy; Good quality Male, % PASI 90 at week 10, % AEs leading to (n=314) PASI≥12 and BSA≥10% publication discontinuation ITT with NRI 2)65.0 2)45.2 through 14 weeks, % ©Institute for Clinical and Economic Review, 2016 Page 136 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3)infusions of placebo Exclusion: 3)69.2 3)0.5 1)5.1 at weeks 0,2 and 6 (n=208) A history or risk of 2)2.4 serious infection, lymphoproliferative Caucasian, % PGA of 1-2 at week disease, or active 10, % 1) and 2) were re- 2)93.3 tuberculosis; previous randomized to receive 2)76.0 anti-TNF treatment 3)90.9 either every-8-week 3)1.0 continuous maintenance therapy or intermittent as- Duration of PsO, yr needed maintenance DLQI of 0 at week therapy; 3)crossed 2)19.1 10, % over to receive infliximab 5mg/kg at 3)17.8 2)39.0 weeks 16,18,and 22, and every 8 weeks 3)1.0 thereafter With PsA, % 2)28.3 DLQI mean change at week 10, % 3)26.0 2) -9.0 3) 0 Previous biologic therapy, % p<0.001 2)14.3 3)13.0 ©Institute for Clinical and Economic Review, 2016 Page 137 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *PGA ranging from 1 to 6 PASI, mean (SD) 2)20.4 (18.6) 3)19.8 (17.4) Yang, 2012 Phase III, multicenter, 1)infusion of Inclusion: Age, median PASI 50 at week 10, % Serious AEs at week double-blind RCT infliximab 5mg/kg at 10, % weeks 0,2, and 6, then A diagnosis of plaque 1)39.4 1)94.0 at weeks 14 and 22 psoriasis for ≥6 1)1.2 Fair quality months; had failed to 2)40.1 2)13.3 (n=84) publication ITT; handling of respond to 2)0 missing data NR 2)placebo at weeks conventional systemic 0,2, and 6, then treatment; PASI≥12 Male, % PASI 75 at week 10, % infliximab 5mg/kg at and BSA≥10%; AEs leading to weeks 10,12, and 16 1)71.4 1)81.0 discontinuation (n=45) Exclusion: through 26 weeks, % 2)77.8 2)2.2 Non-plaque psoriasis; 1)6.7 a history of chronic infectious disease or 2)NR opportunistic infection White, % PASI 90 at week 10, % or lymphoproliferative disease; a serious NR 1)57.1 infection within 2 months; active or 2)0 latent tuberculosis; Duration of PsO, yr pregnancy or planned pregnancy within 12 1)16.0 PGA of 0-1 at week months; an active 10, % malignancy or a ©Institute for Clinical and Economic Review, 2016 Page 138 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents history of malignancy 2)16.0 1)88.1 within 5 years 2)6.7 With PsA, % NR DLQI at week 10, mean 1) 6.5 Previous psoriasis therapy, % 2) 13.1 1) 40.5 P<0.001 for all 2) 31.1 PASI, mean (SD) NR DLQI, mean 1)14.4 2)14.4 Observational Studies ©Institute for Clinical and Economic Review, 2016 Page 139 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Gisondi, 2013 Observational, 1)infliximab 5 mg/kg Inclusion: Age, mean PASI at 1 month, NR prospective, multi- at weeks 0,2, and 6 mean (SD) center study and every 8 weeks Patient data recoded 1) 47.8 thereafter (n=83) at four tertiary 1) 4.1 (4.7) Good quality referral psoriasis 2) 45.7 2) 2.1 (3.2) centers in Italy 2)ustekinumab 45 mg (Universities of Male, % for patients ≤100 kg Verona, Modena and PASI at 7 months, and 90 mg for Padua, 1) 64 mean (SD) patients > 100 kg at weeks 0, 4, and every and Catholic 2) 72 1) 8.1 (5.2) 12 weeks thereafter University of Rome); a (n=79) diagnosis of chronic 2) 4.1 (5.5) plaque psoriasis; all patients who received White, % etanercept or infliximab were NR Improvement in PASI biological therapy at 1 month, % naïve, with PASI≥10 and BSA ≥10% and 1) 64 Duration of PsO, yr resistance to methotrexate, 2) 60 1) 17.5 cyclosporine, acitretin or phototherapy 2) 18.6 Improvement in PASI at 7 months, % Exclusion: Previous biologic 1) 85 therapy, % Patients diagnosed 2) 82 with PsA 0 ©Institute for Clinical and Economic Review, 2016 Page 140 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI, mean (SD) PASI 75 at 1 month, % 1) 16.5 (9.1) 1) 32 2) 18.4 (8.2) 2) 28 PASI 50 at 7 months, % 1) 96 2) 82 PASI 75 at 7 months, % 1) 69 2) 58 *between-group PASI 50 and PASI 75 are not statistically significant ©Institute for Clinical and Economic Review, 2016 Page 141 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Publication Observational, 1) etanercept (n=83) Inclusion: Age, mean PASI 75 at week 12, % Serious AEs, % prospective study 2) adalimumab (n=18) All patients who 71.3 1) 64 1)7.2 received a new Piaserico, 2014 3) infliximab (n=16) treatment with Male, % 2) 65 2)0 Adjustment: systemic traditional 4) ustekinumab (n=4) 58.3 3) 93 3)12.5 for the presence of drugs or biologics for Fair quality comorbidities, White, % 4) 100 4)0 chronic plaque smoking, steroid use psoriasis in various NR and disease severity Italian Dermatology Departments Duration of PsO, yr 22.1 Exclusion: Previous biologic therapy, % 26.2 PASI, mean (SD) 1)14.9 (6.4) 2)14.3 (4.1) 3)14.8 (5.7) ©Institute for Clinical and Economic Review, 2016 Page 142 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 4)17.2 (1.9) Not compared between groups Publication observational, 1) etanercept: 50 mg Inclusion: Age, mean (range) PASI 50 at week 12, % Severe AEs leading to retrospective study weekly as continuous discontinuation, % regimen for PsA and Patients with PsO 1) 70 (65-82) 1)82.0 50 mg twice weekly with/without PsA, ≥65 1)4.9 Esposito, 2012 years undergoing anti- 2) 69 (65-75) 2)85.7 for 12 weeks for PsO adjustment: none TNF-α therapy (i.e. 2)7.1 (n=61) PASI 75 at week 12, % adalimumab or 2) adalimumab: a etanercept) for at Poor quality Male, % 1)54.1 loading dose of 80 mg least 6 months in the followed by 40 mg outpatient 1)54 2)60.7 every other week for collaborative PsA and PsO (n=28) 2)57 Dermatology and Rheumatology Unit of PASI 50 at week 24, % the University of White, % 1)90.2 Rome NR 2)82.1 PASI 75 at week 24, % Duration of PsO, yr 1)78.7 1)29.2 2)71.4 2)24.1 ©Institute for Clinical and Economic Review, 2016 Page 143 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI 50 at year 1, % With PsA, % 1)90.2 1) 2)78.6 2) PASI 75 at year 1, % 1)83.6 Previous biologic 2)67.9 therapy, % 1) PASI 50 at year 2, % Adalimumab: 1.6 1)91.8 Efalizumab: 9.8 2)82.1 Infliximab: 9.8 PASI 75 at year 2, % 2) 1)86.9 Efalizumab: 25.0 2)71.4 Etanercept: 67.9 Infliximab: 50.0 PASI 50 at year 3, % 1)91.8 PASI, mean (range) 2)82.1 1)11.3 (0.4-68.3) ©Institute for Clinical and Economic Review, 2016 Page 144 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2)10.4 (0.4-23.8) PASI 75 at year 3, % 1)83.6 Not statistically 2)71.4 compared between groups Publication Observational, 1)etanercept 25 mg Inclusion: Age, mean PASI at 6 months, Severe AEs, retrospective study twice weekly (n=58) mean (SD) Gisondi, 2008 psoriatic patients 1) 50.2 0 2) infliximab 5 mg/kg affected by chronic 1) 4.8 (4.7) at week 0,2,and 6 and plaque psoriasis 2) 46.8 Adjustment: none then every 8 weeks consecutively 2) 2.1 (3.2) Poor quality 3) 53.1 (n=40) admitted to the 3) 4.3 (6) Male, % 3)methotrexate 15 mg outpatient clinics of once weekly (n=43) the University 1) 67 Improvement in Hospital of Verona; all 2) 70 PASI, % patients who received *doses NR etanercept or 3) 60 1) 74.5 infliximab were biological therapy White, % 2) 88.8 naïve, with PASI≥10 and BSA ≥10% and NR 3) 47.6 resistance to methotrexate, cyclosporine, acitretin Duration of PsO, yr or phototherapy 1) 22 ©Institute for Clinical and Economic Review, 2016 Page 145 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Exclusion: patients 2) 17.5 diagnosed with PsA 3) 18.6 Previous biologic therapy, % 0 PASI, mean (SD) 1) 18.8 (7.4) 2) 17.7 (7.3) 3) 8.2 (3.1) Anti IL-17A Agents Secukinumab (Cosentyx) Publication Phase III 1) secukinumab Inclusion: Age, mean PASI 75 at week 12, % Serious AE at week 300mg at week 12, % RCT 0,1,2,3, and then Plaque psoriasis for ≥6 1) 45.1 1) 75.9 every 4 weeks starting months; moderate-to- 1) 5.1 Blauvet, 2015 Double-blind severe disease 2) 46.0 2) 69.5 from week 4 (n=59) defined by baseline 2) 0 Multicenter 3) 46.5 3) 0 2) secukinumab PASI≥12, IGA mod 3) 1.7 150mg at week 2011≥3, and 0,1,2,3, and then BSA≥10%; ©Institute for Clinical and Economic Review, 2016 Page 146 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents (FEATURE 32 sites in North every 4 weeks starting inadequately Male, % PASI 90 at week 12, % NCT01555125) America and Europe from week 4 (n=59) controlled by topical treatment, 1) 64.4 1) 60.3 AE leading to 3) placebo (n=59) phototherapy, or discontinuation at 2) 67.8 2) 45.8 week 12, % previous systemic Good quality ITT with NRI therapy publication 3) 66.1 3) 0 1) 1.7 Maintenance: dosing every 4 weeks from 2) 0 week 12 to week 52 Exclusion: White, % PASI 100 at week 3) 1.7 12, % Non-chronic-plaque 1) 91.5 psoriasis, except for 1) 43.1 palmoplantar 2) 86.4 psoriasis; prior anti-IL- 2) 8.5 17A therapy; medical 3) 96.6 conditions that 3) 0 confound the evaluation or risky for immunotherapy; Duration of PsO (yr), active infections or mean IGA mod 2011 0/1 history of infections; response at week 1) 18.0 12, % history of lymphoproliferative 2) 20.4 1) 69.0 diseases or malignancy; 3) 20.2 2) 52.5 pregnancy 3) 0 PASI, mean (SD) 1) 20.7 (7.95) ©Institute for Clinical and Economic Review, 2016 Page 147 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2) 20.5 (8.29) *p<0.0001 for all secukinumab vs. 3) 21.1 (8.49) placebo comparisons Previous biologic, % 1) 39.0 2) 47.5 3) 44.1 Publication Phase IIIb 1) secukinumab SQ Inclusion: Age, mean PASI 75 at week 12, % At week 16 300mg dosed at Week RCT 0, 1, 2, 3, & q4wks to Moderate-to-severe 1) 45.2 1)91.0 Nonfatal serious AE, % Week 48 (n=337) psoriasis defined by Thaci, 2015 Double-blind baseline PASI≥12, IGA 2) 44.6 2)79.1 1)3.0 2) ustekinumab SQ mod 2011 of 3 or 4, Multicenter PASI 75 at week 16, % 2)3.0 weight-based dosing and BSA≥10%; a at Week 0, 4, & diagnosis of psoriasis q12wks from Wk 16- for ≥6 months; had ©Institute for Clinical and Economic Review, 2016 Page 148 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents (CLEAR 40 (placebo given at been inadequately Male, % 1)93.1 other wks) (n=339) controlled by topical NCT02074982) 134 sites worldwide treatment, 1) 68.0 2)82.7 AE leading to phototherapy, and/or discontinuation at 2) 74.3 P=0.0001 week 16, % previous systemic therapy Good quality ITT with NRI 1)0.9 publication Caucasian, % PASI 90 at week 12, % 2)1.2 Exclusion: 1) 88.7 1)72.8 Previous biologics 2) 85.0 2)53.4 targeting IL-17A or IL- 12/IL-23 PASI 90 at week 16, % Duration of PsO (yr), 1)79.0 mean 2)57.6 1) 19.6 2) 16.1 PASI 100 at week 12, % PASI, mean (SD) 1)38.9 1) 21.7 (8.50) 2)25.7 2) 21.5 (8.07) P=0.0003 PASI 100 at week 16, % Previous biologic, % ©Institute for Clinical and Economic Review, 2016 Page 149 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 14.2 1)44.3 2) 13.0 2)28.4 IGA mod 2011 0/1 at week 12, % 1)80.8 2)65.1 IGA mod 2011 0/1 at week 16, % 1)82.9 2)67.5 DLQI 0/1 at week 12, % 1)66.2 2)56.5 P=0.0109 DLQI 0/1 at week 16, % ©Institute for Clinical and Economic Review, 2016 Page 150 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1)71.9 2)57.4 Subject-reported sx, absolute change at week 16 from baseline, mean Pain 1)-3.3 2)-2.8 P=0.0414 Itching 1)-5.0 2)-4.6 P=0.0053 Scaling 1)-5.7 2)-5.2 P=0.0001 ©Institute for Clinical and Economic Review, 2016 Page 151 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *p<0.0001 unless specified otherwise Paul, 2015 Phase III 1) secukinumab 300 Inclusion: Age, mean PASI 75 at week 12, % At week 12, mg at week 0,1,2,3, RCT and then every 4 Moderate-to-severe 1) 46.6 1)86.7 Nonfatal serious weeks starting from psoriasis defined by AEs, % (NCT01636687) Double-blind baseline PASI≥12, IGA 2) 43.9 2)71.7 week 4(n=60) mod 2011 of 3 or 4, 1)1.7 Multicenter 3) 43.7 3)3.3 2) secukinumab and BSA≥10%; a 2)4.9 150mg at week diagnosis of psoriasis JUNCTURE 0,1,2,3, and then for ≥6 months; had 3)1.6 38 sites worldwide every 4 weeks starting been inadequately Male, % PASI 90 at week 12, % from week (n=61) controlled by topical Fair quality treatment, 1) 76.7 1)55.0 publication 3) placebo (n=61) phototherapy, and/or AE leading to Did not specify previous systemic 2) 67.2 2)40.0 discontinuation, % handling of missing therapy data 3) 62.3 3)0 1)0 Maintenance: dosing every 4 weeks, week 2)0 12-52 Exclusion: Caucasian, % PASI 100 at week 3)1.6 OTE: week 52-208 and Non-plaque type or 12, % an 8-week treatment- drug-induced 1) 93.3 free FU psoriasis; ongoing use 1)26.7 2) 95.1 of any prohibited 2)16.7 (p=0.0006 vs. treatment; prior 3) 96.7 (3)) exposure to biologics targeting IL-17A; 3)0 medical conditions ©Institute for Clinical and Economic Review, 2016 Page 152 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents including active Duration of PsO (yr), systemic infection, mean tuberculosis, history IGA mod 2011 0/1 of HIV, Hep B, Hep C, 1) 21.0 response or other conditions 2) 20.6 1)73.3 immunocompromising patients. 3) 19.86 2)53.3 3)0 PASI, mean (SD) 1) 18.9 (6.37) *P<0.0001 for secukinumab vs. 2) 22.0 (8.85) placebo comparisons unless specified 3) 19.4 (6.70) otherwise Previous biologic, % 1) 25.0 2) 24.6 3) 21.3 PsA reported, % 1) 23.3 ©Institute for Clinical and Economic Review, 2016 Page 153 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2) 26.2 3) 19.7 Langley, 2014 Phase III 1) secukinumab Inclusion: Age (yr), mean PASI75 at 12 weeks, % At week 12 300mg (n=245) RCT Adults w/ moderate- 1) 44.9 1) 81.6 Nonfatal serious AE, % 2) secukinumab to-severe plaque (NCT01365455) Double-blind 150mg (n=245) psoriasis 2) 44.9 2) 71.6 1) 1.2 Multicenter 3) placebo (n=248) PASI score ≥ 12, IGA of 3) 45.4 3) 4.5 2) 2.1 3 or 4, and BSA ≥10%; ERASURE 3) 0.9 a diagnosis of psoriasis for ≥6 88 sites worldwide Administered once Male, % IGA 0/1 at week 12, % months; poorly weekly and at week 1, Good quality controlled with topical 1) 69.0 1) 65.3 AE leading to 2, 3, 4, then q4wks publication treatments, discontinuation, % until week 48 ITT with NRI phototherapy, 2) 68.6 2) 51.2 systemic therapy, or a 1)1.2 combination of these 3) 69.4 3) 2.4 therapies 2)0.6 At week 12, placebo pt who did not exceed 3)1.9 PASI75 were White, % PASI90 at week 12, % randomized to Exclusion: secukinumab, and 1)69.8 1) 59.2 these patients were ©Institute for Clinical and Economic Review, 2016 Page 154 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents excluded from Non-plaque or drug 2)69.8 2) 39.1 analysis induced psoriasis 3)71.0 3) 1.2 PASI score, mean (SD) DLQI, change in mean score at Wk12 1) 22.5 (9.2) 1) -11.4 2) 22.3 (9.8) 2) -10.1 3) 21.4 (9.1) 3) -1.1 Body surface area involved, % (SD) DLQI, score of 0/1 at Wk12 1) 32.8 (19.3) 1) 58.8 2) 33.3 (19.2) 2) 46.1 3) 29.7 (15.9) 3) 10.3 Psoriatic arthritis, % *all p<0.001 for 1) 23.3 comparisons with placebo 2) 18.8 3) 27.4 ©Institute for Clinical and Economic Review, 2016 Page 155 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Previous biologic, % 1) 28.6 2) 29.8 3) 29.4 Langley, 2014 Phase III 1) secukinumab Inclusion: Age (yr), mean PASI 75 at week 12, % At week 12 300mg (n=327) (same as above) RCT Adults w/ moderate- 1) 44.5 1) 77.1 Nonfatal serious AE, 2) secukinumab to-severe plaque Double-blind 150mg (n=327) psoriasis 2) 45.4 2) 67.0 # events/100 person- year NCT01358578 Multicenter 3) etanercept 50mg PASI score ≥ 12, IGA of 3) 43.8 3) 44.0 BIW until week 12, 3 or 4, and BSA ≥10%; 1) 6.8 4) 44.1 4) 4.9 then QW until week a diagnosis of 2) 6.0 51 (n=326) psoriasis for ≥6 FIXTURE 88 sites worldwide months; poorly 3) 7.0 4) placebo (n=326) controlled with topical Male, % IGA 0/1 at week 12, % treatments, 4) 8.3 Good quality ITT with NRI phototherapy, 1) 68.5 1) 62.5 publication systemic therapy, or a Secukinumab was combination of these 2) 72.2 2) 51.1 administered once therapies AE leading to weekly and at week 1, 3) 71.2 3) 27.2 discontinuation, 2, 3, 4, then q4wks until week 48 4) 72.7 4) 2.8 # events Exclusion: 1) 14 ©Institute for Clinical and Economic Review, 2016 Page 156 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Non-plaque or drug White, % PASI 90 at Wk12, % 2) 10 induced psoriasis; previous etanercept 1)68.5 1) 54.2 3) 12 2)67.0 2) 41.9 4) 3 3)67.2 3) 20.7 4)66.9 4) 1.5 PASI score, mean (SD) 1) 23.9 (9.9) DLQI, change in mean score at week 12 2) 23.7 (10.5) 1) -10.4 3) 23.2 (9.8) 2) -9.7 4) 24.1 (10.5) 3) -7.9 4) -1.9 Psoriatic arthritis, % 1) 15.3 *all p<0.001 for 2) 15.0 comparisons between secukinumab and 3) 13.5 etanercept/placebo 4) 15.0 ©Institute for Clinical and Economic Review, 2016 Page 157 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Previous biologic, % DLQI, score of 0/1 (%) 1) 11.6 1) -10.4 2) 13.8 2) -9.7 3) 13.8 3) -7.9 4) 10.7 4) -1.9 Publication Subanalysis of See original trial See original trial Age Wk 12: AEs (%) Japanese patients (18 sites in Japan) 1) 51.9 PASI 75 (%) 1) 48.3 enrolled in ERASURE Ohtsuki, 2014 Bio-naïve 2) 48.2 1) *82.8, 2) *86.2, 3) 2) 55.2 trial 6.9 1) 23 3) 50.2 3) 41.4 (ERASURE) 2) 24 PASI 90 (%) 3) 23 %male SAEs (per 100 PYs) 1) 89.7 1) *62.1, 2) *55.2, 3) 0 1) 2.7 2) 79.3 PASI 100 Bio-exposed 2) 8.5 3) 79.3 1) 6 3) 0 PASI 100 (%) 2) 5 Mean PASI 1) **27.6, 2) 10.3, 3) 0 ©Institute for Clinical and Economic Review, 2016 Page 158 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3) 6 1) 26.7 2) 28.2 IGA mod 0/1 (%) 3) 21.4 1) *55.2, 2) *55.2, 3) 3.4 PsO duration (years) *p<0.0001, **p<0.01 1) 15.6 2) 15.6 DLQI score of 0/1 (%) 3) 14.1 1) 71.4, 2) 65.5, 3) 24.1 PsA 1 vs. 3, p<0.001 1) 13.8 2 vs. 