ICERE INSTITULE FOR CLINICAL AND ECONOMIC REVIEW JAK Inhibitors and Monoclonal Antibadies for the Treatment of Atopic Dermatitis: Effectiveness and Value Final Evidenca Repert Augurt17, 2001 Updated October 14, 2002 Updated Fabruary 27, 2023 Propared for s NEW ENGLAND - = CEPAC Febraay 27, 2023 Updabe: Par ICER's gukdolnes o the sccaptance i use f - Confidance” dta fram manutacures of pharmaceutial,academic-Tn- dcum the edence a1 rporty und Voteon the comparative circal afectiveness and alue ofmalcal rtarventiona. Mors oeaton about CEPAC I a2 P o /ool Y soand sl comm s angand acac) T fding cmtabved w1 eport re cvant 2 fth data of pucaion, haadaes shouidba waara that i kdance oy amargafoowngthepublcarion o s eport that could tancialy fmnceth reufts. Ky o sty i Formalupdatato i ragrt i the e, Th aconanic modol ied n KSR rport ar ntandad 1 campata th ksl oo, aspechd co',and ot v o dfarnt o s for b grous of patients. Mdlrecufs thereore reprcent: v ge g rous it and o 1 o e e e o ek e o sy Specti et I e, et o KER ks ot coms o el s et o rmay e T real-ward procicesetogs. ‘Dinsttuto for Clnkcal and Economic Review, 2021 Poge 11 JAK nbibitors anc Monocional Antibadies for the Treatment of Atopk: Dermatiis -Edence Report i the dsvelopment of thi rapore, KCER's researchers conulted with several inica! sxpert, petiont, ‘mandfaceurer, and other stabeholders. The foowing experts pravded put that heiped guide the. KCER team 0 we shaped cur cope o repart. 1 is passible that expert reviswers may ot have bt the ogportuniy toreview aft portions of this ruft report. None of theseindhviduols s reonsible Jor the ool contents f i report, o should be orsumed tht they Bipport any pastof . The mportshould be viewad o attbutable solely t the CER tmam cod e offthated ressorcherr. For e complete st of strkehokdersfram whom we requested bput, lecse vidt: juploat \CER_Mopie-Derrats Stakahakder- s p11521, Expert Reviewsrs ‘Wandy Seith Bagolla, MBS, Vice Presidant, Sctemtiicand Clnical Atirs National Ecsema Ascociation Wendy i @ solied empiaye of the Nation! Ecoema Associat which hos recetved gyants and. spansorship cwards from a verety of industy pavtners. Jorathen SBrerbery, MD, PHD, MPH ‘Assordets Professor of Dermatslogy ‘The George Washington nivarsity School of Madicivs and Haaith Sciances . Siverbery hus receivee hanostrie o i corsultent onefor auhisary boord member for Abbiie, 6 L8y treyte, Lea Phorm, Pfve, Rageneran, ond Sansf. $ie b aieo sarved s speates for EY Lo, 180, Pfcer, et Regsnern. EicSimpeon, MD, MGt Profesace of Darmatnlogy ‘Oragan Haalth & Science Univershty, School of Meciing Dr. Simpson receives honorarta and §rants from AbbVie, EY LY, ncyte Lea Pharma, Pficer, ‘Regenerun, and Sanoft ‘Gingttuta for Gincal and Economic Review, 2021 Page v IAKihibitors and Monocional Antibadies for the Tretment of Atopk: Dermatiis -Eudence Report Table of Contents Executive Sumary. 1 Beciground.. 2 Patant and Camghar Perspactives .. 3. Comparative Cinical Effctiveriess —. 3.1, Methods Overview.. 2.3, Resulks for Mkt Moderate Population Sumenary and Camment.. 4 Long:Term Cost ffectiveness... 41, Methods Dverview.... 42, Key Model Cholees and Assurnptions 43, Renus 24 Summary and Camment. 5. Contmtual Cansidarations and Potarti Gther Benefs . Health Beneft Price Benchmarks. 7. Fotential Budget Impact... 7.1, Overview of Key Assumptiors . gorvrrbaasbekybbirLbLLL A2, Potential Cost Saving Measdres In Atopi Dermati.... 6. Patlent Perspectives: Supplemental Information.. AHIIIBEE ‘Dingttute for Gincal and Economis Review, 2021 Pagev IAKirhibitors and Monocional Antibaties for the Trestment of Atopk Dermatiis -Eudence Report 2. Nework Meta-Anatysis Suppismental Information. D3, Addhional Ctiical Eddence. Maderate-to-Severe Population. 