3, p<0.01 2) 17.2 3) 13.8 Improvements persisted after one year Previous biologic: 1) 20.7 PASI 75 2) 17.2 Bio-naïve: ©Institute for Clinical and Economic Review, 2016 Page 159 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3) 20.7 1) 82.6, 2) 83.3, 3) 8.7 Bio-exposed: 1) 83.3, 2) 100, 3) 0 PASI 90 Bio-naïve: 1) 65.2, 2) 54.2, 3) 0 Bio-exposed: 1) 50, 2) 60, 3) 0 Blauvelt, 2014 See ERASURE See ERASURE See ERASURE PsA patients (n=171) PASI 75 at week 12,% NR 1)secukinumab 300 1) 68 mg ERASURE 2) 70 2)secukinumab 150 mg 3) 4 Abstract 3)placebo PASI 90 at week 12,% Reports outcomes of 1) 53 subpopulation w/ PsA 2) 44 ©Institute for Clinical and Economic Review, 2016 Page 160 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3) 0 Papp, 2014 As above As above See ERASURE Previous exposure to no prior biologic NR biologic (n=216/738) exposure PASI 75 at week 12, % ERASURE Reports outcomes based on prior Previous inadequate 1) 84.0 biologic exposure response to biologic (n=72/216) 2) 74.7 Abstract 3) 4.6 IGA 0/1 at week 12, % 1) 67.4 2) 55.0 3) 2.9 w/ prior biologic exposure PASI 75 at week 12, % 1) 75.7% 2) 64.4% 3) 4.1% ©Institute for Clinical and Economic Review, 2016 Page 161 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents IGA 0/1 at week 12, % 1) 60.0% 2) 42.5% 3) 1.4% *p<0.0001 for each secukinumab dose vs. placebo Strober, 2016 Secondary analysis As above See ERASURE and Age (yr), mean Response rate for NR FIXTURE itching (reduction of 1) 43.0 ≥2.2 points from baseline) at week (ERASURE and 39% patients who 2) 45.7 12, % FIXTURE) (n=678/1718) completed Psoriasis 3) 43.1 1) 83.0 Symptom Diary (PSD) were included in this 2) 78.2 Good quality analysis publication Male, % 3) 16.9 1) 62.5 1) secukinumab 2) 65.9 300mg (n=224) Response rate for pain (reduction of ©Institute for Clinical and Economic Review, 2016 Page 162 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2) secukinumab 3) 71.1 ≥2.2points from 150mg (n=229) baseline) at week 12, % 3) placebo (n=225) PASI, mean (SD) 1) 72.8 1) 21.9 (9.0) 2) 65.5 2) 21.8 (9.0) 3) 15.6 3) 21.6 (8.7) Response rate for scaling (reduction of PSD, itching mean ≥2.2points from (SD) baseline) at week 12, % 1) 6.4 (2.4) 1) 83.0 2) 6.5 (2.4) 2) 78.2 3) 6.1 (2.5) 3) 13.8 PSD, pain mean (SD) 1) 5.5 (3.0) 2) 5.3 (3.1) 3) 5.0 (3.0) ©Institute for Clinical and Economic Review, 2016 Page 163 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PSD, scaling mean (SD) 1) 6.4 (2.6) 2) 6.5 (2.4) 3) 6.2 (2.4) Ixekizumab (Taltz) Gordon, 2016 Phase III N=1296 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 12: week 12 (pooled RCT 1) placebo (n=431) ≥18 years 1) 46, 2) 46, 45 across UNCOVER PASI 75 (%): trials): (NCT01474512) Double-blind 2) ixekizumab, 80mg BSA ≥10%, % male: Q4W (n=432) 1) 3.0, 2) 82.6, 3) 89.1 AEs (%): Multicenter PASI ≥12 1) 70.3, 2) 66.9, 3) 3) ixekizumab, 80mg 67.2 PASI 90 (%): 1) 46.8, 2) 58.3, 3) UNCOVER-1 Q2W (n=433) sPGA ≥3 58.4 Weight (kg): 1)0.5 2) 64.6, 3) 70.9 100 sites worldwide ≥6 months of plaque All IXE- 80.9 psoriasis diagnosis <100kg- 1) 67.1, 2) PASI 100 (%): Good quality Patients who had an 66.5, 3) 66.5 SAEs (%): publication sPGA score of Candidates for 1) 0.0, 2) 33.6, 3) 35.3 ITT with NR phototherapy or ≥100kg- 1) 32.9, 2) 1) 1.5, 2) 2.2, 3) 1.7 0 or 1 at week 12 and systemic therapy 32.9, 3) 33.5 sPGA score of 0/1 entered the (%): All IXE (wk 0-60)- 6.7 randomized PsO duration (years): 1) 3.2, 2) 76.4, 3) 81.8 Discontinuation of withdrawal period 1) 20, 2) 19, 3) 20 study due to AEs (%): through 60 weeks All IXE groups vs. PASI: placebo, p<0.001 1) 1.1, 2) 2.1, 3) 2.1 ©Institute for Clinical and Economic Review, 2016 Page 164 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2a) maintained on 1) 20, 2), 20, 3) 20 All IXE (wk 0-60)- 4.4 ixekizumab 80mg Q4W DLQI: At wk 60 (pooled Infections (%): UNCOVER-1 and -2): 2b) switch to NR 1) 22.9, 2) 27.4, 3) ixekizumab 80mg PASI 75 (%): 27.0 PsA (%): Q2W 2a) 80, 2b) 83 All IXE (wk 0-60)- 55.2 NR PASI 90 (%): MACE (%): Previous biologics (%): 2a) 71, 2b) 73 1) 0.1, 2) 0.2, 3) 0.0 1) 42.0, 2) 38.9, 3) sPGA score of 0/1 All IXE (wk 0-60)- 0.6 40.0 (%): Grade 3 or 4 2a) 73, 2b) 75 neutropenia (n): 1) 1, 2) 1, 3) 2 All IXE (wk 0-60)- 10 Deaths (n): 0 in all groups All IXE (wk 0-60)- 0.1 (3 patients) Langley, 2016 Reports improvement See above See above See above DLQI, mean change at NR in HRQoL for IXE Q4W 12 weeks: -11.3* (NCT01474512) ©Institute for Clinical and Economic Review, 2016 Page 165 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents DLQI, mean change at 60 weeks: UNCOVER-1 -11.2* DLQI, score of 0/1 at Abstract 60 weeks (%): 66.4 *p<0.001 from baseline Griffiths, 2015 and Phase III N=1224 Inclusion: Age (years): Primary outcomes at Primary outcomes at Gordon, 2016 week 12: week 12 (pooled RCT 1) placebo (n=168) ≥18 years 1) 45, 2) 45, 3), 45, 4), across UNCOVER-1 45 PASI 75 (%): and -2 trials): Double-blind 2) etanercept (n=358) BSA ≥10%, (NCT01597245) % male: 1) 2.4, 2) 41.6‡, 3) AEs (%): Multicenter 3) ixekizumab 80mg PASI ≥12 77.5‡§, 4) 89.7‡§ Q4W (n=347) 1) 71.4, 2) 65.9, 3) 1) 44, 2) 54, 3) 58, 4) sPGA ≥3 70.3, 4) 63.0 PASI 90 (%): 58 UNCOVER-2 4) ixekizumab, 80mg Sites in USA, Canada, Q2W (n=351) ≥6 months of plaque Weight (kg): 1) 0.6, 2) 18.7‡, 3) SAEs (%): Mexico, Argentina, psoriasis diagnosis 59.7‡§, 4) 70.7‡§ Chile, Europe, Czech <100kg- 1) 66.9, 2) 2% in all groups Good quality Republic, Hungary, Candidates for 65.0, 3) 65.6, 4) 72.9 PASI 100 (%): publication Patients who had an phototherapy or Discontinuation of Romania, Russia, sPGA score of systemic therapy ≥100kg- 1) 33.1, 2) 1) 0.6, 2) 5.3, 3) 30.8, study due to AEs (%): Australia, and Japan 35.0, 3) 34.4, 4) 27.1 4) 40.5 0 or 1 at week 12 and entered the PsO duration (years): ©Institute for Clinical and Economic Review, 2016 Page 166 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents ITT randomized Exclusion: Patients 1) 19, 2) 19, 3) 19, 4) sPGA score of 0/1 1) 0.01, 2) 0.07, 3) withdrawal period who had used 18 with ≥2-point 0.05, 4) 0.03 etanercept at any reduction (%): time before screening PASI: URIs (%): 1) 2.4, 2) 36.0‡§, 3) 1) 21, 2) 19, 3) 20, 4) 72.9‡§, 4) 83.2‡§ 1) 3, 2) 5, 3) 3, 4) 4 19 DLQI, score of 0/1 Deaths (n): DLQI: (%): 0 in all groups NR 1) 6.0, 2) 33.8‡, 3) 59.9‡§, 4) 64.1‡§ PsA (%): NR ‡p<0·0001 compared Previous biologics with placebo (%): §p<0·0001 compared with etanercept (see 1) 25.6, 2) 21.2, 3) Table 2 in publication 24.5, 4) 23.9 for differences between groups and 97.5% CI) Other outcomes reported: sPGA score of 0, PASI % improvement, DLQI mean change, Itch NRS ©Institute for Clinical and Economic Review, 2016 Page 167 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Gottlieb, 2016 Reports improvement See above See above See above Skin pain VAS at 12 NR in skin pain VAS weeks: 1) 44.5, 2) 18.9, 3) (NCT01597245) Mean VAS 10.3, 4) 7.2 1) 49.2 UNCOVER-2 Least squares mean change from baseline: 1) -4.6, 2) -29, 3) - Abstract 37.7, 4) -42.2 All comparisons, p<0.001 Papp, 2016 Reports outcomes for N=200 NR NR Outcomes after 12 SAEs ≥1 (%): patients who failed weeks: etanercept (sPGA≤2) 4.5 during the induction PASI 75 (%): 83.5 (NCT01597245) Discontinuation of period and began PASI 90 (%): 57.0 study due to AEs (%): received IXE Q4W PASI 100 (%): 22.0 4 UNCOVER-2 sPGA score of 0/1 (%): 73 Most AEs were mild or Abstract moderate and were similar placebo non- ©Institute for Clinical and Economic Review, 2016 Page 168 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Outcomes after 44 responders who also weeks of IXE (at 60 started IXE Q4W weeks): PASI 75 (%): 82.5 No outcomes were PASI 90 (%): 68.5 statistically measured PASI 100 (%): 43.5 DLQI, score of 0/1 (%): 58 No outcomes were statistically measured Griffiths, 2015 and Phase III N=1346 Same as UNCOVER-2 Age (years): Primary outcomes at See above Gordon, 2016 week 12: RCT 1) placebo (n=193) 1) 46, 2) 46, 3), 46, 4), (same as above) 46 PASI 75 (%): Double-blind 2) etanercept (n=382) % male: 1) 7.3, 2) 53.4†, 3) Multicenter 3) ixekizumab, 80mg 84.2†‡, 4) 87.3†‡ (NCT01646177) Q4W (n=386) 1) 71.0, 2) 70.4, 3) 66.8, 4) 66.0 PASI 90 (%): 4) ixekizumab, 80mg Sites in USA, Canada, Q2W (n=385) Weight (kg): 1) 3.1, 2) 25.7†, 3) UNCOVER-3 Mexico, Argentina, 65.3†‡, 4) 68.1†‡ Chile, Europe, Czech <100kg- 1) 71.9, 2) Republic, Hungary, 67.0, 3) 71.9, 4) 71.6 PASI 100 (%): ©Institute for Clinical and Economic Review, 2016 Page 169 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Good quality Romania, Russia, ≥100kg- 1) 28.1, 2) 1) 0.0, 2) 7.3†, 3) publication Australia, and Japan 33.0, 3) 28.1, 4) 28.4 35.0†‡, 4) 37.7†‡ PsO duration (years): sPGA score of 0/1 with ≥2-point ITT 1) 18, 2) 18, 3), 18, 4) reduction (%): 18 1) 6.7, 2) 41.6†, 3) PASI: 75.4†‡, 4) 80.5†‡ 1) 21, 2), 21, 3) 21, 4) DLQI, score of 0/1 21 (%): DLQI: 1) 7.8, 2) 43.7‡, 3) 63.7‡§, 4) 64.7‡§ NR PsA (%): †p<0·0001 compared NR with placebo Previous biologics ‡p<0·0001 compared (%): etanercept 1) 17.1, 2) 15.7, 3) (see Table 2 in 15.0, 4) 15.1 publication for differences between groups and 97.5% CI) Other outcomes reported: sPGA score of 0, PASI % ©Institute for Clinical and Economic Review, 2016 Page 170 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents improvement, DLQI mean change, Itch NRS Guenther, 2016 Secondary analysis to See main trials See main trials See main trials Primary outcomes at NR evaluate week 12: improvement in sexual difficulties UNCOVER-2 UNCOVER-2 and -3 using DLQI Item 9 Improvement in sexual difficulties (%): Abstract 1) 24, 2) 51, 3) 68, 4) 80 3 and 4 vs. 1 and 2, p<0.001 UNCOVER-3 1) 27, 2) 69, 3) 78, 4) 81 3 and 4 vs. 2, p<0.05 3 and 4 vs. 1, p<0.001 Armstrong, 2016 See above N=3866 See main trials See main trials WPAI-PSO* NR UNCOVER-1 UNCOVER trials (all) Secondary analysis to Absenteeism: evaluate change in work productivity ©Institute for Clinical and Economic Review, 2016 Page 171 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Good quality from baseline as 1) 0.2, 2) -3.5, p< publication measured by WPAI- 0.001 vs. 1, 3) -2.6, p= PSO scores 0.003 vs. 1 Presenteeism: 1) 0.5 2) -18.8, 3) - 18.3 2 and 3 vs. 1, p<0.001 Work productivity loss: 1) -0.8, 2) -20.6, 3) - 19.8 2 and 3 vs. 1, p<0.001 Activity impairment: 1) 0.8, 2) -24.5, 3) - 25.2 2 and 3 vs. 1, p<0.001 “Similar results were obtained for UNCOVER-2 and UNCOVER-3, with the exception of absenteeism with ©Institute for Clinical and Economic Review, 2016 Page 172 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents ixekizumab Q4W in UNCOVER-2” UNCOVER-2 (from graph) Work productivity loss: 1)-2, 2) -14, 3) -19, 4) - 19.5 2 and 3 vs. 1 and 2, p<0.001 UNCOVER-3 (from graph) Work productivity loss: 1) +0.7, 2) -17, 3) -16, 4) -19 4 vs. 1, p<0.001; all other comparisons NS ©Institute for Clinical and Economic Review, 2016 Page 173 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *Data presented as least squares mean change from baseline relative to placebo Griffiths, 2016 Secondary analysis to N=3119 See main trials QIDS-SR16 median Primary outcomes at NR evaluate score: week 12: improvement in 1) placebo (n=791) depression 14.0 (no difference QIDS-SR16 mean Pooled UNCOVER 2) ixekizumab, 80mg b/w groups) change: (etanercept group not trials (all) Q4W (n=1161) included) 1) -3.6, 2) -6.5, 3) -6.9 3) ixekizumab, 80mg Q2W (n=1167) 2 and 3 vs. 1, p<0.001 Abstract QIDS-SR16 ≥50% improvement from baseline (%)*: 1) 27.1, 2) 49.1, 3) 59.8 2 and 3 vs. 1, p≤0.001 QIDS-SR16 remission (score ≤5) (%)*: 1) 17.8, 2) 33.5, 3) 45.2 2 and 3 vs. 1, p<0.05 ©Institute for Clinical and Economic Review, 2016 Page 174 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *Outcomes presented for NRI analysis Gottlieb, 2016 Secondary analysis to N=3126 See main trials NR Primary outcomes at NR evaluate subgroups of week 12: patients who were 1) placebo (n=792) biologic-naïve vs. PASI 75 (%): Pooled UNCOVER 2) ixekizumab, 80mg biologic-experienced trials (all) Q4W (n=1165) 1a) 2.7, 1b) 5.2, 3) ixekizumab, 80mg 2a) 77.5, 2b) 83.1, Q2W (n=1169) Abstract 3a) 89.5, 3b) 88.4 PASI 90 (%): a) biologic- experienced (n=883) 1a) 0, 1b) 1.7, b) biologic-naïve 2a) 53.7, 2b) 66.9, (n=2243) 3a) 73.0, 3b) 68.7 PASI 100 (%): 1a) 0, 1b) 0.3, 2a) 32.0, 2b) 34.7, 3a) 36.6, 3b) 39.1 All IXE groups vs. placebo, p<0.001 ©Institute for Clinical and Economic Review, 2016 Page 175 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Gottlieb, 2015 Secondary analysis to N=792 See main trials Joint Pain VAS: 49.6 Joint Pain VAS, mean NR evaluate subgroups of change: patients with PsA PASI: 21.6 (etanercept group not Placebo, +1.1 Pooled UNCOVER DLQI: 14.2 included) trials (all) IXE Q4W, -25.2 IXE Q2W, -26.8 Abstract DLQI, mean change: Placebo, -0.8 IXE Q4W, -10.5 IXE Q2W, -11.8 PASI 75 (%): Placebo, 2.9 IXE Q4W, 81.1 IXE Q2W, 89.8 SF-36 MCS, mean score: Placebo, +0.8 IXE Q4W, +4.2 ©Institute for Clinical and Economic Review, 2016 Page 176 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents IXE Q2W, +5.2 SF-36 PCS, mean score: Placebo, -1.1 IXE Q4W, +5.1 IXE Q2W, +5.4 IXE groups vs. placebo for all outcomes, p<0.001 IXORA-S, 2016 Phase III N=302 Inclusion: NR PASI 75 (%): NR (NCT02561806) RCT 1)ixekizumab, 80mg ≥6 months of plaque 1)91% Q2W (n=136) psoriasis diagnosis Abstract Double-blind 2)69% 2)ustekinumab, dosed Failure, Multicenter by weight according contraindication, or PASI 90 (%): to the label(n=166) intolerability of at 1)75 least 1 systemic therapy 2)42 Baseline PASI ≥10 PASI 100(%); Exclusion: 1)37 Prior use of 2)15 ustekinumab, prior ©Institute for Clinical and Economic Review, 2016 Page 177 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents participation of other sPGA of 0 (%): study with ixekizumab or IL-17A or IL12/23 1)43 antagonists, 2)18 concurrent or recent use of biologics within DLQI of 0/1 (%): washout periods, ongoing or serious 1)63 infection. 2)45 Brodalumab Papp, 2012 Phase II N=198 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 12: week 12: RCT 1) brodalumab 70mg ≥18 years 1) 42.1, 2) 44.0, 3) (n=39) 42.1, 4) 41.8 PASI 75 (%): AEs ≥1 (%): (NCT00975637) Double-blind BSA ≥10%, 2) brodalumab 140mg % male: 1) 33, 2) 77, 3) 82, 4) 0 1) 68, 2) 69, 3) 82, 4) Multicenter (n=39) PASI ≥12 62 1) 56, 2) 72, 3) 62, 4) PASI 50 (%): Good quality 3) brodalumab 210mg sPGA ≥3 58 URIs (%): publication (n=40) 1) 51, 2) 90, 3) 90, 4) 23 international sites ≥6 months of plaque Weight (kg): 16 1) 8, 2) 8, 3) 5, 4) 5 4) placebo (n=38) psoriasis diagnosis 1) 88.8, 2) 92.4, 3) PASI 90 (%): SAEs ≥1 (%): Candidates for 88.8, 4) 86.9 ITT phototherapy or 1) 18*, 2) 72, 3) 75, 4) 1) 3, 2) 0, 3) 2, 4) 3 Also evaluated 280mg systemic therapy PsO duration (years): 0 brodalumab monthly Discontinuation due 1) 20.7, 2) 19.2, 3) sPGA score of 0/1 to AEs (%): 17.1, 4) 18.3 (%): 1) 0, 2) 0, 3) 5, 4) 3 ©Institute for Clinical and Economic Review, 2016 Page 178 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Exclusion: patients PASI: 1) 26*, 2) 85, 3) 80, 4) could not have 3 received 1) 18.8, 2) 19.4, 3) Deaths: NR 20.6, 4) 18.9 biologic agents within 3 months, and no DLQI: All BROD groups vs. previous treatment placebo for both 1) 12.4, 2) 11.1, 11.4, outcomes, p<0.001; with ustekinumab or 13.3 *p<0.01 etanercept PsA (%): 1) 21, 2) 28, 3) 30, 4) DLQI, mean change: 18 1) -5.9*, 2) -9.1, 3) - Previous biologics 9.4, 4) -3.0 (%): All BROD groups vs. Etanercept- 1) 18, 2) placebo, p<0.001; 8, 3) 10, 4) 18 *p<0.01 Adalimumab- 1) 8, 2) SF-36, Physical: 13, 3) 18, 4) 11 1) +1.7, 2) +4.2, 3) Ustekinumab- 1) 15, +4.0, 4) +1.5 2) 5, 3) 15, 13 2 vs. placebo, p<0.01 SF-36, Mental: 1) +2.4, 2) +4.4, 3) +5.0, 4) +1.7 ©Institute for Clinical and Economic Review, 2016 Page 179 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2 vs. placebo, p<0.05; 3 vs. placebo, p<0.01 Other outcomes reported: Mean % BSA Gordon, 2013 Secondary analysis of See above See above See above Primary outcomes at NR Phase II data week 12: evaluating quality of life PSI total score = 0 (NCT00975637) (%): 1) 18, 2) 41, 3) 55, 4) 0 Good quality 2 and 3 vs. 4, publication p<0.0001; 1 vs. 4 p=0.006 PSI change: 1) 8.5, 2) 15.8, 3) 16.2, 4) 4.8 2 and 3 vs. 4, p<0.0001; 1 vs. 4, p=0.042 Other outcomes reported: Includes ©Institute for Clinical and Economic Review, 2016 Page 180 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents further breakdown of PSI and DLQI components at weeks 2, 4, 8 Papp, 2014 Secondary analysis of 1) PsA- yes (n=46) See original trial Age (years): Primary outcomes at AEs of any grade were Phase II data week 12: higher among patients evaluating subgroups 2) PsA- no (n=152) 1) 89.7, 2) 90.1, 3) 93, who received with and without PsA 4) 21.3 PASI 75 (%): brodalumab versus (NCT00975637) 3) Biologic use- yes and with and without placebo and were (n=70) PsO duration (years): 1a) 0, 1b) 82, 1c) 92 previous biologic use similar among subgroups (data NR) 4) Biologic use- no 1) 24.3, 2) 17.3, 3) 2a) 0, 2b) 75, 2c) 79 Fair quality (n=158) 21.4, 4) 17.6 publication 3a) 0, 3b) 70, 3c) 88 Subgroups were not PASI: compared statistically 4a) 0, 4b) 60, 4c) 79 due to low statistical a) placebo 1) 26.6, 2) 22.9, 3) power PASI 90 (%): 26.5, 4) 22.2 b) brodalumab 140mg DLQI: 1a) 0, 1b) 73, 1c) 83 c) brodalumab 210mg 1) 2a) 0, 1b) 71, 2c) 71 PsA (%) 3a) 0, 1b) 70, 1c) 81 1) 100, 2) 