5. Previous Spstemaic Reviews and Technology Assessments . . Long Term Gost Effectiveness: Supplemental Iformation. EL Datallnd Mathods 2 R, ES. Samsithity Aralyses _. B4, Scenario ATalses. .., ES. Prior Economic Model.. F. Potential Budget Impart: SupplemertalInformation. ‘Gingttuta for Gincal and Economic Review, 2021 Paevi IAKirhibitors and Monocional Antibadies for the Tretment of Atopk: Dermatiis -Eudence Report List of Acronyms and Abbreviations Used In this Repart S Ty e Dot bmpect St v evert ‘Aganyfo Heakcare Rasearch d Quaty Bodysrfacawan Cuirnt Derraciogy s Qi el Cormarus rice e ‘armatki arnly ngact quaeiornare Darmatiogy le Quay ndax eaem Arae Severe Euro0el fre-rueron cussticrmairs Food wd g Auniisratien ‘Gingttuta for Gincal and Economic Review, 2021 IAKinhibitors and Monocional Antibdies for the Trestment of Atopk: Dermatiis -Eudence Report Page vl Executive Summary ‘Atopic dermatttis s a common, chrankc s condition with persistent o reapsing lesions thatare Ttchy, inflamed, and dry. Commanly referred o as "eczema,” stopk dermati affects both children and aculs, Symptoms ot Rzhing ancl svan skin i vary In sevarty, but can sffact shap, casa Popcholagical distres, and recuk In dificuty with parformance st achool or work 1 The ‘appearance of the s can aisa ead to soctl embarrassent and lsoleion.+ The et effect s that atapidsrmatiiscan have a profount effecton all spact of patients’ Fves and thoss of thelr famiy and cereghvers Inthe United States U}, atopic dermattds b estimated to affect around 11.25% ofehkiren and 7-10% efaduft ™ The overall costs asoristed with stopk dermatis are: entirarta t ba 5.3 billan dollars s the US, Including over 53 bilon in heaith cars costs 12 #topie dermatis lxa can laac o wark and productiy kom. Putients ani caregivers emphaslzed the Importance of having messures of reatment outcomes that ure most meaningu ta them. Hcing and pain wers ssen s the kry autcoms, bt thele Impact on danp, ncreasad ditraction, warry, ity and ather aspacts of e varied accoeeing ta ‘0 chdual's paricur drcumstancas. For example, some patiants refiscted that whan they wars ‘adolescents, appeararice was most Important o the. As they got okder, other Issues such 3 the Impact onthe sinn terms of pan and Infections became more mpartan. Though al recognzed ‘atopic dermatit asu chrenic condition the Importance of flares and the need to break cycles of ‘warserdng tsaasa was sbo emphaszed. Since many Indiidusts ssa are Impected by ather ‘conditians such as asthra and alargies, an some trtmants Improve these canditions xs wel,we heard about the Importancs of thking broadly about the benefis of reatment. Sics Rching s the most bothersome symptom for most patents,the Importance of measuring the Impact of treatments an heh and associated lssues such as skeep disruption are needed. The Importance ot ‘comprehensive putcome measures that capture the diversiky and mpact of atopic dermatts over ima was emphanized. ICER reviewed dupliunal for moderate-to-severe atoplc dermati and topica crisaborole for mild- to-moderute atopkc dermatiiaIn 2017 A number of w bioboglc theraples ars svaliabl or being evahuatad In rtients with stopic darmatth, Tralakinumab, & monoconl antibedy that blocks L 13 mcaptoe bincing s iven subeuaneauly and b under Invstigaton for patlents with modarats- ‘0-sovers atopkc dermatt. Abeoctini, barkTink, an UpadacHnlh are oral Janus nase UAK) Inhibiors that are aso belng evakusted for patents whih moderate-to-severe atopic dermaths. ‘Cancens abouk the safety of oral 14 Inh¥tors thatare approved forather conditons has led the US. Food and Drug Admiistraticn {FDA) to axten the review perio for thesa drugs and tralokinumab racalva 2 Camplate Razporaa Letterfram the FOA requasting addtianal data relating tn 2 davics companant used t3 inject raiokdnumai. A toplcal K inlbitar, nocifinls ‘Binsituta for Cincal and Economi Review, 2021 Page ES1 IAKihibitors and Monocional Antibotles for the Trestmert of Atopk: Dermatiis - Evidance Resport ‘Raturn to Table of Conanty cream, I being evalutad for patents with ik -maderat 20pi dermatii, and s review perod has also been extended by the FDATS Intha moderatesm-aavara population, the four Inerventions al inpraved skin rcings campared whh placaso, a0, whare assessed, appeared to Improve hh, seep, and qualty of M. ‘GuantKative Indirect comparisons across the new agants and dupilumab, as well s head-to-head ‘compartsons between twa of the agents {upadacttib and abrociini) and dupluraeb suggestthat. Higher doses of upadachinl e possibly brocTinl are sormewlsat more efective than duplkarab, whia barctinb (st the dases ikalyt be aparevad) and tralokinumab ara kaly sammwht ess ffacthe than dupikenab; hiwevar, thera & substantial uncartainty In thesa compurieona. Resolution of ch may oceur more qukckdy with hgher-dose abrochini than with duplumab. Sy s Important conslareton with bickagic tharuies and, as above thara hive bean Particuar concsms about the safety aforal IAK nhbitors whan s fr other candiions. ‘Concerns about 1k ot longtem data for dupliumals, noted In ICER's 2017 report have been alleviated over time based on published data and widespread use I clrica practice.® Tralokinumab i @ novelInhibtar of IL-13 that warks through @ meshankm mare simllar to chplumalsthan the JAX Ihitors, but ecks the sama long-tarm safaty profie of dupilumabs. ‘An addtonal conskderation In comparing therapie i that iy patients with atoplc demattis have comorti etoplc conditons such us tha, e dulumab his prven efficacy I treating ‘ertaln pattarts with sthma or chronle tinoaiusits Takdng o consideration the above Informtion on short-berm benefts seen Inthe s bt Iimitee]deta and concers abott ong term sfety, especialy or oral JAK kibitors, we condluded the evidence on net health bene for ahractini, barktint, upaactint, and tralokinumabs ‘eompared whth topical tharapas alores was prmisig but canciusive 'P/) an compered tm each other was nsuficent {1, Wa conchuded that the sukdence for nt heaith beneft for abrockink: ‘and upadaciin compared with duplumab was also fsgiclent ('), and thatthe e heatth benelttof baricinib and traloknumab were comparabie feror 1C-“} when compared whth dupilums. Since the barltinlb and ralokinumab trials ondy Included aduts and abroctinl and upadicktiib ‘il enrolled small numbers of patiens younger than ege 18, there s greter uncertalnty for atlescents with the new therapies. W compared the cost and effectiveness of abrodfini, barchinib, tralokinumab and Upadictinib for moderate to severe atopic dermis 1o toplcal emallents {standard of care) and duplumab, ‘over a fve-year time horizon taking @ health sysem perspective. ‘Binsituta for Cincal and Economi Review, 2021 Page ES2 IAKihibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conenty Estmated nit pices wars usec for barichink, upacaciinl and duplumab tat ars curreny marketed. For abrocTin, we used the average of the net pices of arfotinlb and upacactink as 2 placsholder, For tralokinumab, we used the net prfce of duplurab o5 a placeholder. Tate ES1. praserts the Incramantal resuks fram the bese e cos-effectiveness aralvls. Ghen o modeled gains In M years across the evaluated theraple, the cast per fe year gained i ot reported. Tabia ESL. Incramantal CoetEffectvanee Ratios forthe Bam Cna Tt | Comperr | Gowpr LY | Coporiie Copr e ouzed | Your ounad Rk | Sor Sigzo o FEa ek Soc S0 ) s 800 “Tobokinum [ Soc fimsa0 [} 0400 Upedadtels [ soc 040 I Sue A0 v 3 S0 ) Stinan brockilr | Duphiras A0 ) Ss08a00 D ‘Duplumat | Lo Goty, Lass L) Tac Costy L ffcth e ik | Duphimab | e Comty.Les " Tac Costy e ot Efcie Upeincial | Dupkrah 1912300 W S5 LYG: kv - year ke, ALY iyt -y, SO Somed o G- “Using s pacehoier pe: Mot The coat per ALY and coat e LY rtionwe: the same v tht the trestmerts heve nck been shown lenatien . Fram the msi-affectivaness bass case assuring the standars of care comparatar, wa ustimeted the Heahh Berieftt icn Berchrmaria (HBPRa) for each Imervantion. Tha HBPB range for abraclini 1 530,600t $41,B00 (dscounts nat presantar dus & lacaholer pricel; for barkchinl, $24 40010 29,000 (16% discount o ho discount from Wholesale Acquistion Cost (WAC) needed atthe $150,000 threshold); for ralokinumabfrom $25,700 1 $35,000 (dcounts not pesented dueto lucehoider price; for upadaciin from $30,400 o $41,500 [dacounts of 35% 10 53% from WAL ‘amd for dupikama from 525,000 to $39,500 (dscounts of % to 31% from WAC). ‘Binsituta for Cincal and Economi Review, 2021 Page ES3 