0, 3) 24.3, 4) 4a) 0, 1b) 72, 3c) 71 22.7 DLQI response: Previous biologics 1a) 0, 1b) 100, 1c) 100 (%): 2a) 42, 2b) 75, 2c) 79 ©Institute for Clinical and Economic Review, 2016 Page 181 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Anti-TNF- 1) 32.6, 2) 3a) 33, 3b) 80, 3c) 94 21.7, 3) 68.6, 4) 0 4a) 35, 4b) 83, 4c) 79 Ustekinumab- 1) 4.3, 2) 13.8, 3) 32.9, 4) 0 PSI score ≤8, with no item having a score >1 (%): 1a) 14, 1b) 100, 1c) 94 2a) 13, 2b) 86, 2c) 79 3a) 8, 3b) 100, 3c) 86 4a) 15, 4b) 94, 4c) 79 All BROD groups vs. placebo were SS Outcomes not compared between subgroups Other outcomes reported: PASI 100 Papp, 2015 Secondary analysis of 1) Biologic use- yes See original trial See original trial Primary outcomes at AEs at week 12 (%): Phase II data (n=70) week 12: (NCT00975637) evaluating subgroups 1) brodalumab (combined) – 79% ©Institute for Clinical and Economic Review, 2016 Page 182 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents with and without 2) Biologic use- no sPGA score of 0/1 placebo – 67% previous biologic use (n=158) (%): Abstract 2) brodalumab 1a) 8, 1b) 80, 1c) 81, (combined) – 70% 1d) 0 a) brodalumab 70mg placebo – 60% 2a) 35, 2b) 86, 2c) 79, b) brodalumab 140mg 2d) 4 c) brodalumab 210mg No outcomes were evaluated statistically d) placebo Other outcomes reported: sPGA score of 0 Papp, 2016 Phase III N=661 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 12: week 12: RCT 1) brodalumab 140mg 18 - 75years 1) 46, 2) 46, 3) 47 Q2W (n=219) PASI 75 (%): AEs ≥1 (%): (NCT01708590) Double-blind BSA ≥10%, % male: 2) brodalumab 210mg 1) 60, 2) 83, 3) 3 1) 58, 2) 59, 3) 51 Multicenter Q2W PASI ≥12 1) 74, 2) 73, 3) 73 PASI 90 (%): SAEs (%): AMAGINE 1 3) placebo (n=222) sPGA ≥3 Weight (kg): 1) 42.5, 70.3, 2) 0.9 1) 2.7, 2) 1.4, 3) 1.8 73 sites in the US, ≥6 months of plaque 1) 90.6, 2) 91.4, 3) Canada, and Europe psoriasis diagnosis 90.4 PASI 100 (%): Discontinuation due Good quality Patients who achieved to AEs (%): publication sPGA success (≥2) at PsO duration (years): 1) 0.5, 2) 23.3, 3) 41.9 1) 1.8, 2) 0.9, 3) 1.4 1) 19, 2), 20, 3) 21 ©Institute for Clinical and Economic Review, 2016 Page 183 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents ITT (all randomized week 12 were Candidates for PASI: sPGA score of 0/1 Depression (%) patients) rerandomized phototherapy or (%): systemic therapy 1) 19.7, 2) 18.9, 3) 1) 0.5, 2) 0.5, 3) 0.5 to their induction 19.0 1) 54, 2) 76, 3) 1 doses of brodalumab URIs (≥5% in any or placebo DLQI: HADS-A (treatment group): Exclusion: A washout difference, after 1) 8.2, 2) 8.1, 3) 6.4 period was required NR imputation): for patients receiving PsA (%): 1) -1.3, 2) -1.5 specific drugs No deaths (reported in 1) 27, 2) 26, 3) 29 BROD vs. placebo, supplementary p<0.001 appendix) Previous biologics (%): HADS-D (treatment AE outcomes at week difference, after 52 reported based on 1) 45, 2) 47, 3) 46 number of patients imputation): with exposure- 1) -1.9, 2) -2.1 emergent adverse events per 100 BROD vs. placebo, patient-years p<0.001 PSI responder (score ≤8, with no item 5 deaths (2 suicides, 1 having a score >1) in the placebo group (%): and 1 in the brodalumab 210mg 1) 53, 2) 61, 3) 4 group) At week 52: ©Institute for Clinical and Economic Review, 2016 Page 184 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI 90 (%): BROD 210/BROD 210, 78.3 BROD210/placebo, 0.0 BROD 140/BROD 140, 66.7 BROD140/placebo, 3.4 PASI 100 (%): BROD 210/BROD 210, 67.5 BROD210/placebo, 0.0 BROD 140/BROD 140, 43.9 BROD140/placebo, 1.7 sPGA score ≥2 (%): BROD 210/BROD 210, 83.1 ©Institute for Clinical and Economic Review, 2016 Page 185 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents BROD210/placebo, 0.0 BROD 140/BROD 140, 70.2 BROD140/placebo, 5.1 All BROD vs. placebo, p<0.001 Other outcomes reported: sPGA score of 0 Strober, 2016 PROs from AMAGINE- See original trial See original trial See original trial Primary outcomes at NR 1 week 12: DLQI improvement ≥5 (NCT01708590) (%) 1) 74, 2) 84, 3) 22 AMAGINE 1 DLQI score of 0/1 (%) 1) 43, 2) 56, 3) 5 Abstract PSI score = 0 (%) ©Institute for Clinical and Economic Review, 2016 Page 186 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 17, 2) 22, 3) 1 All BROD groups vs. placebo, p<0.001 PSI responder data same as Papp, 2016 Lebwohl, 2015 Phase III N=2,492 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 12: week 12: RCT 1) placebo (n=309) 18 - 75years 1) 44, 2) 45, 3) 45, 4) 45 PASI 75 (%) AMAGINE-2 NCT01708603 Double-blind 2) ustekinumab BSA ≥10%, (n=300) % male: 1) 8, 2) 70, 3) 67, 4) 86 AEs ≥1 (%): Multicenter PASI ≥12 3) brodalumab 140mg 1) 71, 2) 68, 3) 68, 4) PASI 90 (%) 1) 53.4, 2) 59.0, 3) AMAGINE-2 Q2W (n=610) sPGA ≥3 69 60.1, 4) 57.8 1) 3, 2) 47, 3) 49, 4) 70 142 international sites 4) brodalumab 210mg ≥6 months of plaque Weight (kg): SAEs (%): (US, Canada, Europe, Q2W (n=612) psoriasis diagnosis PASI 100 (%) Good quality Australia) 1) 92, 2), 91, 3) 92, 4) 1) 2.06, 2) 1.3, 3) 2.1, publication Candidates for 91 1), 2, 2) 22, 3) 26, 4) 4) 1.0 phototherapy or 44 At week 12, patients systemic therapy PsO duration (years): Discontinuation due ITT receiving brodalumab sPGA score of 0 or 1 to AEs (%): underwent 1) 18, 2) 19, 3) 19, 4) (%) 19 1) 0.3, 2) 1.3, 3) 1.2, 4) rerandomization to 1) 4, 2) 61, 3) 58, 4) 79 1.2 receive one of four PASI: p1 (%) brodalumab 1) 20.4, 2) 20.0, 3) 20.0, 4) 20.3 1) 7, 2) 55, 3) 51, 4) 68 ©Institute for Clinical and Economic Review, 2016 Page 187 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents maintenance DLQI: 1 attempted suicide regimens in the brodalumab NR All BROD groups vs. 210mg group placebo, p<0.001 PsA (%): 1) 17, 2) 17, 3), 21, 4) 1 death in the 19 *BROD 210mg was SS brodalumab 210mg better than UST in group (cerebral Previous biologics both trials on PASI 75, infarction) (%): 90, 100 and sPGA score of 0/1 (p-values 1)29, 2) 28, 3) 29, 4) in Table 2; no 29 AE outcomes at week comparison b/w BROD and UST for PSI) 52: Based on number of patients with Other outcomes exposure-emergent reported: sPGA score adverse events per of 0 100 patient-years (reported in supplementary appendix) At week 52 (after switching to brodalumab 210 mg): 2 additional PASI 75 (%) attempted suicides in the same patient as 1) 94, 2) 91 the induction period and 1 in the UST PASI 100 (%) group ©Institute for Clinical and Economic Review, 2016 Page 188 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 62, 2) 46 sPGA score of 0/1 (%) 1) 87, 2) 73 PSI score ≤8, with no item having a score >1 (%) 1) 81, 2) 84 Lebwohl, 2015 Phase III N=1,881 See above Age (years): Primary outcomes at AEs ≥1 (%): week 12: (same as above) RCT 1) placebo (n=315) 1) 44, 2) 45, 3) 45, 4) 1) 48.6, 2) 53.7, 3) 45 PASI 75 (%) 52.6, 4) 56.8 Double-blind 2) ustekinumab (n=313) % male: 1) 69, 2) 85*, 3) 69, 4) SAEs (%): (NCT01708629) Multicenter 6 3) brodalumab 140mg 1) 66, 2) 68, 3) 70, 4) 1) 1.0, 2) 0.6, 3) 1.6, 4) Q2W (n=629) 69 PASI 90 (%) 1.4 AMAGINE-3 142 international sites 4) brodalumab 210mg Weight (kg): 1) 2, 2) 48, 3) 52, 4) 69 Discontinuation due (US, Canada, Europe, Q2W (n=624) to AEs (%): Australia) 1) 89, 2), 90, 3) 89, 4) PASI 100 (%) 90 1) 1.0, 2) 0.6, 3) 0.8, 4) Good quality 1) 0.3, 2)19, 3) 27, 4) 1.1 publication PsO duration (years): 37 ITT 1) 18, 2), 18, 3) 17, 4) sPGA score of 0/1 18 (%): AE outcomes at week 52 based on number PASI: 1) 6), 2) 69, 3) 69, 4) of patients with 85 exposure-emergent ©Institute for Clinical and Economic Review, 2016 Page 189 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 20.1, 2) 20.1, 3) PSI score ≤8, with no adverse events per 20.1, 4) 20.4 item having a 100 patient-years score >1 (%) (reported in DLQI: supplementary 1) 6, 2) 52, 3) 53, 4) 61 appendix) NR PsA (%): All BROD groups vs. No attempted 1) 19, 2) 20, 3) 21, 4) placebo, p<0.001 suicides at any point 20 during the study Previous biologics (%): *BROD 210mg was SS better than UST in 1) 24, 2) 24, 3) 25, 4) both trials on PASI 75, 25 90, 100 and sPGA score of 0/1 (p-values in Table 2; no comparison b/w BROD and UST for PSI) Other outcomes reported: sPGA score of 0 At week 52 (after switching to brodalumab 210 mg): PASI 75 (%) ©Institute for Clinical and Economic Review, 2016 Page 190 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 93 2) 92 PASI 100 (%) 1) 68 2) 40 sPGA score of 0/1 (%) 1) 90 2) 70 PSI score ≤8, with no item having a score >1 (%) 1) 86 2) 73 Anti IL-12/13 Agent Ustekinumab (Stelara) Griffiths, 2010 Phase III N=903 Inclusion: Age (years): Primary outcomes at Primary outcomes at wk 12: week 12: RCT 1) ustekinumab 45mg ≥18 years 1) 45.1, 2) 44.8, 3) (n=209) 45.7 PASI 75 (%) AEs ≥1 (%): (NCT00454584) Multicenter BSA ≥10%, % male: 1) 67.5 2) 73.8, 3) 56.8 ©Institute for Clinical and Economic Review, 2016 Page 191 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 2) ustekinumab 90mg PASI ≥12, sPGA ≥3 1) 63.6, 67.4, 3) 70.9 1 vs. 3, p=0.01 1) 66.0, 2) 69.2), 3) (n=347) 70.0 ACCEPT Dose of UST was ≥6 months of plaque Weight (kg): 2 vs. 3, p<0.001 blinded, but otherwise 3) etanercept psoriasis diagnosis URIs (%): patients knew which 1) 90.4, 2) 91.0, 3) PASI 90 (%) drug they were 50mg (n=347) Candidates for 90.8 1) 6.2, 2) 6.3, 3) 5.8 Fair quality phototherapy or 1) 36.4, 2) 44.7, 23.1 receiving publication systemic therapy PsO duration (years): SAEs ≥1 (%): sPGA score of 0/1 (%) Patients who did not 1) 18.9, 2) 18.7, 3) 1) 1.9, 2) 1.2, 3) 1.2 respond on etanercept 18.8 1) 65.1, 2) 70.6, 3) 67 sites worldwide crossed over to Exclusion: patients 49.0 Infections (%): receive ustekinumab could not have PASI: Both UST groups vs. 1) 30.6, 2) 29.7, 3) received ITT but unclear about 1) 20.5, 2) 19.9, 3) ETN, p<0.001 29.1 handling of missing biologic agents within 18.6 Discontinuation due data 3 months, and no DLQI: to AEs (%): previous treatment Patients who did not with ustekinumab or NR respond on ETN and 1) 1.9, 2) 2.0, 3) 2.3 etanercept crossed over to UST PsA (%): 90mg: 1) 29.7, 2) 27.4, 3) PASI 75 (%): 48.9 3 deaths, 1 in each 27.4 active treatment arm PASI 90 (%): 23.4 Previous biologics (%): PGA- cleared or minimal (%): 40.4 Common AEs at wk 1) 12.4, 2) 10.4, 3) 64: adverse events 11.8 were similar in the lower-dose and Other outcomes higher-dose reported: PGA cleared ustekinumab groups ©Institute for Clinical and Economic Review, 2016 Page 192 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents and also before and after crossover from etanercept to ustekinumab Leonardi, 2008 Phase III N=766 Inclusion: Age: Primary outcomes at Primary outcomes at wk 12: week 12: RCT 1) ustekinumab ≥18 years 1) 44.8, 2) 46.2, 3) 44.8 PASI 75 (%) AEs ≥1 (%): (NCT00267969) Double-blind 45mg (n=255) PASI ≥12 % male: 1) 67.1, 2) 6 1) 57.6, 2) 51.4, 3) Multicenter 2) ustekinumab BSA ≥10% 48.2 1) 68.6, 2) 67.6, 3) PHOENIX 1 90mg (n=256) ≥6 months of plaque 71.8 URIs (%): psoriasis diagnosis 48 sites in the US, 3) placebo (n=255) Weight (kg): 1) 7.1, 2) 6.3, 3) 6.3 Canada, and Belgium Candidates for Good quality phototherapy or 1) 93.7, 2) 93.8, 3) SAEs (%): publication systemic therapy 94.2 6.4, 3) 3.1 Ustekinumab patients 1) 0.8, 2) 1.6, 3) 0.8 ITT with NRI with PASI ≥75% PsO duration (years): PASI 50 (%) improvement re- Exclusion: previous 1)19.7, 2) 19.6, 3) 20.4 Infections (%): randomized at wk 40 1) 83.5, 2) 85.9, 3) treatment with any PASI: 10.2 1) 31.4, 2) 25.9, 3) agent that targets 1) maintenance 26.7 (n=162) 1) 20.5, 2) 19.7, 3) PASI 90 (%) IL-12 or -23, received biological or 20.4 2) withdrawal (n=160) 1) 41.6, 2) 36.7, 3) 2.0 investigational agents DLQI: No dose response was within previous 3 All UST groups vs. seen in the rates of months, had received placebo, p<0.0001 1) 11.1, 2) 11.6, 3) adverse events, conventional systemic 11.8 serious adverse psoriasis therapy, or events, or adverse ©Institute for Clinical and Economic Review, 2016 Page 193 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Cross-over to phototherapy within PsA: PGA- cleared or events leading to ustekinumab 45 or 90 the previous 4 weeks, minimal (%): study agent mg at week 12 or had received 1) 29.0, 2) 36.7, 3) discontinuation topical psoriasis 35.3 1) 60.4, 2) 61.7, 3) 3.9 treatment within the Previous biologics 1 vs. 3: 56.5%, 95% CI previous 2 weeks (%): 50.0–62.9, p<0.0001 Similar AEs in withdrawal phase 1) 52.2, 2) 50.8, 3) 2 vs. 3: 57.8%, 95% CI 50.2 51.4–64.2, p<0.0001 DLQI score of 0 or 1 AEs also reported wk (%): 12-40 (crossover) and wk 40-74 (withdrawal) 1) 53.1, 2) 52.4, 3) 6.0 1 and 2 vs. 3: p<0.0001 3 deaths, 1 in the 45mg and 2 in the placebo groups Maintenance vs. withdrawal on PASI and PGA (data NR): p<0.0001 Other outcomes reported: PGA clear and marked or severe and DLQI mean change also reported at week 12 and 28, ©Institute for Clinical and Economic Review, 2016 Page 194 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents DLQI mean change reported at wk 28 Kimball, 2013 5-year long-term N=517 (those who See above Similar to original trial At wk 244: Serious infections (n): safety extension of received one dose of PHOENIX 1 ustekinumab) PASI 75 (%) 1) 13, 2) 19 (in 30 patients) PHOENIX 1 1) ustekinumab 45mg 1) 63.4, 2) 72.0 (n=259) MACE (n): PASI 90 (%) 2) ustekinumab 90mg 1) 8, 2) 2 (reported in 1) 39.7, 2) 49.0 10 patients) (n=258) PASI 100 (%) Discontinuation: 68.7% of 1) 21.6, 2) 26.4 ustekinumab-treated patients completed PGA- score of 0/1 (%): the 5-year f/u 1) 42.5, 2) 51.0 5 deaths unrelated to Other outcomes treatment reported: % PASI improvement Papp, 2008 Phase III N=766 Inclusion: Age (years): Primary outcomes at Primary outcomes at wk 12: week 12: RCT 1) ustekinumab 45mg ≥18 years 1) 45.1, 2) 46.6, 3) (n=409) 47.0 PASI 75 (%): AEs ≥1 at wk 12 (%): PHOENIX 2 Double-blind PASI ≥12 2) ustekinumab 90mg % male: 1) 66.7, 2) 75.7, 3) 3.7 1) 53.1, 47.9, 3) 49.8 Multicenter (n=411) BSA ≥10% ©Institute for Clinical and Economic Review, 2016 Page 195 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Good quality 3) placebo (n=410) ≥6 months of plaque 1) 69.2, 2) 66.7, 3) PASI 50 (%): URIs (%): publication psoriasis diagnosis 69.0 70 sites in Europe and 1) 83.6, 2) 89.3, 3) 1) 4.4, 2) 2.9, 3) 3.4 North Weight (kg): 10.0 Partial responders SAEs (%): America (i.e., patients Exclusion: 1) 90.3, 2) 91.5, 3) PASI 90 (%): achieving ≥50% but 91.1 1) 2.0, 1.2, 3) 2.0 <75% improvement patients who had 1) 42.3, 2) 50.9, 3) 0.7 received treatment PsO duration (years): Infections (%): from baseline in PASI) ITT with NRI with any agent PGA, cleared/minimal were re-randomized 1) 19.3, 2) 20.3, 3) (%): 1) 21.5, 2) 22.4, 3) at week 28 that specifically 20.8 20.0 targeted IL-12 or -23, 1) 68.0, 2) 73.5, 3) 4.9 PASI: Discontinuation due had received DLQI, score of 0/1 to AEs (%): NR biological or 1) 19.4, 2) 20.1, 3) (%): investigational agents 19.4 Patients not achieving within the previous 3 1) 55.3, 2) 56.4, 3) 3.2 PASI 50 at wk 28 months DLQI: discontinued the study All UST groups vs. 1) 12.2, 2) 12.6, 3) placebo, p<0.0001 12.3 AEs at wk 52: No dose PsA (%): response had been observed in rates of 1) 26.2, 2) 22.9, 3) adverse events, 25.6 Other outcomes serious adverse reported: PGA clear events, or adverse Previous biologics and marked or severe events leading to (%): and DLQI mean treatment change also reported discontinuation. 1) 38.4, 2) 36.5, 3) at week 12 and 28, 38.8 ©Institute for Clinical and Economic Review, 2016 Page 196 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents DLQI mean change 1 death (cardiac- reported at wk 28 related) Baseline characteristics for partial responders at wk 28 also reported PASI 50, 90, 100 scores also reported at week 28 Langley, 2015 5-year long-term N=1212 See above BSA (%): At wk 244: AEs at wk 264 (n): safety extension of PHOENIX 2 1) ustekinumab 45mg a) 29.0, b) 22.9 PASI 75 (%): 1) 222, 2) 195, 3) 206 (n=606) PHOENIX 2 PASI: 1) 76.5, 2) 78.6 a) 187, 216, 3) 202 2) ustekinumab 90mg Also compared dose (n=606) a) 20.5, b) 18.4 PASI 90 (%): *Discontinuation due adjusters to non- to AEs (%): 3) combined Hyperlipidemia 1) 50.0, 2) 55.5 adjusters after wk 28 1) 2.17, 2) 2.58, 3) a) 24.6, b) 16.4 PASI 100 (%): 2.43 N=1112 Hypertension (%)ⱡ: 1) 28.1, 2) 31.3 a) 2.51, b) 1.66, c) 2.06 a) adjusters (n=544) a) 29.6, b) 24. PGA, cleared/minimal (%): *SAEs (%): b) non-adjusters PsA (%)*: (n=568) 1) 54.0, 2) 58.6 1) 7.99, 2) 6.87, 3) a) 28.7, b) 21.9 2.43 c) combined Systemic therapies: a) 6.57, b) 7.43, c) 7.02 a) 63.2, b) 47.8 ©Institute for Clinical and Economic Review, 2016 Page 197 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Previous biologics “The greatest *MACE (%): (%): incidence of dosing adjustments occurred 1) 0.56, 2) 0.42, 3) a) 44.4, b) 30.3 among patients 0.48 weighing > 100 kg a) 0.38, b) 0.54, c) originally randomized 0.46 to 45 mg” *p=0.009, ⱡp=0.046, all other comparisons *Infections (%): p<0.001 1) 85.6, 2) 75.9, 3) 79.7 a) 22.5, b) 25.9, c) 24.3 *Results presented per 100 patient-years Langley, 2010 Secondary analysis of See original study See original study See original study Primary outcomes at All psychologic AEs patients from wk 12: were mild and did not PHOENIX 2 evaluating result in treatment anxiety, depression HADS-A, mean discontinuation PHOENIX 2 and QoL 1) -1.6, 2) -1.6, 3) - 0.11 Good quality HADS-D, mean publication 1) -1.7, 2) -2.1, 3) - 0.21 ©Institute for Clinical and Economic Review, 2016 Page 198 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents DLQI, mean 1) -9.3, 2) -10.0, 3) - 0.5 UST vs. placebo, p<0.001 Other outcomes reported: % of patients with symptoms of depression and anxiety Reich, 2011 Secondary analysis of See original study See original study See original study Primary outcomes at NR patients from wk 12: PHOENIX 2 evaluating productivity Median improvement PHOENIX 2 Median productivity from baseline in work VAS score: days missed (%): 1) 2.7, 2) 3.2, 3) 2.6 1) 81.6, 2) 78.4, 3) Good quality 10.6 publication Median improvement from baseline in productivity VAS (%): 1) 72.6, 2) 71.4, 3) 0.0 ©Institute for Clinical and Economic Review, 2016 Page 199 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *WLQ-physical demands 1) 7.6, 2) 5.1ⱡ, 3) 0.2 *WLQ-time management 1) 6.6, 2) 9.1, 3) -0.7 *WLQ-mental- interpersonal 1) 7.8, 2) 7.5, 3) -1.1 *WLQ-output demands 1) 6.8, 2) 7.0, 3) -1.1 UST vs. placebo, p<0.001 (ⱡ=NS) At wk 24: Median improvement from baseline in work days missed (%): Placebo/UST45, 87.2 Placebo/UST90, 72.6 ©Institute for Clinical and Economic Review, 2016 Page 200 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents UST45, 83.3 UST90, 80.7 Median productivity VAS (%): Placebo/UST(combine d), 1.29 UST(combined), 1.31 *WLQ-physical demands Placebo/UST45, 5.8 Placebo/UST90, 5.6 UST45, 8.6 UST90, 10.6 *WLQ-time management Placebo/UST45, 10.8 Placebo/UST90, 9.7 UST90, 8.0 UST45, 10.2 ©Institute for Clinical and Economic Review, 2016 Page 201 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents *WLQ-mental- interpersonal Placebo/UST45, 9.2 Placebo/UST90, 8.1 UST45, 8.0 UST90, 9.1 *WLQ-output demands Placebo/UST45, 7.5 Placebo/UST90, 8.0 UST90, 7.8 UST45, 7.8 *Mean improvement from baseline, not measure statistically Sofen, 2010 Pooled analysis of N=563 See original studies PASI: Primary outcomes at NR patients from wk 12: PHOENIX 1 and 2 for a 20.7 subgroup with PsA Primary: PASI 75 (%): PHOENIX 1 and 2 DLQI: 1) 63.0, 2) 61.5, 3) 3.6 ©Institute for Clinical and Economic Review, 2016 Page 202 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 12.6 DLQI, mean score: Abstract 1) -9.2, 2) -9.7, 3) - 0.01 DLQI, ≥5 improvement: 1) -9.2, 2) -9.7, 3) - 0.01 All UST groups vs. placebo, p<0.001 Guenther, 2011 Pooled analysis of See original trials See original trials Impaired sexual Primary outcomes at NR patients from function (score of 2 or wk 12: PHOENIX 1 and 2 for 3 on DLQI item 9) (%): patients with sexual DLQI, mean change: PHOENIX 1 and 2 All UST, 22.6 difficulties UST, -9.13 UST45, 22.8 Placebo, -0.53 Good quality UST90, 22.1 publication TE (Cohen’s d score): - Placebo, 23.0 1.36 DLQI, ≥5: UST45, 69.0 UST90, 74.7 Placebo, 20.1 ©Institute for Clinical and Economic Review, 2016 Page 203 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents UST vs. placebo, p<0.001 Patients with impaired sexual function (%): UST, 2.7 UST45, 2.6 UST90, 2.8 Placebo, no change (23.0) UST vs. placebo, p<0.001 At wk 28: Patients with impaired sexual function (%): UST (crossover), 4.4 UST45, 3.4 UST, 90, 2.3 ©Institute for Clinical and Economic Review, 2016 Page 204 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Igarashi, 2012 Phase II/III N=158 Inclusion: Age (years): Primary outcomes at Primary outcomes at wk 12: wk 12: RCT 1) ustekinumab 45mg ≥20 years 1) 45, 2) 44, 3) 49 (n=64) PASI 75 (%): AEs ≥1 (%): Good quality Double-blind PASI ≥12 % male: publication 2) ustekinumab 90mg 1) 59.4, 2) 67.7, 3) 6.5 1) 65.6, 2) 59.7, 3) Multicenter (n=62) BSA ≥10% 1) 82.8, 2) 75.8, 3) 65.6 83.9 PASI 50 (%): 3) placebo (n=32) ≥6 months of plaque SAEs (%): psoriasis diagnosis Weight (kg): 1) 82.8, 2) 83.9, 3) 35 sites in Japan 12.9 1) 0.0, 2) 4.8, 3) 6.3 1) 73.2, 2) 71.1, 3) Cross-over to 71.2 PASI 90 (%): Infections (%): ustekinumab 45 or 90 ITT with NRI PsO duration (years): 1) 32.8, 2) 43.5, 3) 3.2 1) 20.3, 2) 24.2, 3) mg at week 12 18.8 1) 15.8, 2) 17.3, 3) PGA, cleared/minimal 16.0 (%): Discontinuation from AEs (%): PASI: 1) 57.8, 2) 69.4, 3) 9.7 1) 0.0, 2) 6.5, 3) 6.3 1) 30.1, 2) 28.7, 3) DLQI score of 0/1 (%): 30.3 1) 30.6, 2) 32.8, 3) 6.7 AEs also reported DLQI: through wk 72 All UST groups vs. (generally comparable 1) 11.4, 2) 10.7, 10.5 placebo, p<0.0001 between groups) PsA (%): VAS improvement (mean) 1) 9.4, 2) 11.3, 3) 3.1 No deaths through wk 1) -38.5, 2) -9.3. 3) 72 Previous biologics +8.0 (%): ©Institute for Clinical and Economic Review, 2016 Page 205 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 1.6, 2) 0.0, 3) 0.0 p=NR Other outcomes reported: DLQI mean change, SF-36 summary, MCS, and PDI scores also included through wk 64 Tsai, 2011 Phase III N=121 Inclusion: Age (years): Primary outcomes at Primary outcomes at wk 12: wk 12: RCT 1) ustekinumab 45mg ≥20 years 1) 40.9, 2) 40.4 (n=61) PASI 75 (%): AEs ≥1 (%): PEARL Double-blind PASI ≥12 % male: 2) placebo (n=60) 1) 67.2, 2) 5.0 1) 65.6, 2) 70.0 Multicenter BSA ≥10% 1) 82.0, 2) 88.3 1 vs. 2, p<0.001 SAEs (%): Good quality ≥6 months of plaque Weight (kg): publication Placebo group psoriasis diagnosis PASI 50 (%): 1) 0.0, 2) 3.3 Conducted at 13 sites crossed-over to 1) 73.1, 2) 74.6 in Korea and Taiwan ustekinumab 45mg at 1) 83.6, 2) 13.3 URIs (%): PsO duration (years): wk 12-36 Exclusion: patients 1 vs. 2, p<0.001 1) 11.5, 2) 11.7 could not have 1) 11.9, 13.9 ITT with NRI received PASI 90 (%): Discontinuation from PASI: AEs (%): biologic agents within 1) 49.2, 2) 1.7 1) 0.0, 2) 5.0 1) 25.2, 2) 22.9 3 months 1 vs. 2, p<0.001 Infections (%): DLQI: PASI 100 (%): ©Institute for Clinical and Economic Review, 2016 Page 206 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 16.1, 15.2 1) 8.2, 2) 0.0 1) 32.8, 2) 23.3 PsA (%): 1 vs. 2, p=0.024 1) 16.4, 2) 11.7 PGA, cleared/minimal At wk 36: (%): Previous biologics AEs ≥1 (%): (%): 1) 70.5, 2) 8.3 Placebo/UST, 67.3 1) 21.3, 2) 15.0 1 vs. 2, p<0.001 UST45, 67.8 DLQI, mean change: SAEs (%): The population was 1) -11.2, 2) -0.5 evenly distributed Placebo/UST, 9.1 1 vs. 2, p<0.001 Between UST45, 3.4 Taiwanese/Chinese URIs (%): (49.6%) and Korean At wk 28: (50.4%) Placebo/UST, 3.6 PASI 75 (%): UST45, 8.5 Placebo/UST, 74.1 Discontinuation from UST45, 72.4 AEs (%): Placebo/UST, 0.0 PASI 50 (%): UST45, 1.6 Placebo/UST, 87.0 Infections (%): UST45, 84.5 Placebo/UST, 25.5 PASI 90 (%): ©Institute for Clinical and Economic Review, 2016 Page 207 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Placebo/UST45, 46.3 UST45, 32.2 UST45, 60.3 PASI 100 (%): No deaths during the study Placebo/UST45, 16.7 UST45, 20.7 PGA, cleared/minimal (%): DLQI, mean change: Placebo/UST45, 59.3 UST45, 69.0 p-values for wk 28 outcomes=NR Other outcomes reported: % PASI improvement, PGA cleared Also reported response at wk 12 and ©Institute for Clinical and Economic Review, 2016 Page 208 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 28 by weight (≤70kg vs. >70kg) Zhu, 2013 Phase III N=322 Inclusion: Age (years): Primary outcomes at At week 12: wk 12: RCT 1) ustekinumab 45mg ≥18 years 1) 40.1, 2) 39.2 AEs (%) (n=160) PASI 75 (%): LOTUS Double-blind PASI ≥12 % male: 1) 42.5, 2) 38.5 2) placebo (n=162) 1) 82.5 BSA ≥10% 1) 78.1, 2) 75.9 2) 11.1 Good quality 14 sites in China ≥6 months of plaque Weight (kg): SAEs (%) publication Placebo patients psoriasis diagnosis PASI 50 (%): crossed over to 1) 69.9, 2) 70.0 1) 0.6 receive ustekinumab 1) 91.3 ITT with NRI PsO duration (years): 2) 0.6 for wks 12-16 2) 19.8 1) 14.6, 14.2 PASI 90 (%): PASI: Infections (%) 1) 66.9 1) 23.2, 2) 22.7 1) 19.3 2) 3.1 DLQI: 2) 25.6 PGA, cleared/minimal 1) 13.7, 2) 13.1 (%) PsA (%): 1) 78.8 Discontinuation due to AEs (%) 1)8.8, 2)8.6 2) 14.8 1) 1.2 Previous biologics All UST groups vs. (%): placebo, p<0.001 2) 1.9 ©Institute for Clinical and Economic Review, 2016 Page 209 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 11.9, 6.8 Response was No deaths, serious maintained through infections, wk 28 malignancies, or cardiovascular events reported through wk 36 Observational Studies Clemmensen, 2011 Database of Danish N=179 Inclusion: Age (years): “No difference in the Discontinuation (%): patients to evaluate PASI75 response drug adherence in 1) All ustekinumab Failure of two or more 1) 43.1, 2) 41.8, 3) between the subjects Ustekinumab survival anti-TNF-naïve vs. (n=71) conventional systemic 43.7, 4) 43.7 exposed to was significantly DERMBIO agents or lack of better than the anti-TNF exposed over 2) ustekinumab anti- efficacy or intolerance % male: 1, 2 or 3 anti-TNFa adherence to anti-TNF 1 year TNF-naïve (n=24) to methotrexate and agents (data NR)” drugs (p<0.001, HR 1) 50.7, 2) 41.7, 3) narrow- band 0.32, 95% CI 0.15– Publication 55.3, 4) 53.7 ultraviolet B; for 0.67) biologic-naive ©Institute for Clinical and Economic Review, 2016 Page 210 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3) ustekinumab anti- patients, PASI >10 or PASI: “Previous failure to TNF exposed (n=37) DLQI >10 one or more TNFa Poor quality 1) 10.9, 2) 13.7, 3) 9.6, inhibitors did not 4) Anti-TNFs (n=47) 4) 10.4 influence treatment responses measured Observation time by the time to PASI 75 (days): or the proportion of patients achieving 1) 142.6, 2) 132.8, 3) PASI 75” 147.5, 4) 173.1 Differences between groups not measured statistically Gelfand, 2012 Cross-sectional study N=713 N/A No compared PGA clear or almost NR of 10 outpatient between groups clear (%): dermatology sites 1) ADA (n=152) across the US 1) 47.7% Publication 2) ETN (n=191) participating in the Age (years): 48.6 2) 34.2% Dermatology Clinical 3) UST (n=73) % male: 50.6 3) 36.1% Effectiveness Good quality Research Network Weight (kg): NR p<0.001 PsO duration (years): 19 PGA clear or almost PsA (%): 22.6 clear (*adjusted relative rates): ©Institute for Clinical and Economic Review, 2016 Page 211 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Previous biologics 1) 2.15; 95% CI, 1.60- (%): 37.3 2.90 2) 1.45; 95% CI 1.06- 1.97 3) 1.57; 95% CI 1.06- 2.32 Differences in median PGA: (p<0.001), PASI (p=.02), and BSA (p=0.01) across therapies Treatment doses were double the recommended doses in 36.1% of patients taking etanercept and 11.8% of those taking adalimumab; 10.6% of patients undergoing phototherapy received the ©Institute for Clinical and Economic Review, 2016 Page 212 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents recommended treatment frequency *Adjusted for sex, race, ethnicity, body mass index, skin type, frequency of topical use, practice setting of dermatologist, marital status, income, and insurance Gniadecki, 2011 Database of Danish N=1277 Inclusion: Patients on Age (years): *OR for treatment NR patients to evaluate biologics with: termination: long-term drug 1) ADA (n=567) 1) 44.4, 2) 46.3, 3) survival (time to drug PASI > 10 45.5, 4) 44.6 1 vs. 4: 1.77, 95% CI DERMBIO 2) ETN (n=364) 1.39-2.26, p<0.0001 discontinuation) DLQI > 10 % male: followed up to 10 3) INF (n=176) 2 vs. 4: 2.55, 95% CI years BSA > 10% 1) 63.8, 2) 65.9, 67.6, 1.98-3.29, p<0.0001 Publication 4) UST (n=170) 4) 60.6 in whom treatments 3 vs. 4: 1.99, 95% CI Good quality Weight (kg): 1.5-2.63, p<0.0001 previously failed or who have 1) 87.4, 2) 88.6, 3) 2 vs. 1: 1.42, 95% CI, contraindications to 92.0, 4) 89.6 1.20-1.68, p<0.0001 topical therapies, ultraviolet B PsO duration (years): 2 vs. 3: 1.30, 95% CI phototherapy and 1.04-1.61, p=0.02 1) 18.7, 2) 19.5, 3) methotrexate 18.7, 4) 17.9 ©Institute for Clinical and Economic Review, 2016 Page 213 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PASI: Bio-naïve vs. bio- exposed: 1.24, 95% CI The choice of drug 1) 12.5, 2) 12.6, 3) 1.05-1.46, 0.011 15.8, 4) 11.4 was the decision of Male vs. female: 1.51, the physician DLQI: 95% CI 1.31-1.74, p<0.0001 1) 12.6, 2) 11.9, 3) 13.9, 4) 11.5 PsA (%): Adjusted for covariates 1) 38.1, 2) 39.6, 3) 43.8, 4) 14.1 Previous biologics (%): NR Goren, 2015 Web-based survey N=250 Inclusion: Age (years): Significantly higher NR from a US claims proportion of bio- database study 1) bio-naïve (n=68) ≥18 years 1a) 45.8, 1b) 47.6, 2a) naïve ustekinumab evaluating differences 51.1, 2b) 46.4 users reported a score Publication 1a) ADA (n=26) between ustekinumab of 0 on the DLQI % male: and adalimumab for compared with bio- 1b) UST (n=42) patients previously or naïve adalimumab 1a) 61.5, 1b) 54.8, 2a) Fair quality not previous on 2) etanercept- users (45.2% vs 19.2%, 42.9, 2b) 55.4 etanercept experienced p<0.05). After Weight (kg): adjusting for 2a) ADA (n=49) covariates in NR multivariable models, 2b) UST (n=65) ©Institute for Clinical and Economic Review, 2016 Page 214 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PsO duration (years): the results were still significant. 1a) 11.4, 1b) 18.5, 2a) 21.2, 2b) 17.9 Adjusting for covariates, no Bio-naïve ADA significant overall patients had a differences were significantly shorter realized on health duration of psoriasis outcomes across UST then ustekinumab and ADA users. Kalb, 2013 Multicenter, N=11466 Inclusion: Age (years): NR *Incidence rate of longitudinal, psoriasis- serious infections based registry study 1) UST (n=3474) Non-biologic 1) 47.2, 2) 48.7, 3) (unadjusted): evaluating the risk of therapies included 47.6, 4) 48.5, 5) 50.1, PSOLAR 2) ETN (n=1854) (but were not limited 6) 55.1 Overall: 1.45 infection in biologics and other systemic 3) ADA (n=2675) to) methotrexate, % male: 1) 0.83, 2) 1.47, 3) therapies followed up systemic retinoids, 1.97, 4) 2.49, 5) 1.05, Publication to 8 years 4) INF (n=1151) psoralen plus UV-A, 1) 57.5, 2) 56.0, 3) 6) 1.28 and UV-B, which may 56.3, 4) 56.6, 5) 51.6, Nonmethotrexate/no also impact infection 6) 42.2 Biologic-exposed nbiologics, (n=1610) (June 20, 2007, risk in different ways (incident): 1.35 Good quality PsA (%): 5) Methotrexate/ through August 23, and to different Bio-naïve: 1.12 1) 32.6, 2) 42.3, 3) 2013) nonbiologics, (n=490) degrees. 41.6, 4) 52.2, 5) 14.7, The trend was similar 6) 28.6 across the biologic Previous biologics cohorts in the incident (22,311 patient-years) (%): 71.4 ©Institute for Clinical and Economic Review, 2016 Page 215 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Treatment dosing was and bio-naive determined by the populations treating physician SS differences between the biologics (ie, lowest rates for and the ustekinumab or nonmethotrexate/ etanercept cohorts, nonbiologics cohorts followed by either the (age, sex, BMI, and infliximab or disease characteristics adalimumab cohort) [PGA score, PsO duration]), as well as among the individual *Most common AEs: biologic groups (higher prevalence of Pneumonia: psoriatic arthritis, history of serious 1) 0.19, 2) 0.27, 3) infection) 0.39, 4) 0.44, 5) 0.21, 6) 0.16 Cellulitis: 1) 0.19, 2) 0.37, 3) 0.19, 4) 0.40, 5) 0.13, 6) 0.24 *per 100 patient- years for those that occurred at least 4 ©Institute for Clinical and Economic Review, 2016 Page 216 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents times across treatment cohorts Multivariate analysis for the overall population: Increasing age: HR, 1.37; 95% CI, 1.24- 1.52) Presence of diabetes: HR, 1.70; 95% CI, 1.25- 2.32 History of significant infections: HR, 1.67; 95%CI, 1.28- 2.18 Increased risk of serious infections, all outcomes p<0.001 Papp, 2015 Multicenter, N=12094 NR Age (years): NR *Cumulative longitudinal, psoriasis- incidence rates based registry study 1) UST (n=4134) 1) 47.2, 2) 49.2, 3) evaluating adverse 48.4, 4) 51.2 ©Institute for Clinical and Economic Review, 2016 Page 217 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents PSOLAR events in a real-world 2) INF (n=1435) Treatment dosing was % male: All-cause mortality setting for 8 years determined by the (overall): 0.46 3) ⱡother biologics treating physician 1) 57.5, 2) 55.1, 3) (n=2151) 55.25, 4) 49.3 1) 0.36, 2) 0.45, 3) Publication 0.42, 4) 0.70 (June 20, 2007, 4) *non-biologics PsA (%): (n=2151) MACE (overall): 0.36 through August 23, 1) 34.0, 2) 55.2, 3) Good quality 2013) 39.6, 4) 18.1 1) 0.34, 2) 0.38, 3) 0.33, 4) 0.45 (31,818 patient-years) Previous biologics (%): 1) 88.4, 2) 94.8, Serious infections 3) 85.8, 4) 0.0 (overall): 1.50 ⱡ4188 were treated 1) 0.95, 2) 2.78, 3) with adalimumab 1.80, 4) 1.26 and/or etanercept *511 were exposed to methotrexate *Data are presented as rate/100 patient- years Missing values for covariates were imputed as the mean for continuous factors and as the median for categorical factors. ©Institute for Clinical and Economic Review, 2016 Page 218 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Strober, 2016 Multicenter, N=2076 (patients Inclusion: Patients Age (years): 12 Month Analysis (6 NR longitudinal, psoriasis- initiating a new may have been bio- months also based registry study biologic) naive or may 1) 46.3, 2) 46.8, 3) reported): evaluating 46.7, 4) 47.9 PSOLAR 1) UST (n=1041) have been exposed PGA of 0/1 (%): effectiveness of before enrollment to % male: biologics in a real- 2) ETN (n=116) a biologic 1) 59.9, 2) 57.6, 3) world setting 1) 56.8, 2) 56.0, 3) 56.5, 4) 42.0 Publication 3) ADA (n=662) 58.0, 4) 62.9 other than their newly initiated treatment in *Odds of achieving a 4) INF (n=257) PsO duration (years): PGA score of 0/1 (June 20, 2007, the (logistic regression): Fair quality 1) 19.1, 2) 14.7, 3) through August 23, registry 16.1, 4) 17.2 1 vs. 4: OR 0.449, 95% 2013) CI 0.260-0.774, PsA (%): p=0.040 Excluded: 1) 33.5, 2) 35.8, 3) No other comparisons Patients restarting a 35.0, 4) 44.0 to UST were SS biologic received before enrollment *DLQI mean improvement (least Baseline clinical values mean square): numerically reflected more severe disease in 1 vs. 2: -5.011, 1.917 the infliximab group. (95% CI 0.909-2.925), p=0.0002 1 vs. 3: -6.185, 0.743 (95% CI 0.025-1.492), p=0.427 ©Institute for Clinical and Economic Review, 2016 Page 219 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents No other comparisons to UST were SS *Adjusted multivariate analysis Missing data excluded in the analysis Other outcomes reported: 6-month data and BSA Anti-PDE4 Agent Apremilast (Otezla) Papp, 2012 Phase IIb N=352 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 16*: week 16: RCT 1) placebo (n=88) ≥18 years 1) 44.1, 2) 44.4, 3) 44.6, 4) 44.1 PASI 50 (%): AEs ≥1 (%): (NCT00773734) Double-blind 2) apremilast 10mg BSA ≥10%, BID (n=89) % male: 1) 25, 2) 38.2, 3) 47.1, 1) 65, 2) 66, 3) 77, 4) Multicenter PASI ≥12 4) 60.2 82 3) apremilast 20mg 1) 60, 2) 71, 3) 63, 4) Good quality BID (n=87) ≥6 months of plaque 57 2 vs. 1, p=NS SAEs ≥1 (%): publication psoriasis diagnosis 35 sites in the US and 4) apremilast 30mg Weight (kg): 3 vs. 1, p<0.001 1) 2, 2) 0, 3) 2, 4) 2 Canada BID (n=88) 4 vs. 1, p=0.002 Infections ≥1 (%): ©Institute for Clinical and Economic Review, 2016 Page 220 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Candidates for 1) 90.4, 2) 95.9, 3) PASI 75 (%): 1) 33, 2) 33, 2) 41, 4) phototherapy or 20.2, 4) 91.4 48 ITT with LOCF Patients in the systemic therapy 1) 5.7, 2) 11.2, 3) 28.7, placebo group were PsO duration (years): 4) 40.9 Discontinuation due rerandomized to APR to AEs (%): 20mg or 30mg (n=70); 1) 19.6, 2) 18.0, 3) 2 vs. 1, p=NS those in the APR Exclusion: use of 19.2, 4) 19.2 1) 5.7, 2) 2.2, 3) 9.2, 4) adalimumab, 3 and 4 vs. 1, p<0.001 11.47 groups continued to etanercept, PASI: the active treatment PASI 90 (%): Deaths (n): phase wk 16-24 efalizumab, or 1) 18.1, 2) 18.1, 3) (n=210) infliximab within 12 18.5, 4) 19.1 1) 1.1, 2) 4.5, 3) 9.2, 4) 1 in the placebo group weeks; or had used 11.4 alefacept within 24 DLQI: weeks of 2 vs. 1, p=NS randomization NR At week 24 (those 3 vs. 1, p=0.016 continuing PsA (%): apremilast): 4 vs. 1, p=0.005 1) 19, 2) 23, 3) 18, 4) AEs ≥1 (%): 24 PASI 100 (%): 2) 39, 3) 39, 4) 46 Previous biologics 1) 1, 2) 0, 3) 3.4, 4) 2.3 (%): SAEs ≥1 (%): 2 vs. 1, p=NR NR [see exclusion 1) 1, 2-4) 0 3 and 4 vs. 1, p=NS criteria] Infections ≥1 (%): sPGA score of 0/1 (%): 2) 18, 3) 15, 4) 22 1) 12.5, 2) 10.1, 3) Discontinuation due 24.1, 4) 33.0 to AEs (n): ©Institute for Clinical and Economic Review, 2016 Page 221 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents p=NR 2) 4, 3) 0, 4) 0 sPGA mean change Deaths (n): (%): None 1) -0.6, 2) -0.8, 3) -1.2, 4) 37.7 2 vs. 1, p=NS 3 and 4 vs. 1, p<0.001 Pruritus VAS, mean % change (%): 1) -6.1, 2) -10.2, 3) - 35.5, 4) -43.7 2 vs. 1, p=NS 3 vs. 1, p=0.005 4 vs. 1, p<0.001 DLQI ≥ 5-point decrease (only patients with score >5) (%): 1) 25, 2) 34, 3) 49, 4) 44 2 vs. 1, p=NR ©Institute for Clinical and Economic Review, 2016 Page 222 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 3 vs. 1, p=0.001 4 vs. 1, p=0.011 *All outcomes LOCF for missing data Other outcomes reported: BSA mean change, SF-36 domain scores at wk 16 and 24, DLQI mean change at wk 24 Strand, 2013 Reporting of PRO See above See above See above At wk 16: NR measures DLQI mean change (%): (NCT00773734) 1) -1.9, 2) -3.2, 3), - 5.9, 4) -4.4 Good quality publication Other outcomes reported: MCID between groups for PROs ©Institute for Clinical and Economic Review, 2016 Page 223 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Papp, 2013 Reporting of symptom See above See above See above At wk 24 (those NR measures continuing apremilast): (NCT00773734) Pruritus VAS, mean change (%): 2) -36.7, 3) -41.5, 4) - Phase IIb 41.0 p=NR Abstract Other outcomes reported: MCID between groups for pruritus VAS Papp, 2015 Phase III N=844 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 16: week 16: RCT 1) placebo (n=282) ≥18 years 1) 46.5, 2) 45.8 PASI 50 (%): AEs ≥1 (%): (NCT01194219) Double-blind 2) apremilast 30mg BSA ≥10%, % male: BID (n=562) 1) 17.0, 2) 58.7ⱡ 1) 55.7, 2) 69.3 Multicenter PASI ≥12 1) 68.8, 2) 67.4 PASI 75 (%)*: SAEs ≥1 (%): ESTEEM 1 sPGA ≥3 Weight (kg): 1) 5.3, 2) 33.1ⱡ 1) 2.8, 2) 2.1 72 sites in the US, ≥6 months of plaque 1) 93.7, 2) 93.2 Canada, and Europe psoriasis diagnosis PASI 90 (%): Discontinuation due Good quality PsO duration (years): to AEs (%): publication 1) 0.4, 2) 9.8 1) 18.7, 2) 19.8 ©Institute for Clinical and Economic Review, 2016 Page 224 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents ITT with LOCF and NRI Candidates for PASI: sPGA score of 0/1 1) 3.2, 2) 5.3 results phototherapy or with ≥2-point systemic therapy 1) 19.4, 2) 18.7 reduction (%)*: Deaths (n): DLQI: 1) 3.9, 2) 21.7ⱡ 1) 1, 2) 1 Exclusion: use of 1) 12.1, 2) 12.7 DLQI ≥ 5-point biologics within 12 to decrease (only PsA (%): At week 52: 24 weeks patients with score >5) NR AEs ≥1 (%): 1) 33.5, 2) 70.2 Previous biologics Apremilast- 78.7 (%): Pruritus VAS, mean SAEs ≥1 (%): change (mm) 1) 28.4, 28.8 Apremilast- 4.2 1) -7.3, 2) -31.5ⱡ Discontinuation due to AEs (%): ⱡ1 vs. 2, p<0.0001 Apremilast- 7.3 Deaths (n): *LOCF for missing Apremilast- 1 data (NRI also reported) Patients remaining on APR over 52 weeks maintained or ©Institute for Clinical and Economic Review, 2016 Page 225 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents continued improvement. Other outcomes reported: NPSI, c, BSA mean change, PASI mean % improvement Paul, 2015 Phase III N=411 Inclusion: Age (years): Primary outcomes at Primary outcomes at week 16: week 16: RCT 1) placebo (n=137) ≥18 years 1) 45.7, 2) 45.3 PASI 50 (%)*: AEs ≥1 (%): (NCT01232283) Double-blind 2) apremilast 30mg BSA ≥10%, % male: BID (n=274) 1) 19.7, 2) 55.5 1) 60.3, 2) 68.0 Multicenter PASI ≥12 1) 73.0, 2) 64.2 PASI 75 (%)*: SAEs ≥1 (%): ESTEEM 2 sPGA ≥3 Weight (kg): At week 16, placebo 1) 5.8, 2) 28.8 1) 2.2, 2) 1.8 40 sites in the US, patients switched to ≥6 months of plaque 1) 90.5, 2) 91.4 Canada, and Europe apremilast (N=380) psoriasis diagnosis PASI 90 (%)*: Discontinuation due Fair quality PsO duration (years): to AEs (%): publication Candidates for 1) 1.5, 2) 8.8 phototherapy or 1) 18.7, 2) 17.9 (p=0.0042) 1) 5.1, 2) 5.5 Modified ITT systemic therapy PASI: sPGA score of 0/1 Deaths (n): (%)*: 1) 20.0, 2) 18.9 1) 0, 2) 0 1) 4.4, 2) 20.4 DLQI: DLQI, mean change: ©Institute for Clinical and Economic Review, 2016 Page 226 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Exclusion: use of NR 1) -12.2, 2) -33.5 At week 52: biologics within 12 to 24 weeks PsA (%): DLQI ≥ 5-point AEs ≥1 (%): decrease (only NR patients with Apremilast- 77.9 score >5) Previous biologics SAEs ≥1 (%): (%): 1) 42.9, 2) 70.8 Apremilast- 4.7 (p<0.001 from 1) 32.1, 2) 33.6 baseline only) Discontinuation due to AEs (%): Pruritus VAS, mean change (mm) Apremilast- 7.1 1) -12.5, 2) -33.5 Deaths (n): Apremilast- 0 APR groups vs. placebo, p<0.001 *LOCF for missing data (NRI also reported for PASI 75 and 90) PASI 75 by prior therapy (%): ©Institute for Clinical and Economic Review, 2016 Page 227 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Biologic naïve- 1) 6.5, 2) 31.9 1 vs. 2, p<0.001 Biologic-experienced- 1) 4.5, 2) 22.8 1 vs. 2, p=0.0069 Other outcomes reported: NPSI, ScPGA, PASI mean % improvement Foley, 2015 Pooled analysis for N=1250 NR NR NR At wk 16: AEs 1) placebo (n=418) AEs ≥ 5%: ESTEEM 1 and 2 2) apremilast (n=832) Diarrhea 1) 6.7%, 2) 17.8% Abstract Nausea 1) 6.7%, 2) 16.6% URTI ©Institute for Clinical and Economic Review, 2016 Page 228 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 6.5%, 2) 8.4% Nasopharyngitis 1) 6.9%, 2) 7.3%) Rates of tension headache and headache also reported. SAEs (%): 1) 2.6, 2) 2.0 Reich, 2016 Phase IIIb Through wk 16: All patients were NR Primary outcomes at NR biologic-naïve week 16: RCT 1) placebo (n=84) PASI 75 (%): LIBERATE 2) apremilast 30mg BID (n=83) 1) 11.9, 2) 39.8, 3) Reports efficacy 48.2 through wk 52 3) etanercept 50mg Abstract QW (n=83) 1 and 2 vs. 3, p<0.0001 2 vs. 3, p=NS Wk 16-52 (crossover period): sPGA score of 0/1 (%): ©Institute for Clinical and Economic Review, 2016 Page 229 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) placebo-apremilast 1) 3.6, 2) 21.7, 3) 28.9 (n=73) 1 vs. 3, p=0.0005 2) apremilast- apremilast (n=74) 2 vs. 3, p<0.0001 3) etanercept- apremilast (n=79) At week 52: sPGA score of 0/1 (%): 1) 24.1, 2) 24.1, 3) 25.3 p=NR Outcomes also reported: LS-PGA at wk 0-16, 16-52 Crowley, 2016 As above 1) placebo-apremilast As above NR NR AEs in ≥5% of patients (n=73) (%): 2) apremilast- Diarrhea, nausea, LIBERATE Reports safety apremilast (n=74) headache did not outcomes for wks 16 increase for those to ≤52 vs. 0-16 3) etanercept- continuing apremilast apremilast (n=79) (data NR) Abstract ©Institute for Clinical and Economic Review, 2016 Page 230 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents SAEs: 4.11-9.16 across groups for wks 16-52 vs. 3.93 for etanercept and 12.47 for apremilast (wk 0-16) [per 100 patient-yrs] Discontinuation due to AEs: 4.11-6.78 across groups for wks 16-52 vs. 7.87-12.40 across groups (wk 0- 16) [per 100 patient- yrs] Rates of depression: 2 patients wks 16-52 for apremilast- apremilast (both patients had baseline depression) 1 patient in apremilast-apremilast group developed ©Institute for Clinical and Economic Review, 2016 Page 231 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents suicidal ideation in wks 16-52 Weight loss also reported Green, 2016 As above As above As above NR Primary outcomes at NR week 16: DLQI (mean change): LIBERATE Reports pruritus and Patients who received HrQOL up to wk 52 ≥1 dose at baseline 1) -3.8, 2) -8.3, 3) -7.8 Abstract and f/u included in this analysis 1 vs. 3, p<0.0001 2 vs. 3, p=0.0004 Pruritus VAS (mean change from baseline, mm): 1) -22.5, 2) -35.6, 3) - 36.4 1 vs. 2, p=0.00261 1 vs. 3, p<0.0001 ©Institute for Clinical and Economic Review, 2016 Page 232 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents % of patients achieving MCID (p=NR): DLQI (≥5 points): 1) 41.7, 2) 65.1, 3) 65.1 Pruritus VAS (>20% improvement): 1) 53.6, 2) 79.5, 3) 83.1 Outcomes at week 52 (p=NR): Pruritus VAS (>20% improvement): 1) -35.8, 2) -35.9, 3) - 34.6 DLQI (mean change): 1) -6.6, 2) -8.9, 3) -8.0 DLQI (≥5 points): ©Institute for Clinical and Economic Review, 2016 Page 233 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1) 59.4, 2) 75.7, 3) 71.2 ©Institute for Clinical and Economic Review, 2016 Page 234 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix C. Previous Systematic Reviews and Technology Assessments We identified five systematic reviews comparing the effectiveness of biologics in moderate-to- severe psoriasis, four of which also conducted NMAs. All reviews focused on PASI response rate at the end of induction phase as the measurement of effectiveness. Some included unapproved dosing but the results are not described below. Most NMAs used ordered multinomial models within a Bayesian framework to analyze PASI50, 75, and 90 jointly. Biologics were consistently found to have statistically significantly higher response rate than placebo. According to the NMAs, the ranking of biologics was similar among these analyses. Collectively, infliximab ranked the highest, followed by ustekinumab, adalimumab, and etanercept. Reich 2011 This systematic review and network meta-analysis focused on the comparative effectiveness of biologic agents in moderate-to-severe psoriasis available in Europe. The outcomes of interest were PASI 50,75, and 90 response rates measured as the primary endpoints in RCTs (at 10-16 weeks). Nineteen placebo-controlled and head-to-head trials published between 1995-2008 were identified and included in the analysis, including 60-70% males, with a mean age of 44 to 47 years. A Bayesian hierarchical model on ordered probit scale was used to analyze PASI 50,75, and 90 jointly. The NMA showed that all biologics were more effective than placebo and infliximab had the highest probability of achieving PASI response, followed by ustekinumab 90 mg, ustekinumab 45 mg, adalimumab, etanercept 50 mg, and placebo (RRs for PASI 75 were 22.6, 20.9, 19.5, 16.5, 14.7, and 1.0, respectively; Risk Ratios (RR) for PASI 50 and 90 were also reported). When analyzed according to the dosing recommendations (45 mg in patients ≤100 kg and 90 mg in patients > 100 kg) in a sensitivity analysis, ustekinumab 45 mg showed a higher comparative effectiveness than ustekinumab 90 mg. Lin 2012 This Bayesian network meta-analysis compared the effectiveness of ustekinumab to other biologics and placebo in moderate-to-severe psoriasis. Seventeen trials were identified from a systematic search of 1992 to 2012 and their primary endpoints within 10 to 16 weeks were analyzed. Patient characteristics were similar among trials, with mean age ranging from 41 to 47 years, mean disease duration from 14 to 21 years, mean BSA involvement at baseline from 20% to 50%, and baseline PASI from 13 to 33. PASI 75 was analyzed as the main outcome, but PASI 50 and 90 were analyzed separately as well. The odds of achieving PASI 75 for ustekinumab was higher compared to ©Institute for Clinical and Economic Review, 2016 Page 235 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents adalimumab [Odds Ratio (OR) 1.84], etanercept (OR 2.07), but lower than infliximab (OR 0.36), all treatments given according to the FDA-approved dosing (table x in this report). Previous experience with biologics was not found to be a statistically significant predictor of PASI response in the adjusted model. Signorovitch 2014 This systematic review and NMA looked at biologic treatments marketed in the U.S. and Europe for moderate-to-severe psoriasis. Fifteen phase II or III trials conducted in the U.S. and Europe were included. The authors proposed an NMA model adjusted for placebo response rate as a way to control for measured and unmeasured patient- and trial- level characteristics and reduce heterogeneity in the model. The NMA results were similar to the other publications, showing all biologics between than placebo, with infliximab ranked the highest (RR 19.49), followed by ustekinumab 90 mg (RR 17.54), ustekinumab 45mg (RR 16.33), adalimumab (RR 16.01), and etanercept (RR 12.54). Etanercept had statistically significantly lower effectiveness than the other biologics, but the differences between the others were not statistically significant. Gomez-Garcia 2016 This systematic review and meta-analysis included secukinumab besides the older biologics and evaluated evidence on both effectiveness and adverse events. Efficacy outcomes, including PASI 75 and 90, and safety outcomes, including any AE, SAE, and infectious AE, at week 10-16 from 27 RCTs were analyzed in the NMAs using frequentist method to generate odds ratios (OR) of direct and indirect comparisons. Other efficacy outcomes, such as IGA, PGA, and DLQI data were also analyzed but not presented as main results due to missing data for some biologics. All biologics showed superior efficacy compared to placebo on all efficacy outcomes, but some biologics also had higher ORs for AEs. Based on PASI 75 and 90, Infliximab (OR 118.89 and 84.11 for PASI 75 and PASI 90, respectively) and secukinumab (OR 87.07 and 95) were found to be the most effective but also the most likely to produce any adverse events or infectious AE (OR 1.85 and 1.34 for any AE compared to placebo). Ustekinumab ranked the third in effectiveness (OR 73.67 and 61.34) and was the only agent showing no increased risk for all safety outcomes compared to placebo. The ranking of the others is: ustekinumab 45 mg (OR 59.16 and 55.95), adalimumab (OR 30.69 and 22.11), and etanercept (OR 17.88 and 16.53). Mixed treatment comparisons based on PASI 75 showed no difference between infliximab and secukinumab, but both were statistically significantly more effective than the other biologics; etanercept had statistically significantly lower OR for PASI 75 than the others; adalimumab and ustekinumab were not distinguished from each other. Zweegers 2016 ©Institute for Clinical and Economic Review, 2016 Page 236 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents The authors conducted a literature review of prospective and retrospective observational studies from 1990 to 2014 on the daily practice biologics and conventional systemic therapies. A total of 32 studies were identified, among which two retrospective and two prospective studies compared PASI responses of biologics of our interest, including adalimumab, infliximab, etanercept, and ustekinumab. Only one of these four studies found a statistically significant difference between biologics: percentage improvement in PASI at 24 weeks was greater with infliximab compared to etanercept (89% vs. 75%, p=0.02). The other studies either did not conduct statistical tests or found non-statistically significant results. The authors identified the gap in the availability of direct evidence on effectiveness between agents. NICE HTA submissions The apremilast NICE submission125 showed apremilast to dominate its comparator, which in