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conenty Tably ES2. Arcs Cont-Effecthvanaes Health Berf Prics Beachrmartsfor Abroctinb, Bariiiall, Trloidnuma, Upadactialh, and DupSkaneb versis Standrs of Care: Tt Dot | AW | Aenmipicast | famaimiast | Gowantiem Wi hamre 10 Thradold | $11000 Trasheld | 1 Aasch Thrshold Prims ) A G T S S [ T I s S0 | s L] ] T o [oRe TR T ] S B e 1e st oA ot A 23,70 S W i e =0 T | W et A G ] S T [ SR E T o A T [ Dopiat oA Gt ] 00 o [ T ] 2] 0 e WA kot 5oV ot TG ouml ko W e Flneds QALY by ot e yeor = Nok apolabl Ay Bl coholdor pies mere v It ikt mocarats popubrtion, opical ookl cream was marn effactive than vahicls (placabo). Wl ruxoltinlcream also appearsd o be mare efectiva tan 3 medlum posacy ‘topical coticosterld, K as ot compared o More potet topical cortcoszeroids and diferences In ‘il destgns precluded quantative ndirect comparisons across topical theraples. There ks ‘uvently limed Informartion on long:term ety of namiltinib cream. A3 toplcsl JAK nhlofor tharapy, sufety concem ara ikaly ot ax grest s with oealJAK nhlitors, but thare st b systeric: ‘absorption f th topical agent. Topicalcortoastersids have known harms both t the sn and, particuarty with hgher pocsncy preparationsIn chiren, arisk or systemic harms. Topical caldneurtn Inhibars cany a "black box* waming fo a potentla ik for causing malgnancy, although many linical experts feal the evidence does nat warmant this cancern. We 255065 the et health benefitfor Rorolti cream compared with topical emolients 1o be ‘compurable o better ("Gr+). We conskler the evdenceforthe ne health benefit for noxoltini eream compared with other topical medications t be bsufficent (). ‘Binsituta for Cincal and Economi Review, 2021 Page ES¢ IAKihibitors and Monocional Antibotle for the Trestment of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conenty ‘Appratsal comittes votes on questions of compargtive affectivenass and value, long with ksy olicy recommendtions regareing picing, acoess, and frture research are Inchuded Inthie main Teport;several key polcy themes are highighted below: « Allstakehoiders have a resporslbilty and sn mportant rale o lay In erauring tht effecthe e truatment options for patants with stoplc darmatth ara ntroducsd In 2 way that wil help reckce beaith Ineguites. « Payers should only use scep therapy when It provides adequate flexbilty to meet the needs of the diverse range of patients with atoplc dermatits and when implementation can meet. estabished stward of transparency and efficeny. @ Spaciahy soceties chaukd upcrte traatment. gidelines for petants with atapic darmtits 1o refiect curent tregtment options In a form that s 625y o Interpeet and uss by cliictars, patients, and payers. « Manufatturers, payers, and patient advoedcy groups should support aricng i rebate. rafarm affort that wil craats battar ewardsfor dlidcal and scanamic valua while sisa helping patiants afford sccass to the rastrents thay noed. ‘Binsituta for Cincal and Economi Review, 2021 Page ESS IAKihibitors and Monocional Antibotle for the Trestment of Atopk: Dermatiis - Evidence Rsport ‘Raturn to Table of Conenty 1. Background ‘Atopic dermatttis s a common, chrankc i conditon with prslstent o relapsing lesions thatare chy, inflmed, and dry. Commanly referred o as "eczema,” stopk dematil affects both chidren ‘and atuls. Symptoms of Rehing an wvan i vary i severty, but an effact doap, cmsa Popchological distres, and rexuk Indificuty with parformance st achool or work 4 The ‘appearance of the s can isa kead to soctl smbarrassment and loletion 4 The net effect s that atapidsrmatiiscan have a profount effect on all a5pact of patients’ Fves and those of thelr famiy and coreghvers. %4 In the Unftad States (US]. atople dermatts s estimated to affect around 11-15% ofehkiren and 7-10% of aduft.