this case, was a treatment sequence starting with adalimumab. The NICE ERG noted that the manufacturer used a high cost of basic supportive care, a US EQ-5D measure instead of a UK measure for utility estimates, and a lower number of annual physician visits than seen in real world practice. Correcting for these, as well as other measures, the ERG’s final guidance slated apremilast had an incremental cost-effectiveness ratio versus adalimumab of about £30,300/QALY in the DLQ1>10 population and £60,000/QALY in the DLQ1<10 population. The secukinumab NICE submission resulted in an incremental cost-effectiveness of £2,515/QALY versus etanercept and £7,231/QALY versus supportive care.157 Additionally, secukinumab dominated all other biologics in the analysis. Key differences between this model and our analysis are 1) treatment non-responders move to supportive care, while in our model non-responders move to a ‘pooled’ biologic treatment – the latter representing a more real-world scenario; 2) a discontinuation rate of 11.7% for patients who stopped biologic treatment and moved to PASI<50 and receiving supportive care, and an all- cause discontinuation rate of 20%, versus in our model where discontinuation rate varied by targeted immunomodulator. The ERG committee also stated that the resource utilization and associated costs for hospitalization during supportive care were not plausible. The adalimumab NICE submission126 reported an incremental cost-effectiveness of £30,538/QALY for adalimumab versus supportive care. The number of hospitalization days avoided influenced model outcomes significantly, ranging from £60,600/QALY for no days avoided to £4,800/QALY for 39 days avoided. The ERG noted this to be a key factor driving model results and expressed uncertainty of this model input. The infliximab NICE submission127 reported infliximab to be cost- effective over etanercept at £26,095/QALY. This model reflects a lack of clarity on the patient population the it includes – the model population is defined as those in the fourth quartile of DLQ1, which does not clearly state if these patients fall under the moderate-to-severe psoriasis category. The model also had significant uncertainty related to the assumed cost offsets associated with ©Institute for Clinical and Economic Review, 2016 Page 237 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents hospitalization. The ustekinumab NICE submission128 resulted in an incremental cost-effectiveness of £29,587/QALY for ustekinumab versus supportive care. The model assumed that 80% of the population was less than 100kgs and thus received a 45mg dose of ustekinumab, while the remaining patients received a 90mg ustekinumab. The manufacturer, while submitting the evidence, proposed a patient access scheme (PAS), discounting the price of the 90mg dose to that of the 45mg dose. Doubling the price to the listed 90mg dose resulted in ustekinumab no longer dominating its comparators at the UK threshold of £20,000/QALY to £30,000/QALY. ©Institute for Clinical and Economic Review, 2016 Page 238 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix D. Ongoing Trials Title/ Trial Sponsor Study Design Comparators Patient Population Primary Outcomes Estimated Completion Date Adalimumab Phase 3 Study of M923 Phase III RCT 1) M923 (adalimumab N = 827, ages ≥18 PASI 75 at week 16 May 2017 and Humira in Subjects biosimilar) Inclusion criteria: with Chronic Plaque- 2) Adalimumab - PsO duration ≥ 6 Selected secondary type Psoriasis 3) M923 and months outcomes: PASI 50, 90; adalimumab Exclusion criteria: sPGA, DLQI, EQ-5D, NCT02581345 - Prior use of TNF clinically significant AEs inhibitors, or 2 or more non-TNF biologic therapies MSB11022 in Phase III RCT 1) MSB11022 N = 406, ages ≥18 PASI 75 at week 16 September 2017 Moderate to Severe (adalimumab Inclusion criteria: Chronic Plaque biosimilar) 80mg initial - 10% BSA, sPGA ≥ 3, Selected secondary Psoriasis (AURIEL-PsO) dose, 40mg Q2W PASI ≥ 12 outcomes: % PASI starting week 1 - Patients who have improvement, HrQoL, NCT02660580 2) adalimumab received > 1 biologic AEs and SAEs following same dosing Exclusion criteria: schedule above - Patients who have previously received adalimumab or an investigational or licensed biosimilar of adalimumab Comparison of CHS- Phase III RCT 1) CHS-1420 N = 545, ages ≥18 PASI 75 at week 12 March 2017 1420 Versus Humira in (adalimumab Inclusion criteria: Subjects with Chronic biosimilar) 80mg initial ©Institute for Clinical and Economic Review, 2016 Page 239 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Plaque Psoriasis dose, 40mg Q2W -10% BSA, sPGA ≥ 3, No other outcomes (PsOsim) weeks 1 to study PASI ≥ 12 listed completion Exclusion criteria: NCT02489227 2) Adalimumab 80mg Presence of significant initial dose, 40mg Q2W comorbid conditions weeks 1-15, re- randomized to either arm weeks 17-23, CHS- 1420 weeks 17 to study completion Etanercept Safety and Efficacy Phase III 1) Etanercept biosimilar N = 216, ages 18-65 PASI 75 at week 12 December 2017 Study of Etanercept RCT (Qiangke) 50mg Inclusion criteria: (Qiangke) to Treat 2) Etanercept biosimilar -10% BSA, sPGA ≥ 3, Selected secondary Moderate to Severe (Qiangke) 25mg PASI ≥ 12, PsO duration outcomes: PASI 50, 90; Plaque Psoriasis 3) Placebo ≥ 6 months PGA, DLQI Exclusion criteria: NCT02701205 -Previous use of systemic therapy or phototherapy with inadequate response -No use of adjuvant therapy, including traditional Chinese medicine and acupuncture, during first two weeks of study -No use of TNF antagonists or other biologics within 6 weeks before baseline ©Institute for Clinical and Economic Review, 2016 Page 240 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Infliximab Psoriasis Longitudinal Obs. Cohort (Phase IIII 1) Infliximab N = 12051, ages 18-99 Number of patients May 2021 Assessment and study) 2) Ustekinumab Inclusion criteria: with AEs or SAEs over 8 Registry (PSOLAR) 3) Other biologic - Candidate for, or years agents currently receiving, NCT00508547 4) Conventional conventional systemic Selected secondary systemic agents agents or biologic outcomes: DLQI, EQ- treatment for psoriasis 5D, HADS Exclusion criteria: - No participation in clinical trial with non- marketed investigational agents Secukinumab Study of Secukinumab Phase III RCT 1) Secukinumab 300mg N = 1100, ages ≥18 PASI 90 at week 12 August 2018 Compared to 2) Ustekinumab 45mg Inclusion criteria: IGA score of 0 or 1 at Ustekinumab in or 90mg (weight- - 10% BSA, IGA ≥ 3, week 12 Subjects with Plaque dependent) PASI ≥ 12, PsO duration Psoriasis (CLARITY) ≥ 6 months Selected secondary - Inadequate response outcomes: TEAEs NCT02826603 to prior topical treatment, phototherapy, or systemic treatment Exclusion criteria: - Prior use of secukinumab or drugs targeting IL-17A receptor Ixekizumab ©Institute for Clinical and Economic Review, 2016 Page 241 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents A Study Comparing Phase III RCT 1) Ixekizumab 160mg N = 1227, ages ≥18 PASI 75 and sPGA score September 2017 Different Dosing initial dose, 80mg Q2W Inclusion criteria: of 0 or 1 at week 52 regimens of 2) Ixekizumab 160mg - 10% BSA, PGA ≥ 3, Ixekizumab initial dose, 80mg Q4W PASI ≥ 12, PsO duration Selected secondary (LY2439821) in 3) 160 mg ixekizumab ≥ 6 months outcomes: PASI 90, Participants with initial dose, 80mg Exclusion criteria: 100; sPGA score of 0, Moderate to Severe ixekizumab Q4W with - No concurrent/recent DLQI, Itch NRS, EQ-5D, Plaque Psoriasis step-up to Q2W use of biologic agent VAS-skin pain (IXORA-P) 4) Placebo NCT02513550 A Study of Ixekizumab Phase III RCT 1) Ixekizumab 160mg N = 300, ages ≥18 ≥ PASI 90 at week 12 May 2017 (LY2439821) in initial dose, 80mg Q2W Inclusion criteria: Participants with 2) Ustekinumab 45 or - PASI ≥ 12, PsO Selected secondary Moderate-to-Severe 90mg (weight- duration ≥ 6 months outcomes: Plaque Psoriasis dependent) - Failure, SF-36, PGA, EQ-5D, (IXORA-S) contraindication, or WPAI intolerability to at least NCT02561806 1 systemic therapy (including cyclosporine, methotrexate, or phototherapy) Exclusion criteria: - No concurrent/recent use of biologic agent - No prior use or contraindication to ustekinumab - No previous TX with ixekizumab or other IL- ©Institute for Clinical and Economic Review, 2016 Page 242 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 17A or IL-12/23 antagonists A Study in Japanese Phase III (extension Ixekizumab 160mg N = 90, ages ≥20 PASI at week 12 December 2016 Participants with study) initial dose, 80mg Q2W Inclusion criteria: Moderate-to-Severe until week 12, Q4W - 10% BSA, PGA ≥ 3, Selected secondary Psoriasis (UNCOVER-J) until week 52, and up PASI ≥ 12, PsO duration outcomes: PGA, PROs, to 192 weeks following ≥ 6 months efficacy in patients with NCT01624233 relapse during drug- Exclusion criteria: PsA free period - No prior use of etanercept - No concurrent/recent use of biologic agents Brodalumab – no ongoing studies identified Apremilast A Phase 4 Study of Phase IIII RCT 1) Apremilast 30mg BID N = 197, ages ≥18 Mean percentage November 2016 Efficacy and Safety of 2) Placebo Inclusion criteria: change in BSA Apremilast in Subjects - 5-10% BSA, sPGA=3, multiplied by sPGA at With Moderate Plaque After week 16, all PASI ≥ 12, PsO duration week 16 Psoriasis (UNVEIL) subjects take ≥ 6 months apremilast 30mg until Exclusion criteria: Selected secondary NCT02425826 week 52 - No prior exposure to outcomes: PASI 50, 75; systemic or biologic DLQI, TSQM, AEs treatment for psoriatic arthritis, psoriasis, or other indications that could impact psoriasis assessment - No prior apremilast treatment Source: www.ClinicalTrials.gov (NOTE: studies listed on site include both clinical trials and observational studies) ©Institute for Clinical and Economic Review, 2016 Page 243 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix E. Comparative Clinical Effectiveness Supplemental Information We performed screening at both the abstract and full-text level. A single investigator screened all abstracts identified through electronic searches according to the inclusion and exclusion criteria described earlier. We did not exclude any study at abstract-level screening due to insufficient information. For example, an abstract that did not report an outcome of interest would be accepted for further review in full text. We retrieved the citations that were accepted during abstract-level screening for full text appraisal. One investigator reviewed full papers and provided justification for exclusion of each excluded study. We used criteria published by the US Preventive Services Task Force (USPSTF) to assess the quality of RCTs and comparative cohort studies, using the categories “good,” “fair,” or “poor” (see Appendix Table F2) 51 Guidance for quality ratings using these criteria is presented below, as is a description of any modifications we made to these ratings specific to the purposes of this review. Good: Meets all criteria: Comparable groups are assembled initially and maintained throughout the study; reliable and valid measurement instruments are used and applied equally to the groups; interventions are spelled out clearly; all important outcomes are considered; and appropriate attention is paid to confounders in analysis. In addition, intention-to treat-analysis is used for RCTs. Fair: Studies were graded "fair" if any or all of the following problems occur, without the fatal flaws noted in the "poor" category below: Generally comparable groups are assembled initially but some question remains whether some (although not major) differences occurred with follow-up; measurement instruments are acceptable (although not the best) and generally applied equally; some but not all important outcomes are considered; and some but not all potential confounders are addressed. Modified intention-to-treat analysis is done for RCTs. Poor: Studies were graded "poor" if any of the following fatal flaws exists: Groups assembled initially are not close to being comparable or maintained throughout the study; unreliable or invalid measurement instruments are used or not applied equally among groups (including not masking outcome assessment); and key confounders are given little or no attention. For RCTs, intention-to treat-analysis is lacking. ©Institute for Clinical and Economic Review, 2016 Page 244 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table E1. Table PASI outcomes by trial Trial treatment Time N %PASI P value %PASI P value %PASI P value %PASI P value point 75 50 90 100 (weeks) Head-to-head trials Griffiths 2010 Etanercept 12 347 57 NR 23 NR ACCEPT Ustekinumab 12 209 68 0.01 NR 36 P<0.001 NR 45 mg Ustekinumab 12 347 74 <0.001 NR 45 P<0.001 NR 90 mg Langley 2014 Etanercept 12 326 44 NR 21 4 FIXTURE Secukinumab 12 327 77 P<0.001 NR 54 P<0.001 24 P<0.001 300 mg Griffiths 2015 Etanercept 12 358 42 NR 19 5 UNCOVER 2 Ixekizumab 12 351 90 P<0.0001 NR 71 P<0.0001 41 P<0.0001 Gordon 2015 Etanercept 12 382 53 NR 26 7 UNCOVER 3 ixekizumab 12 385 87 P<0.0001 NR 68 P<0.0001 38 P<0.0001 Thaci 2015 Etanercept 12 339 79 NR 53 26 IXORA-S Ixekizumab 12 136 91 P<0.001 NR 75 P<0.001 37 P<0.001 Ustekinumab 12 166 69 42 15 CLEAR Secukinumab 12 337 91 P<0.0001 NR 73 P<0.0001 39 P<0.0001 300 mg Ustekinumab 16 339 83 NR 58 28 WBD Secukinumab 16 337 93 P=0.0001 NR 79 P<0.0001 44 P<0.0001 300 mg Lebwohl 2015 Ustekinumab 12 300 70 NR 47 22 WBD AMAGINE 2 Brodalumab 12 612 86 0.08 NR 70 P<0.001 44 P<0.001 210 mg Lebwohl 2015 Ustekinumab 12 313 69 NR 48 19 WBD AMAGINE 3 Brodalumab 12 624 85 0.007 NR 69 P<0.001 37 P<0.001 210 mg Placebo-controlled trials Sauret 2008 Adalimumab 16 108 80 88 52 17 CHAMPION placebo 16 53 19 P<0.001 30 P<0.001 11 P<0.001 2 P<0.01 Menter 2008 Adalimumab 16 814 71 NR 45 20 REVEAL placebo 16 398 7 P<0.001 NR 2 P<0.001 1 P<0.01 Papp 2005 Etanercept 12 203 46 72 19 NR placebo 12 204 3 P<0.001 9 P<0.001 <1 P<0.001 NR Leonardi 2003 Etanercept 12 164 49 71 22 NR placebo 12 166 4 P<0.001 14 P<0.001 1 P<0.001 NR Tyring 2006 Etanercept 12 300 47 74 21 NR placebo 12 300 5 P<0.001 14 P<0.001 1 P<0.001 NR Bagel 2012 Etanercept 12 62 59 85 25 NR placebo 12 62 5 P<0.001 7 P<0.001 2 P<0.001 NR Gottlieb 2011 Etanercept 12 141 56 NR 23 7 M10-114 placebo 12 68 7 P<0.001 NR 1 P<0.001 0 NR Strober 2011 Etanercept 12 139 40 NR 14 6 M10-315 placebo 12 72 7 P<0.001 NR 4 P<0.001 0 NR Bachelez 2015 Etanercept 12 335 59 80 32 NR placebo 12 107 6 P<0.001 21 P<0.001 1 P<0.001 NR Griffiths 2016 Etanercept 12 241 75 NR NR NR EGALITY Erelzi 12 239 73.4 NS NR NR NR Reich 2015 Infliximab 10 301 80 91 57 NR placebo 10 77 3 P<0.001 8 p<0.001 1 P<0.001 NR Menter 2007 Infliximab 10 314 76 NR 45 NR placebo 10 208 2 P<0.001 NR 1 P<0.001 NR ©Institute for Clinical and Economic Review, 2016 Page 245 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Langley 2016 ixekizumab 12 433 89 NR 71 35 placebo 12 431 3 P<0.001 NR 1 P<0.001 0 P<0.001 Griffiths 2015 ixekizumab 12 351 90 NR 71 41 placebo 12 168 2 P<0.0001 NR 1 P<0.0001 1 P<0.0001 Gordon 2015 ixekizumab 12 351 87 NR 68 38 placebo 12 168 7 P<0.0001 NR 3 P<0.0001 0 P<0.0001 Leonardi 2008 Ustekinumab 12 255 67 84 42 13 45 mg Ustekinumab 12 256 66 P<0.0001 86 p<0.0001 37 P<0.0001 11 P<0.0001 90 mg placebo 12 255 3 P<0.0001 10 p<0.0001 2 P<0.0001 0 P<0.0001 Papp 2008 Ustekinumab 12 255 67 84 16 18 45 mg Ustekinumab 12 256 76 P<0.0001 89 P<0.0001 42 P<0.0001 18 P<0.0001 90 mg placebo 12 255 4 P<0.0001 10 P<0.0001 1 P<0.0001 0 P<0.0001 Langley 2014 Secukinumab 12 245 82 91 59 29 300 mg ERASURE placebo 12 248 5 P<0.001 9 P<0.001 1 P<0.001 1 P<0.001 Secukinumab 16 245 86 91 NR 42 300 mg placebo 16 248 NR P<0.001 NR NR NR Langley 2014 Secukinumab 12 327 77 92 54 24 300 mg FIXTURE placebo 12 326 5 P<0.001 15 P<0.001 2 P<0.001 0 P<0.0001 Secukinumab 16 327 87 94 NR 37 300 mg placebo 16 326 NR P<0.001 NR NR NR Blauvet 2015 Secukinumab 12 59 76 88 60 43 300 mg placebo 12 59 0 P<0.0001 5 P<0.0001 0 P<0.0001 0 P<0.001 Paul 2015 Secukinumab 12 60 87 NR 55 27 300 mg placebo 12 61 3 P<0.0001 NR 0 0 P<0.001 Papp 2016 Brodalumab 12 220 83 NR 70 42 210 mg placebo 12 222 3 P<0.001 NR 1 P<0.001 1 P<0.001 Lebwohl 2015 Brodalumab 12 612 86 NR 70 44 210 mg AMAGINE 2 placebo 12 309 8 P<0.001 NR 3 P<0.001 2 P<0.001 Lebwohl 2015 Brodalumab 12 624 85 NR 69 37 210 mg AMAGINE 3 placebo 12 315 6 P<0.001 NR 2 P<0.001 0 P<0.001 Papp 2015 Apremilast 16 562 33 59 9.8 NR placebo 16 282 15 P<0.001 17 P<0.001 0 NS NR Paul 2015 Apremilast 16 274 29 56 9 NR placebo 16 137 6 P<0.001 20 P<0.001 2 P=0.004 NR ©Institute for Clinical and Economic Review, 2016 Page 246 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix F. Network Meta-Analysis Methods and Results Network Meta-Analysis Methods In addition to summary evidence tables, we performed quantitative indirect comparisons using Bayesian network meta-analysis (NMA) for PASI outcomes.158 A ordinal multinomial model with a probit link for PASI 50, PASI 75, and PASI 90 was used. This model assumes the treatment effect is the same regardless of the PASI cut-off and allowed us to use the data efficiently when some PASI outcomes were missing. All the analyses were conducted in WINBUGS 1.4,3 using code from the NICE DSU technical support document. Review of the deviance information criterion (DIC) statistics as well as comparison of the residual deviance (resdev) to the number of unconstrained data points was used to assess the best model fit under multiple alternative assumptions.159 Given the expectation of at least some degree of heterogeneity in patient populations and/or study design, there is a general preference for a random-effects approach. A total of 50,000 iterations each were employed for both “burn-in” (for model convergence) and model (for model results) simulations. Relative risks and probabilities of patients having a given PASI response state was generated. We conducted a sensitivity analysis to assess ustekinumab 45 mg and 90 mg doses separately by excluding a head-to-head trial where the two doses were combined. We also conducted a sensitivity analysis in which placebo response rate in each trial was adjusted as a covariate in the above described model. The median and credible interval of the adjustment coefficient (β) of placebo response from a previous network meta-analysis was used as input to our model. The adjustment coefficient (β) was tested against zero.49 ©Institute for Clinical and Economic Review, 2016 Page 247 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table F1. Basecase NMA. Relative risks and credible intervals of treatments compared to placebo on PASI outcomes from the NMA treatment PASI 75 Crl PASI 50 Crl PASI 90 Crl ixekizumab 17.89 12.68-25.94 7.359 5.619-9.884 75.22 47.87-121.7 brodalumab 210 17.25 11.94-25.39 7.232 5.49-9.75 69.85 40.62-118.9 infliximab 16.72 11.75-24.34 7.13 5.442-9.576 64.84 39.78-106.8 secukinumab 300 15.37 10.93-22.17 6.844 5.246-9.148 54.63 34.57-87.98 ustekinumab 45/90 13.99 10.02-20.0 6.509 5.014-8.654 45.62 29.37-72.65 adalimumab 13.01 8.977-19.27 6.242 4.74-8.418 40.16 23.6-69.32 secukinumab 150 12.98 9.116-18.79 6.241 4.773-8.325 39.97 24.45-65.41 etanercept 9.57 6.943-13.54 5.196 4.046-6.839 23.89 15.63-37.58 Erelzi 8.92 4.465-15.46 4.95 3.062-7.278 21.5 7.749-49.13 apremilast 6.148 3.807-9.804 3.874 2.731-5.473 12.14 6.179-23.34 Table F2. Base case NMA. Probabilities of patients having a given PASI response state at the end of induction period Treatment %PASI 0-50 %PASI 50- %PASI 75- %PASI90-100 75 90 placebo 87.0 8.1 4.0 0.9 adalimumab 18.3 16.9 27.7 37.2 apremilast 49.3 20.1 19.4 11.2 brodalumab 210 5.3 8.4 21.3 65.0 etanercept 32.3 20.3 25.5 22.0 infliximab 6.9 10.0 23.3 59.8 ixekizumab 4.1 7.1 19.4 69.5 secukinumab 150 18.5 17.0 27.7 36.8 secukinumab 300 10.8 13.0 26.0 50.3 ustekinumab 45/90 15.2 15.5 27.4 42.0 ©Institute for Clinical and Economic Review, 2016 Page 248 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Erelzi 35.0 20.5 24.7 19.9 ©Institute for Clinical and Economic Review, 2016 Page 249 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table F3. Base case NMA: league table of PASI 75 response ixekizumab 1.03 brodalumab (0.91-1.25) 210 mg 1.07 1.04 (0.95-1.24) (0.85-1.23) infliximab 1.16 1.13 1.09 secukinuma (1.04-1.33) (0.92-1.32) (0.93-1.26) b 300 mg 1.28 1.24 1.20 1.1 ustekinuma (1.14-1.45) (1.01-1.45) (1.02-1.38) (0.96-1.26) b 45/90 mg 1.37 1.15 1.28 1.18 1.07 (1.14-1.74) (1.02-1.34) (1.02-1.65) (0.95-1.52) (0.87-1.37) adalimumab 1.37 1.33 1.29 1.18 1.08 1.00 secukinuma (1.18-1.66) (1.06-1.64) (1.07-1.56) (1.04-1.37) (0.91-1.30) (0.76-1.30) b 150 mg 1.87 1.81 1.75 1.61 1.46 1.37 (1.05- 1.36 (1.62-2.19) (1.45-2.19) (1.45-2.10) (1.36-1.91) (1.25-1.73) 1.71) (1.10-1.65) etanercept 1.99 1.92 1.86 1.71 1.56 1.45 1.45 1.07 (1.31-3.83) (1.22-3.73) (1.20-3.59) (1.11-3.30) (1.01-3.00) (0.90-2.86) (0.92-2.9) (0.71-1.99) Erelzi 2.90 2.79 2.70 2.49 2.26 2.11 2.10 1.55 1.45 (2.03-4.46) (1.90-4.36) (1.86-4.22) (1.72-3.78) (1.58-3.49) (1.42-3.31) (1.42-3.31) (1.07-2.4) (0.70-2.64) apremilast 17.89 17.25 16.72 15.37 (12.68- (11.94- (11.75- (10.93- 13.99 13.01 12.98 9.57 8.92 6.15 25.94) 25.39) 24.34) 22.17) (10.02-20.0) (8.98-19.27) (9.12-18.79) (6.94-13.54) (4.47-15.46) (3.81-9.80) placebo ©Institute for Clinical and Economic Review, 2016 Page 250 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table F4. Base case NMA: league table of PASI 50 response ixekizumab 1.01 brodalumab (0.96-1.11) 210 mg 1.03 1.02 (0.98-1.11) (0.92-1.10) infliximab 1.07 1.06 1.04 secukinumab (1.02-1.15) (0.96-1.15) (0.97-1.12) 300 mg 1.13 1.11 1.10 1.05 ustekinumab (1.07-1.21) (1.01-1.21) (1.01-1.18) (0.98-1.13) 45/90 mg 1.17 1.15 1.14 1.09 1.04 (1.06-1.35) (1.02-1.34) (1.01-1.32) (0.97-1.27) (0.93-1.20) adalimumab 1.18 1.16 1.14 1.09 1.04 1.00 secukinumab (1.08-1.31) (1.03-1.30) (1.04-1.28) (1.02-1.20) (0.95-1.16) (0.85-1.16) 150 mg 1.41 1.39 1.37 1.32 1.25 1.21 1.20 ( (1.30-1.57) (1.24-1.56) (1.23-1.54) (1.19-1.47) (1.14-1.39) (1.03-1.38) 1.06-1.36) etanercept 1.47 1.45 1.43 1.37 (1.06- 1.30 1.25 1.25 1.04 (1.14-2.30) (1.11-2.27) (1.10-2.23) 2.14) (1.01-2.03) (0.94-1.98) (0.95-1.96) (0.81-1.59) Erelzi 1.89 1.86 1.83 1.76 1.67 1.61 1.61 1.34 1.28 (1.50-2.57) (1.45-2.53) (1.44-2.50) (1.38-2.39) (1.32-2.27) (1.24-2.19) (1.24-2.20) (1.05-1.82) (0.78-1.90) apremilast 7.36 7.23 7.13 6.84 6.51 6.24 6.24 5.20 4.95 3.87 (5.62-9.88) (5.49-9.75) (5.44-9.58) (5.25-9.15) (5.01-8.65) (4.74-8.42) (4.77-8.32) (4.05-6.84) (3.06-7.28) (2.73-5.47) placebo ©Institute for Clinical and Economic Review, 2016 Page 251 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table F5. Base case NMA: league table of PASI 90 response ixekizumab 1.07 brodalumab (0.8-1.60) 210 mg 1.16 1.08 (0.89-1.57) (0.71-1.56) infliximab 1.38 1.29 1.19 secukinumab (1.08-1.79) (0.85-1.80) (0.87-1.59) 300 mg 1.65 1.54 1.42 1.20 ustekinumab (1.30-2.10) (1.02-2.12) (1.04-1.89) (0.93-1.54) 45/90 mg 1.86 1.74 1.61 1.35 1.13 (1.31-2.83) (1.07-2.77) (1.05-2.54) (0.91-2.10) (0.77-1.74) adalimumab 1.88 1.76 1.62 1.36 1.14 1.01 secukinumab (1.39-2.64) (1.12-2.61) (1.14-2.31) (1.08-1.77) (0.84-1.59) (0.63-1.59) 150 mg 3.15 2.94 2.71 2.29 1.91 1.69 ( 1.67 (2.46-4.07) (1.91-4.17) (1.93-3.75) (1.70-3.05) (1.46-2.51) 1.09-2.50) (1.17-2.33) etanercept 3.48 3.23 3.00 2.52 2.11 1.86 1.85 1.11 (1.70-9.30) (1.46-8.91) (1.41-8.12) (1.21-6.80) (1.02-5.65) (0.84-5.22) (0.86-5.02) (0.56-2.82) Erelzi 6.17 5.73 5.32 4.48 3.74 3.3 3.28 1.96 1.77 (3.57-11.6) (3.04-11.17) (2.91-10.33) (2.51-8.60) (2.13-7.07) (1.76-6.47) (1.77-6.43) (1.12-3.72) (0.59-4.51) apremilast 75.22 69.85 64.84 54.63 45.62 39.97 23.89 (47.87- (40.62- (39.78- (34.57- (29.37- 40.16 (24.45- (15.63- 21.5 12.14 121.7) 118.9) 106.8) 87.98) 72.65) (23.6-69.32) 65.41) 37.58) (7.75-49.13) (6.18-23.34) placebo ©Institute for Clinical and Economic Review, 2016 Page 252 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table F6. Sensitivity analysis NMA. Ustekinumab 45 mg and 90 mg separately, relative risks Treatment PASI 75 Crl PASI 50 Crl PASI 90 Crl infliximab 17.5 12.59-24.85 6.974 5.392-9.222 70.19 45.69-110.1 brodalumab 210 17.11 12.2-24.46 6.904 5.333-9.137 67.16 41.81-108.1 ixekizumab 17.08 12.42-23.97 6.903 5.356-9.087 66.48 44.44-101.3 secukinumab 300 15.7 11.52-21.84 6.638 5.185-8.663 55.85 37.55-84.99 ustekinumab 90 14.93 11.03-20.62 6.474 5.088-8.418 50.74 34.35-76.42 ustekinumab 45 14.12 10.52-19.33 6.294 4.972-8.128 45.73 31.44-67.82 secukinumab 150 13.61 10.08-18.79 6.172 4.867-7.975 42.79 28.73-65.04 adalimumab 11.77 8.436-16.57 5.687 4.452-7.392 33.35 20.6-53.38 etanercept 9.708 7.552-12.69 5.08 4.145-6.321 24.18 17.56-33.82 Erelzi 9.088 4.991-14.67 4.852 3.253-6.759 21.89 8.968-44.91 apremilast 5.252 3.365-7.822 3.395 2.47-4.546 9.553 5.115-16.92 Table F7. Sensitivity analysis NMA. Ustekinumab 45 mg and 90 mg separately, probabilities Treatment %PASI 0-50 %PASI 50-75 %PASI 75-90 %PASI90-100 placebo 86.4 8.7 4.0 0.9 adalimumab 21.9 19.3 27.1 31.6 apremilast 53.5 20.4 17.1 9.0 brodalumab 210 5.3 9.1 21.5 64.1 etanercept 30.6 21.2 25.4 22.8 infliximab 4.6 8.3 20.4 66.7 ixekizumab 5.7 9.5 21.9 62.9 secukinumab 150 15.6 16.7 27.2 40.6 secukinumab 300 9.3 12.7 25.1 52.9 ustekinumab 45 13.9 15.9 26.9 43.3 Erelzi 33.1 21.5 24.7 20.8 ustekinumab 90 11.4 14.3 26.2 48.1 ©Institute for Clinical and Economic Review, 2016 Page 253 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table F8. Sensitivity analysis NMA. Placebo response adjustment, relative risks treatment PASI 75 Crl PASI 50 Crl PASI 90 Crl infliximab 17.7 12.78-25.21 6.962 5.39-9.221 70.9 46.21-111.9 brodalumab 210 17.35 12.41-24.91 6.896 5.339-9.152 68.17 42.56-110.0 ixekizumab 17.28 12.59-24.25 6.894 5.353-9.069 67.21 45.22-102.5 secukinumab 300 16.29 11.97-22.62 6.712 5.247-8.771 59.4 40.43-89.26 ustekinumab 45/50 14.38 10.78-19.58 6.312 4.999-8.139 46.8 32.62-68.38 secukinumab 150 14.08 10.45-19.42 6.24 4.933-8.077 45.09 30.48-68.1 adalimumab 11.96 8.533-16.81 5.698 4.459-7.39 33.99 20.86-54.34 etanercept 9.801 7.616-12.84 5.077 4.144-6.329 24.41 17.7-34.21 Erelzi 9.202 5.01-14.82 4.864 3.245-6.753 22.2 8.962-45.5 apremilast 5.284 3.366-7.948 3.395 2.466-4.555 9.609 5.113-17.04 Table F9. Sensitivity analysis NMA. Placebo response unadjustment, probabilities Treatment %PASI 0-50 %PASI 50- %PASI 75- %PASI90-100 75 90 placebo 86.4 8.8 4.0 0.9 adalimumab 21.7 19.5 27.1 31.7 apremilast 53.5 20.7 16.9 8.9 brodalumab 210 5.3 9.2 21.5 64.1 etanercept 30.5 21.5 25.3 22.7 infliximab 4.6 8.5 20.5 66.4 ixekizumab 5.7 9.7 21.9 62.7 secukinumab 150 14.5 16.5 27.0 42.0 secukinumab 300 8.2 12.1 24.4 55.3 ustekinumab 45/90 20.4 19.1 27.3 33.3 Erelzi 55.7 20.2 16.0 8.0 ©Institute for Clinical and Economic Review, 2016 Page 254 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix G. Comparative Value Supplemental Information Table G1. Targeted therapies with dosing regimens Drug Route Initiation phase Maintenance phase Adalimumab Subcutaneous 80 mg once 40 mg once every two weeks (starting one week after first dose) Apremilast Oral 10 mg once in the 30 mg twice a day morning on the first day; increase by 10 mg per day to maintenance dose (6 days) Brodalumab Subcutaneous 210 mg once every 210 mg once every two weeks for eight four weeks weeks Etanercept Subcutaneous 50 mg twice a week 50 mg once a week through week 12 Infliximab Intravenous 5 mg / kg at weeks 0, 5 mg / kg once every 2, and 6 8 weeks Ixekizumab Subcutaneous 160 mg once, then 80 80 mg once every 4 mg every 2 weeks weeks until week 12 Secukinumab Subcutaneous 300 mg once a week 300 mg once every 4 through week 4 weeks Ustekinumab Subcutaneous 45 mg at weeks 0 and 45 mg once every 12 4 (90 mg if patient > weeks (90 mg if 100 kg) patient > 100 kg) ©Institute for Clinical and Economic Review, 2016 Page 255 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table G2. Ranges of PASI 75 for selected targeted therapies Drug Low Baseline High value value value Infliximab 0.132 0.221 0.310 Etanercept 0.158 0.254 0.350 Ixekizumab 0.141 0.220 0.299 Secukinumab 0.158 0.245 0.332 Table G3. Alternative sources of health state utilities Drug Pickard NICE NICE adalimumab ustekinumab PASI 90- 0.856 0.861 0.892 100 PASI 75- 0.847 0.782 0.862 89 PASI 50- 0.798 0.782 0.812 74 PASI < 0.723 0.696 0.682 50 Second- 0.846 0.739 0.789 line Non- 0.696 0.642 0.642 targeted ©Institute for Clinical and Economic Review, 2016 Page 256 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Table G4. Costs for laboratory tests Test Baseline Source Latent TB screen $22.56 CMS fee schedule, 2016 (71010) Active TB screen $7.88 CMS fee schedule, 2016 (86580) CBC (2016) $19.11 Hankin, Drug Ben Trends, 2005 Hepatitis B screen (2016) $17.29 Eckman, Clin Inf Dis, 2011 Liver function test (2016) $19.11 Hankin, Drug Ben Trends, 2005 Renal function test (2016) $20.88 Hankin, Drug Ben Trends, 2005 Clinic visit (2016) $87.90 Hankin, Drug Ben Trends, 2005 Table G5. Per-cycle laboratory regimens for anti-psoriasis drugs Drug Latent Active CBC HBV LFT Renal TB TB adalimumab 0.0 0.0 0.2 once* 0.3 0.0 apremilast 0.0 0.0 0.0 0.0 0.0 once brodalumab 0.0 0.0 0.0 0.0 0.0 0.0 etanercept once 0.3 0.2 once 0.3 0.0 infliximab once 0.2 0.2 0.0 0.0 0.0 ixekizumab once 0.2 0.0 0.0 0.0 0.0 secukinumab once 0.2 0.0 0.0 0.0 0.0 ustekinumab once 0.2 0.2 0.0 0.0 0.0 *Laboratory tests marked “once” indicate a single administration of the test at the initiation of therapy Sensitivity analyses of economic model One-way sensitivity analysis Below are one-way sensitivity analyses showing the incremental cost and QALYs for four comparisons: ixekizumab versus non-targeted, infliximab versus non-targeted, infliximab versus ixekizumab, and ixekizumab versus etanercept. Table G6. One-way SA results – Ixekizumab vs. non-targeted therapy Ixekizumab vs non-targeted Parameter Low value Base value High value Low value Base ICER High value Rate of severe URI 0% 0.40% 0.80% $144,874 $144,888 $144,903 Cost per clinic-admin sub-q inj. $20.35 $25.44 $30.53 $144,863 $144,888 $144,913 2L -> non-targeted d/c rate 5.0% 10.0% 15.0% $144,799 $144,888 $144,949 d/c % to 2L 25% 50% 75% $144,578 $144,888 $145,129 ©Institute for Clinical and Economic Review, 2016 Page 257 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents 1L d/c rate (year 1, PASI 75+) 12% 16% 20% $144,272 $144,888 $145,501 PASI 75 81.98% 88.83% 93.64% $146,182 $144,888 $144,022 1L d/c rate (year > 1, PASI 75+) 2.50% 5% 10.00% $143,728 $144,888 $147,138 Annual productivity cost offset $3,920.00 $4,900 $5,880.00 $148,688 $144,888 $140,780 Cost of 2L $2,958.52 $3,698 $4,437.78 $138,996 $144,888 $150,781 Utility (change from baseline) -5% 0% +5% $152,514 $144,888 $137,989 Price (per 80mg) $3,693.29 $4,103.65 $4,514.02 $126,611 $144,888 $163,166 Cost of non-targeted $495.09 $990 $1,485.28 $169,038 $144,888 $120,739 Doses per maintenance cycle 0.80 1 1.2 $112,298 $144,888 $177,479 Table G7. One-way SA results - Infliximab Vs. non-targeted therapy Infliximab vs non-targeted Parameter Low value Base value High value Low value Base ICER High value Rate of severe URI 1% 1.70% 2.40% $110,514 $110,573 $110,632 1L d/c rate (year 1, PASI 75+) 25% 30% 35% $109,254 $110,573 $111,915 2L -> non-targeted d/c rate 5.0% 10.0% 15.0% $112,271 $110,573 $109,046 1L d/c rate (year > 1, PASI 75+) 11.25% 15% 16.50% $107,386 $110,573 $111,779 Cost per IV admin $286.03 $357.54 $429.05 $107,748 $110,573 $113,398 PASI 75 72.41% 83.05% 90.81% $114,406 $110,573 $108,023 Annual productivity cost offset $3,920.00 $4,900 $5,880.00 $114,303 $110,573 $106,126 d/c % to 2L 25% 50% 75% $106,060 $110,573 $114,497 Utility (change from baseline) -5% 0% +5% $116,392 $110,573 $105,307 Price (per 100mg) $964.33 $1,071.48 $1,178.63 $100,596 $110,573 $120,549 Cost of 2L $2,958.52 $3,698 $4,437.78 $97,200 $110,573 $123,945 Doses per maintenance cycle 2.0 2.5 3.0 $93,200 $110,573 $127,946 Cost of non-targeted $495.09 $990 $1,485.28 $120,654 $110,573 $85,369 ©Institute for Clinical and Economic Review, 2016 Page 258 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure G1. Incremental costs of ixekizumab versus non-targeted therapy Incremental costs of ixekizumab vs non-targeted therapy Cost of non-targeted ($410, $1230) Discount rate (0%, 5%) 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) PASI 75 (82%, 94%) 1L d/c rate (year 1, PASI 75+) (12%, 20%) Annual rate of severe URI (0, 0.8%) Targeted treatment utility (-5%, +5%) $0 $50,000 $100,000 $150,000 $200,000 $250,000 High parameter value Low parameter value Figure G2. Incremental QALYs of ixekizumab versus non-targeted therapy Incremental QALYs of ixekizumab vs non-targeted therapy Non-targeted treatment utility (-10%, +10%) Targeted treatment utility (-5%, +5%) Discount rate (0%, 5%) 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) d/c % to 2L (25%, 75%) PASI 75 (82%, 94%) 2L -> non-targeted (5%, 15%) 1L d/c rate (year 1, PASI 75+) (12%, 20%) Annual rate of severe URI (0, 0.8%) Annual prod. cost offset ($0, $4,900) Cost per clinic-admin sub-q inj ($20.35, $30.53) Cost of non-targeted ($410, $1230) Cost of 2L ($2,055, $3083) Price (per 80 mg) ($2,145, $3,218) 0.0 0.5 1.0 1.5 2.0 2.5 High parameter value Low parameter value ©Institute for Clinical and Economic Review, 2016 Page 259 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure G3. Incremental costs of infliximab versus non-targeted therapy Incremental costs of infliximab vs non-targeted therapy Cost of non-targeted ($410, $1230) d/c % to 2L (25%, 75%) Price (per 100 mg) ($891, $1336) Annual prod. cost offset ($0, $4,900) Cost of 2L ($2,055, $3083) Discount rate (0%, 5%) 2L -> non-targeted (5%, 15%) PASI 75 (72%, 91%) Cost per clinic-admin sub-q inj ($20.35, $30.53) 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) 1L d/c rate (year 1, PASI 75+) (12%, 20%) Annual rate of severe URI (1%, 2.4%) Non-targeted treatment utility (-10%, +10%) Targeted treatment utility (-5%, +5%) $0 $20,000$40,000$60,000$80,000 $100,000120,000140,000160,000 $ $ $ High parameter value Low parameter value Figure G4. Incremental QALYs of infliximab versus non-targeted therapy Incremental QALYs of infliximab vs non-targeted therapy Non-targeted treatment utility (-10%, +10%) Targeted treatment utility (-5%, +5%) d/c % to 2L (25%, 75%) Discount rate (0%, 5%) PASI 75 (72%, 91%) 2L -> non-targeted (5%, 15%) 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) 1L d/c rate (year 1, PASI 75+) (12%, 20%) Annual rate of severe URI (1%, 2.4%) Annual prod. cost offset ($0, $4,900) Cost per clinic-admin sub-q inj ($20.35, $30.53) Cost of non-targeted ($410, $1230) Cost of 2L ($2,055, $3083) Price (per 100 mg) ($891, $1336) 0.0 0.5 1.0 1.5 2.0 High parameter value Low parameter value ©Institute for Clinical and