™® The overal costs assoeiated with tapi dermatitisare entirmta to ba $5.3 bilian dollrs s the US, Includig over 53 bilon in heaith cars costs 232 Atopie dermathis lxa can laac o wark and productiy kom: ‘Atoplc dermatlts s thought 1 be caused by charges in the burrler properties of the skin and problems with the body' Immura rsponse. '3 Fatiants with stoplc dermaits ltan Fava 3 famy history . can ab includa asthema and llergi thinkis; mapic darmacith T aho acsoclved with a0cioaconomic and amviranmental factors @ Atopi dermatis frequently begina during childhond and persiss Into adufthood In about 50% of affected chiken, s lagrosed primary by s ‘appearance, the ski lesions can be locallzed or widespread, varylng I thelr ocation by age, and ‘an come and go o be persbiet ™ When acute, the sppearunce b o red pupules and vesiries Wi wasping, Dozing and crustng. Whan subscta ar hrork, eslons ars thy, scaly,or exzoristad with skin thickening, arasions, cracking and bleading. Disoass savarty 4 ificuf o conststantly define because It s based upon the amount and locstion of sin wolkes It appearance, and the subjective Impactof symptoms. Mot chidren with xtpic darmiathi have mild diceasa, whth 12-26% having moderate and 6-7% having severs dsease. %7 Moderste or ssvars diseass appears ta be mare comman n s ‘The severtty of atopk dermatts can aso vary b season and gsographk region™ _For al patients with atoplc dermatii,treatmentincludes maintaiing the skin barier with moisturtzers and emallients, svalding riggers uch as hest/cald, kow humidity, and known aiergens # Toplcal ‘corticasteroids are racommandia far short-term, Intarmitsent use, ancl ang term malerance Fray Inclue the tapical calcinaurkn Inhiitars tacrollmus and pimecrafimus, or the phosphodiestarase & (PDE-4) Inhibior,crisaborole. For those with stopk dermats not controlied with topcal theraples, photatherapy of systernlc Immunomodulators are used = Short-term use of ‘systemicoral cortioosteralds or yelosporine can be used 10 more quiddy control skin dscase, whie oral mathotraate, azithioprioe or mycophanclata ot can be used forlong-darm control. Dudluma, an L4 racuptor artaganist, becarne waltableIn 2017, L« apprrved n the US far thoss ‘Dinstuta for Cancal and Economic Review, 2021 Page 1 IAKinbibttors el Monoconal Arilaliesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Return to Table of Contenty I s 3 commonly used systemic mmunamodulator for moderate-to- o treatmars, marsy Indvidiala da nat respand o multipls iffarart toplcal a PStermic theraples supporting the e for new tresEment ptons. ™ Ths s sspectally e for chikiren, where there Is greater conoem about the effect of topical and systemic corticasterokis A numbar of new biclaghc tharagies ara avalable o baing svakuated In rtents with atopic dermatits. Ore now targst o therapy I Interieukin (IL113.7 Tralokinuma, a monccional ‘amody that biocks 13 receptor bindingfs given suboutaneously and s under Investigation or atients with moderate-to-severe atopkc dermatiis. It received a Complete Response Letter from the FDW requesting sclidonl datarelatng 10 device companent used t Infect traiokinumab. Ianus inases 1AXs), oytoplasmic proteln tyrosine Kinases that are artlal for signal transduction v the cell rudleus, are other new targets for therapy™® Oral AK Inhlbiors being evalusted for patients it moderte1o-aevers atopic dermatitaIncue abroctilb, barckint, and upedaciinb. (Concarms abouk the safaty of oral IAK nhE#tmrs thet arw maaravad for other candions has led the US. Faod and Drug Administraion {FOA) e avtend the review pariad for thesa crugs A tapical JAXinbitor, acifini cream 5 being evaluated for patients with miid-o-moterata stopic dermatttis. The FOA has also estended the review period for ol cream.3® Tabla 1L ntarvantions ofintarast Tearvarion Wackmiim o At | Dalry Fowtn Prascbingforrmtion Sonark Hama [arand an ‘rodi P ol TRl Db fGlaan] | WK nblor onl 3 2mg one dlly Lt (o) | 1 el ot 35 g vy Tasitial Crarn T bR Togieal TN s Gy ok, 18 manodoral | Subcutanecis rjecion | 60mg Inkia]dous thar antbody g every 2 wenls I s Vo, Lt Mota: Thare mary baan opton fo dograckanumasavryfour weela b sorma patents. ‘Dinstuna for Cincal and Exonormic Review, 2021 Page2 IAKinbibttors anl Monoconal Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Raturn to Table of Contenty 2. Patient and Caregiver Perspectives Oiscusslons with