Economic Review, 2016 Page 260 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure G5. Incremental costs of ixekizumab versus infliximab Incremental costs of ixekizumab vs infliximab [ixe] Price (per 80 mg) ($2,145, $3,218) [inf] d/c % to 2L (25%, 75%) [inf] Price (per 100 mg) ($891, $1336) [ixe] d/c % to 2L (25%, 75%) [ixe] 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) Cost of non-targeted ($410, $1,230) [inf] 2L -> non-targeted (5%, 15%) Discount rate (0%, 5%) [ixe] PASI 75 (82%, 94%) Cost of 2L ($2,055, $3083) inf vs ixe RR [inf] PASI 75 (72%, 91%) [ixe] 2L -> non-targeted (5%, 15%) Annual prod. cost offset ($0, $4,900) Cost of administration (-20%, +20%) [inf] 1L d/c rate (year>1, PASI 75+) (11%, 17%) [ixe] 1L d/c rate (year 1, PASI 75+) (12%, 20%) [inf] 1L d/c rate (year 1, PASI 75+) (25%, 35%) Rate of severe URI (-40%, +40%) Non-targeted treatment utility (-10%, +10%) Targeted treatment utility (-5%, +5%) $0 $20,000 $40,000 $60,000 $80,000 $100,000 High parameter value Low parameter value ©Institute for Clinical and Economic Review, 2016 Page 261 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure G6. Incremental QALYs of ixekizumab versus infliximab Incremental QALYs of ixekizumab vs infliximab [inf] d/c % to 2L (25%, 75%) [ixe] 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) [ixe] d/c % to 2L (25%, 75%) Non-targeted treatment utility (-10%, +10%) inf vs ixe RR [inf] PASI 75 (72%, 91%) [ixe] PASI 75 (82%, 94%) Targeted treatment utility (-5%, +5%) [inf] 2L -> non-targeted (5%, 15%) Discount rate (0%, 5%) [inf] 1L d/c rate (year>1, PASI 75+) (11%, 17%) [ixe] 2L -> non-targeted (5%, 15%) [ixe] 1L d/c rate (year 1, PASI 75+) (12%, 20%) [inf] 1L d/c rate (year 1, PASI 75+) (25%, 35%) [ixe] Price (per 80 mg) ($2,145, $3,218) Rate of severe URI (-40%, +40%) Annual prod. cost offset ($0, $4,900) Cost of administration (-20%, +20%) Cost of non-targeted ($410, $1,230) Cost of 2L ($2,055, $3083) [inf] Price (per 100 mg) ($891, $1336) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 High parameter value Low parameter value ©Institute for Clinical and Economic Review, 2016 Page 262 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure G7. Incremental costs of etanercept versus ixekizumab Incremental costs of etanercept vs ixekizumab [ixe] Price (per 80 mg) ($2,145, $3,218) [eta] d/c % to 2L (25%, 75%) [eta] Price (per 100 mg) ($574, $717) Cost of non-targeted ($410, $1,230) [eta] PASI 75 (34%, 66%) [ixe] d/c % to 2L (25%, 75%) [ixe] 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) [eta] 2L -> non-targeted (5%, 15%) Cost of 2L ($2,055, $3083) Annual prod. cost offset ($0, $4,900) Discount rate (0%, 5%) [ixe] PASI 75 (82%, 94%) ixe vs eta RR (1.62, 2.19) [ixe] 2L -> non-targeted (5%, 15%) [eta] 1L d/c rate (year>1, PASI 75+) (11%, 16.5%) [ixe] 1L d/c rate (year 1, PASI 75+) (12%, 20%) [eta] 1L d/c rate (year 1, PASI 75+) (30%, 40%) Cost of administration (-20%, +20%) Rate of severe URI (-40%, +40%) Non-targeted treatment utility (-10%, +10%) Targeted treatment utility (-5%, +5%) $0 $20,000 $40,000 $60,000 $80,000 $100,000 $120,000 High parameter value Low parameter value ©Institute for Clinical and Economic Review, 2016 Page 263 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Figure G8. Incremental QALYs of etanercept versus ixekizumab Incremental QALYs of etanercept vs ixekizumab [eta] d/c % to 2L (25%, 75%) Non-targeted treatment utility (-10%, +10%) [ixe] 1L d/c rate (year>1, PASI 75+) (2.5%, 10%) [eta] PASI 75 (34%, 66%) Targeted treatment utility (-5%, +5%) [ixe] d/c % to 2L (25%, 75%) [eta] 2L -> non-targeted (5%, 15%) Discount rate (0%, 5%) [ixe] PASI 75 (82%, 94%) ixe vs eta RR (1.62, 2.19) [ixe] 2L -> non-targeted (5%, 15%) [eta] 1L d/c rate (year>1, PASI 75+) (11%, 16.5%) [ixe] 1L d/c rate (year 1, PASI 75+) (12%, 20%) [eta] 1L d/c rate (year 1, PASI 75+) (30%, 40%) [ixe] Price (per 80 mg) ($2,145, $3,218) Rate of severe URI (-40%, +40%) Annual prod. cost offset ($0, $4,900) Cost of administration (-20%, +20%) Cost of non-targeted ($410, $1,230) Cost of 2L ($2,055, $3083) [eta] Price (per 100 mg) ($574, $717) 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 High parameter value Low parameter value ©Institute for Clinical and Economic Review, 2016 Page 264 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Scenario analysis Table G8: Results comparing each drug to non-targeted therapy using non-discounted WAC prices Cost QALYs LYs Incremental cost/QALY vs. non- target Non-targeted $88,086 5.531 8.64 - therapy Adalimumab $281,311 6.649 8.64 $172,821 Apremilast $203,594 6.353 8.64 $140,529 Brodalumab $363,916 7.151 8.64 $170,285 Etanercept $263,757 6.469 8.64 $187,340 Infliximab $268,224 6.776 8.64 $144,669 Ixekizumab $374,055 7.187 8.64 $172,732 Secukinumab $341,425 7.018 8.64 $170,342 Ustekinumab $323,962 6.930 8.64 $168,583 Table G9: Results comparing each drug to non-targeted therapy using a lifetime time horizon Cost QALYs LYs Incremental cost/QALY vs. non- targeted therapy Non-targeted $220,024 13.81550 21.59 - therapy Adalimumab $379,625 15.31003 21.59 $106,790 Apremilast $319,243 14.90620 21.59 $90,968 Brodalumab $474,113 16.59990 21.59 $91,254 Etanercept $362,729 15.06425 21.59 $114,279 Infliximab $374,606 15.48090 21.59 $92,820 Ixekizumab $495,999 16.66841 21.59 $96,734 Secukinumab $441,245 16.34461 21.59 $87,470 Ustekinumab $511,815 16.17419 21.59 $123,709 ©Institute for Clinical and Economic Review, 2016 Page 265 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Appendix H. Public Comments. This section includes summaries of the public comments prepared for the New England CEPAC Public Meeting on November 18, 2016 in Boston, MA. These summaries were prepared by those who delivered the public comments at the meeting and are presented in order of delivery. Frank Zhang, Global Head of Pricing and Market Access of Celgene Corporation, declined to submit a summary of his remarks. A video recording of these comments can be found on our site here, at minute 1:27:14. Conflict of interest disclosures are included at the bottom of each statement. Jonathan Wilcox, Patients Rising Co-Founder and Policy Director I know that those representing ICER feel strongly about what they are doing. I appreciate that. But the intense reaction you are feeling is not unlike psoriasis itself: roiling underneath the surface, misunderstood, and its origin well out of your sight. The major crisis at hand and ahead for patients has less to do with the very real flaws in drug- pricing and more to do with insurance and regulatory practice that is, every day, overriding doctor decisions and blocking patients from getting treatments. With all that we know is wrong in the system, this is truly health care’s secret scandal. I ask you today to hear another voice. Stronger than mine. Apart from mine. It is a quiet voice. It is a specific voice. It is the patient voice of value. We all hope in this room that there is a chance that a deeper dialogue may occur that will advance the truth that patient access should drive value frameworks, not the other way around. And those speaking today should say nothing that might impact that chance. But after all of this time and all of this sacrifice and all of this support there is still no reform in this deeply flawed approach, then we say and patients say and their doctors say and their families say the time has come for the design and the development and the delivery of a new patient-friendly, patient-focused, patient-centered value framework ideal not tied to the mistakes and the policies of the past. ©Institute for Clinical and Economic Review, 2016 Page 266 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Conflict of Interest Disclosure. Patients Rising receives financial support from Amgen, Bristol- Meyers Squibb, Celgene Corporation, Genentech, PhRMA Dr. Michael Siegel, National Psoriasis Foundation Vice President, Research Programs On behalf of the National Psoriasis Foundation (NPF), thanks to ICER for engaging with our organization, patients, and leading psoriatic disease researchers and clinicians during the assessment of psoriasis treatments. We appreciate the attention ICER has given to our comments and concerns throughout the process, and are pleased to see that the analysis has evolved to more appropriately note the value advanced therapies provide to individuals living with psoriatic disease. As Vice President of Research of the largest advocacy organization serving patients with psoriasis, I will focus on the heterogeneity, complexity, and uncertainty facing the 8.3 million Americans living with this disease. Psoriasis has a heterogeneous genetic foundation, complex immunological pathogenesis, and uncertain environmental triggers. Symptoms are heterogeneous, there is complexity in disease progression, and uncertainty around the development of comorbidities. Finally, there is heterogeneity of treatment efficacy, complexity determining appropriate treatment, and uncertainty around access. These issues are compounded by the fact that psoriasis is a chronic disease, affecting patients throughout life. Given these challenges, NPF is committed to the preservation of patient-provider dialog driving all treatment decisions. We believe that broad treatment access is central to the individual patient’s success. Much uncertainty exists for patients living with psoriasis. What we know is that most patients say psoriasis is a problem in everyday life, are dissatisfied with treatment, and are not treating to the level dictated by their disease severity. We urge ICER to consider these challenges and ensure recommendation do not disrupt the sanctity of the patient-provider relationship. Conflict of Interest Disclosure. The National Psoriasis Foundation receives financial support from: Amgen, Abbvie, Celgene, Eli Lilly, Janssen, Leo, Novartis, Pfizer, Wisconsin Pharmaceuticals, Valeant Pharmaceuticals, Alva Amco Pharmaceuticals ©Institute for Clinical and Economic Review, 2016 Page 267 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Dr. Jerry Bagel, Psoriasis Treatment Center of New Jersey Director My initial involvement of treating psoriasis decades ago was on the inpatient unit at Columbia- Presbyterian where I cared for 30 patients with severe psoriasis who were hospitalized for one month. They would receive daily crude coal tar applications for 3 hours, coal tar baths for one hour, petrolatum for 2 hours, and then increasing doses of UVB light. Clear after one month they would invariably return one year later for re-treatment. Fortunately, over the last 15 years there have been FDA approved medications that significantly improve the quality of life of psoriatics. These medications differ in mechanics, route of administration, efficacy, and safety. The TNF inhibitors have increased risk with demyelination and congestive heart failure. The IL-17 inhibitors may have a risk with inflammatory bowel disease. Apremilast allows for oral administration but has a risk for depression and a lower efficacy but no risk for infections. Ustekinumab allows for every three month subcutaneous administration. Ixekizumab reveals data which shows complete clearing of 40% of the patients within twelve weeks. These medications, however, are not a one size fits all proposition. Some patients have high risk/benefit tolerance, others low risk/benefit tolerance. There is also an increased frequency of depression, anxiety, loss of self-esteem, suicidal ideation that affects not only the individual but also transcends the family unit. Psoriasis also correlates with is an increase in metabolic syndrome, obesity, diabetes, hyperlipidemia, cigarette smoking and alcoholism. There is a fivefold increase of myocardial infarction frequency in young severe psoriatics – which some studies have shown treating with biologics decreases. In addition to the average life span of an individual with psoriasis being reduced by four years, severe psoriatic is also tied to higher rates of poverty. Unfortunately, individuals with severe psoriasis indicate they would gladly sacrifice four years of life in exchange for normal skin. Despite advancements in care, and all we know about the value of treating, over 50% of people with moderate-to-severe psoriasis are not adequately treated (i.e. they receive either topical or no treatment). It seems the Product Benefit Managers, specialty pharmacies, and in fact the pharmaceutical and insurance industry by being more transport could decrease the cost of some of these medications to allow more access to the patients that require them. In my opinion, the goal needs to be for all parties to be more transparent and cooperative in order for more psoriatics to have an improved quality of life. Conflict of Interest Disclosure. Dr. Jerry Bagel is a speaker, consultant and investigator with AbbVie, Novartis, Eli Lilly, Celgene, and Leo Pharmaceuticals. He is a consultant and investigator with Amgen. He is a consultant with Sun Pharmaceuticals. ©Institute for Clinical and Economic Review, 2016 Page 268 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents Dr. Bradley Stolshek, Amgen Director, Global Health Economics Amgen’s commitment to psoriasis patients began over 20 years ago with Enbrel in development, which continues to maintain an important place in psoriasis therapy. While Amgen believes ICER’s revised report for plaque psoriasis has several issues, it nonetheless shows that biologics, including Enbrel, are good value (below ICER’s $150K/QALY threshold when using market-based discounts). Amgen disagrees with ICER’s methodology: lack of full transparency, narrow use of CE analysis, arbitrary thresholds, and no acknowledgement of patient experience. In addition, Enbrel would achieve greater value with inclusion of safety, impact of psoriatic arthritis, and flexible treatment options. • Safety and comorbidities were not adequately included in ICER’s evaluation. Enbrel has an established safety profile and over 14 years of use in psoriatic arthritis. • Flexibility in treatment options based on individualized patient response is not incorporated. Enbrel is efficacious in naïve patients and as an alternative option to previous therapies. • ICER’s Evidence Ratings lack consistency. NMA comparisons with point estimates above zero with significant credible intervals were rated “Comparable”, yet the Enbrel:Apremilast comparison is rated “Insufficient.” Consistent application of methodology would lead to a “Comparable Plus” rating for Enbrel. Enbrel’s recent approval as the only treatment of moderate-to-severe plaque psoriasis for pediatric patients aged 4-17 broadens its value beyond adults. All of these important aspects should be taken into account. We expect ICER to recognize the full value of Enbrel and recommend that payers provide broad access at equal co-payments for biologic treatment options so psoriasis patients can cope with this lifelong, burdensome condition. Conflict of Interest Disclosure. Dr. Bradley Stolshek is an employee of Amgen. Dr. Matthew Frankel, Novartis Vice President and Head, Immunology & Dermatology Medical Unit Secukinumab, indicated for moderate to severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis, is an example of Novartis’ commitment to innovation. ICER’s findings ©Institute for Clinical and Economic Review, 2016 Page 269 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents support secukinumab’s value as the most cost-effective agent for plaque psoriasis versus non- targeted therapy.160 The ICER report is an important step in determining the relative value of psoriasis medicines, but still has key limitations. ICER should improve on transparency of methods used in network meta- analyses, cost-effective analyses and net price calculations. Moreover, we have an obligation to consider critical patient concerns: (1) Patients suffering this lifelong chronic disease need effective, safe, and durable therapies: Up to half of those individuals with psoriasis are dissatisfied with treatment.161 • Secukinumab is the only IL-17A inhibitor with demonstrated sustained efficacy up to 4 years for PASI 90 and 100162. Secukinumab also has demonstrated sustained superiority compared to ustekinumab and etanercept for up to one year.20,163 • Secukinumab’s safety profile has been consistent over 4 years of treatment.162 (2) The total impact of plaque psoriasis goes beyond the skin: A great concern for individuals with psoriasis is high emotional, psychological, and social burden.164 • Secukinumab has demonstrated early and sustained superior improvement in patient- reported symptoms, skin related quality of life, and work productivity compared to etanercept and ustekinumab.20,165-167 (3) Location matters: Patients with psoriasis in hard-to-treat areas such as palms, soles, nails and scalp have different needs. • Secukinumab is the only IL-17A inhibitor that has dedicated studies for plaque psoriasis in these hard-to-treat areas, and has demonstrated sustained superior efficacy relative to placebo.168-170 Conflict of Interest Disclosure. Dr. Matthew Frankel is an employee of Novartis. ©Institute for Clinical and Economic Review, 2016 Page 270 Final Evidence Report Appendices– Targeted Immunomodulators for the Treatment of Moderate-Severe Plaque Psoriasis Return to Table of Contents