Indhdual patents, caregivers and patient acvocacy grougs dentifed Important Insghts and perspectives. Commman themes emphasized ineuded: the coniderable burden of this chonic condRian on patierts, caregivers an familes; the dhversy ofthe mxperunce with atzpic derratits aspectally st dffarant Hmes i ane's s; the damands of curant traatment anc the rasd for batte trestmant options; the Impact o all aspectsof e Ickudng school work and socalftamityrelatonships; the Impartancs of measurng autcomes of cars that are meast eaningtul to petiens; and the high costs and efordablity o cae for patients and familles ‘Though the maforty of thase with atop: dermatts have a mildsr coursa that can be adequately managed with topicaltheragy, tis peroegtion may lead to an underappreclaton of the profound ffectthat atoplc dermatiiscan have on ol aspects of patientsHfe. The considerable burden of stopkc dermatids reflects s chronlc nature foftzn beginning In chlkdhood and progressing through ‘alescance and o adulthood), and the unerecictabilty of iewesa larus. As such, 1 ot oaly Impactsthe patiant but isa familes careghvers, french, and refsfonahia. The prmary symetom of atopkc dermatits, eh,can lead 1.2 ost of additional problams Inculing sk pain anc Infections as well s dsTupting sleep and causing psychological distess Inchcing loss of seit- steem, arufety, depression, and suldidal estion. Because flares ofthe disease can lead Indhviduala to search for some behavlor o action to explaln the worsening,there can be gult, o Fray bl others 1o blarme the patiant far the lare. Tha rasult s thatatopic darmatlis an hve s profound Impact an s activites, ntarparsoral relstanships and perfarmance st chool and work. ‘The impact of stopc dermatis can vary dependiing on many factors, Inckading the age of the putiens,leading 0 chvary of expartances. For chiiran with stoplc dermati, Intarparsanl ffacts can Incul bubying ky cther childreand changas In family dynarics amang parersts and sibings associated with exta time and atsantion spent by caregluers focussd on the patirt, eading other chidren na household to feel neglected. For adolescents, the Impact o atoplc dermattts on ‘appearance was emphasized, eading to seftsolation and insecur s, all affectng soclal Intaractiars. Acroes al g graups, siopic darmatits can mpact s scthfties such a1 warrise and Facrustin due to the negative efects anthe s raisted tn excassive swating ar coldhat expoaure. As an llrgic condiion, stopkc dermatil £an aka necamtate resrirtions an dstthat canbe diMcu. ‘Aai resut of the symptom of atopic dermatits thet can kead 1o bewp disturhance and daytima fatigue, X can affect performance Inchacing that in schoal and work. For sudents t can affect school attendance and lead % dtraction when I cass, negatively Impactig developmental illestones. Simtarly, atoplc dermatis can afect work through missed days, decreased work ‘Dinstuta for Cancal and Economic Review, 2021 Paged IAKinbibttors anl Monoconal Arilaliesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Return to Table of Contenty perfarmance (resentpetsm), missed promations,mited career ogtions, and even disabily from ‘one's chosen profession, The net result s 2 inandal Ipack on Individuals and familes over the ‘course of one's e terms of eccational and work achancement opRorturites delayed oflost. ‘Awida rangs of daficancles with currently saliabie toplcal and systemic testmentsfor acoplc dermattts were noted. There was broad recogniion that current therapies do not address allof the needs of patients with atopic dermatis. The nesd for therapies that work quidly, provide sustalnen rele and ure sae fo long-ten use were Hghlighted. Thaugh some patierts derive beneft from mxisting theruple, the corakdarabl tima and effot Invalved I upphing topical ralsturiars anct wrape or traveling o and fram phatctherapy sexsians s taing on patents and thelr caregivers. Moregver, ravel o recalve carecan be particuarly demanding fo patients nthe U who Ive outside ofargs metropoiltan areas. For those with mld 1o moderate disease, there s 2 need for new topicaltherapies. Topleal strolds can damage skin with prolonged use, whie topkcal ‘caldneurtn Inhlbors carry a black box warning, arel taplcal phosphod esterase-4 (PE-4) Inhibltors bava limitad fficacy; these latar agents can aba cause sin dacomfart/burring. Forthose with moderat to severe disease not adequately managed with topkal therapies, oral ‘corticasteroidl are commoly used for short courses, ut have welkrucognized sida effucts, can bava rabound ares whan discantinued, and are avolded I younger petlent. Othr systarmic tharaples such as yriosporin, methotrexate s othar ror-sslactie systamic Immuncmadiztars e imited baneft and patertialyserious sde effects. Even duplkumab, the st blokoglc ‘approved Inthe US or stopic dermatiti, takes time to begin woridng, does not help allInddusls, ‘and has side effect, such as conjunctivils tha result In some patienss discontinuing use. Faly, patients and ciragtvars cammentad about the haleniga of choosing therupies where the long-term ffacts are nat comlataly known or mary larve uncammon but potertall sarious side efects. Putients and caregivers emphaslzed the importance of having measures o treatment Outcomes that are mast mianingf ta them. ching and skin pain wera somn i the ey autcomis, but thek Impact on daup, Increasacditraction, warry and sty and ather aspectsaf fu varid sccording 0 an Indiduas particular eumstances. For axampls, some patents refectnd that when they were adolescens, appearance was Mot POt to them. As they gotolder, other bsues such as. the Impacton the sk Interms of pan and Infections became mare Important. Though all recogriaed stople dermstits 35 8 chronic conditian, the Importance of flares and the need to bveak el of worsaning dloeuse was alao amphastzed. Sinca many Individats also wa impactad by other candttons such ax msthra and allergia, and sam trastments Improve theas conditians as wll, we heard about the Importance of thinking hrac about the bensts of restments. Since chingsthe mast burdensome sympoor for most patients, the mportance of measuring the Impoct of reatrments on heh and associated Isses such as seep dsruption are needed. The ‘Dinstuna for Cincal and Exonormic Review, 2021 Paped IAKinbibttors anl Monoconal Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Reaport ‘Return to Table of Contenty Importance of comprehens e sutcams measres that capture the hversty and kmpactof 2toplc: dermatits over e was emphasked. Far many patiants an pararts, the high cost of ca for atopi dermaris was notad. Toplcal ‘emailierss and wraps v non-presigtion and often nct covered by heaith Insurance. Even for those with health Insurance, the afordablty ot care s a chalenge for patents and familes. The chvonlc nature of kopic dermattis with copayments and deductibles for numerols docsr vihs, mukiple triabs of dHferent toplcaltherapies, and photntherapy sessons sid up uicKly. Morover, ewer ystamic tharapies for etopic dermatits are very xparatve and ptients and carsghvar face the hurdan of negatlstig Insuranca coverage palites and the poemialfar igh ot of packet corte. ‘Dinstuna for Cincal and Exonormic Review, 2021 Page 5 IAKinbibttors anl Monoconal Arflaiesfor the Treatmat of Apk: Dermatls - Evidance Report ‘Raturn to Table of Contenty 3. Comparative Clinical Effectiveness 3.1. Mathods Overview Procedures for the systematic Inerature review (SLN assessing the evidence on abrocitb, barickin, tralokinuma, and upadodtin In moderate-to severe atapie dermatiis and nooitinb rwam I mlkto-moderata stopic darmatts ars descfbed n Saction D1 of the Report Sucolsmat. Scope of Review “Ths SLR sompares the clinkaleffectiveness of broxitin, bariint, traiokirumab, and upmctinta fopica tharaples, dupilumab, and each other for the traatment: of modarate-to- ‘savarm atopic dermatits I aciclascants ancl aclukz, The SLR slka compares nusskink: craam to ‘topical therapls for the trastmart of mito-moderate atopl: dermatts It adoleszants and 3dult. ‘The ull PICOTS crteta are detalled In Secton D1 ofthe Reoort upelement, Evidenca Base Modercte-toSevere Popuiction ‘Atotal of S8 referenoss mes our inclusion criferkafor the moderste-to-severe populstion @ OF these, we dertifid five rarcormized conirolld trsks (RCTs) af abrocitnds one phs Il and faur htsn 15723407734 fye RCTs of barctini (one phase | ancfour phate 1), %A% theas RCTS of ‘ralokinumat two phase 1], fve RCTs af upacachinks(one phase Il and four phase )55 an s RCTs of cuplkamab (one phase | an ive phase ) that met our Incluskon crteria @@ Of these ral, 21 enrolled achuts, where 14 were placebo-controlied monatherapy ‘ot and s were placebo-controlled combiration tis that permitted background topical rachcution. Twa hesctz-haai sk were kdestfed, und thaze wars ore placabo-and actve- ‘controliad combinution tral UADE COMPARE) and ane acthve-comtralad manatherapy tral (Hacs Up). Severai ral soley envollec childresor alescants, where one was & placebo-controlied ‘manotherapy til and two were placebo-coneroled comblnacion trias, ‘Tiasthat anraled auits are describec it fabwed by il trart slefy ervriied chikrn and ailescants. OF note, oy the FDA-approved toss of uplkumab wes svaluated In aduls (300 mg once every two weels). Evitance Tablss 61.3:1.7 conakthe key sty desgn and baseline character st of ach trial, while 3 sumimary s resented below In Table 3.1, Please note that blacked out cata represents ‘Dinstuta for Cancal and Economic Review, 2021 Page IAKinbibttors anl Monoconal Arilaiesfor the Treatmat of Aspk: Dermatls - Evidance Reaport ‘Return to Table of Contenty ‘acacerioin-confidance data submissions. WhTis most trals enriled patients 218 ysars o, the pivotaltrilsfor abrochtin, JAOE MONO-1 and LADE MONO-2, and the pivotal ras for upadaciinib, MEASURE UP 1, MEASURE UP 2, and AD-UP envolied patierts 12 years od. However, mast patients Iy these tiaa were 218 years old, and we searched for evidence siratified by uge. Tha primary andpoints of the abrocin triak, JADE MONO-1, JADE MONG-2, and JADE COMPARE, ‘were massured at 12 waeks, whi the remaining e’ primary andpoints wara mezired at 16 waeks. Trigl populatins wers comparabie with respect 1o e (3141 years, duration of dissase (2128 years, and disease severty {3236-55% I6A o 4], Primary endpolns varied slightly amorg the triaks bt typlallyconslsted of EASI 75 and/or A (1A sore of O/L or 01 and 22 polts from buseline Improvement). RCTsthat anly enrollec chlren or adolescents were Imhed. LIBERTY AD ADOL envolied patierts 12-27 yeers and measture it co-primary endpoints of EASI 75 and 1GA (iGA score of /1 and 22 ol from baselne Improvement) ut 16 weeks. JADE TEEN also enrolled patients 12-17 yesrs and Freacured Hs co-primary endpolnts of EASI 75 an KGA (IGA scare of /1 and 22 pofrés fram baseine Improvernent) 212 waala. In cantrast, LIBERTY AD PEDS anvailed patierts 5-11 yaars with severs ‘apic cermatis and measured s primary endpoint of GA (1GA score of /1) at 16 weeks. ‘Ackitioa! et are vl In Saction D3 o tha Raport Sueplamant. ‘Dinstna for Cancal and Exonormic Review, 2021 Page? IAKinbibttors anl Monoconal Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Reaport ‘Raturn to Table of Contenty Table 3.1, Ovaret of Placabio-cortrolied Monotharapy and Combination Trisk of Abeockinh, Barickin', Trabokinumes, Upadactn, and Duptumab n Adults g | men | oan | sasanon | Aeore e A Smi | Ghel | ey | unmmy | ofap) Aotk w0 1c0me soemon- | JE0200 w | w2 | ma - s - "o RO THTE LDEMOR: | ano 200mg = | ous | = 2o 22 oo ARO Do raTE ot 2300 200mgs TS coweme | somges | 7 29| 77 a1 ] PRo4TS 0 Tc0me Sonderhans | sne 20y w | ms | as nr s a PBo. ) @ | a0 | =7 =7 as as | ms | s =0 s w | 71| wr a7 az m | mo | = U w0 BN T S amzmgas | s | aa | ses a0 w by P04 TS Tkt o [ w | ma | m s s o | Am m | ar | = = w2 ARG TS s | AT w | ms | we =0 - (="} ‘Dinstuna for Cincal and Exonormic Review, 2021 IAKinbibttors anl Monoconal Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Return to Table of Conterey Paged - e | o9 | o | oo | atore SealM) | an] | ngy Duretion, ¥ ofa) W e |2 200 w | ms | me | mr | wa s s e |20 o | ma | ome | ms | s £ mue |ammerm | s | me | s | oms | o o oo ity | w | me | ws | w | = Az e |tekivee o |ipme w [ we | ws | me | e £ gt o UBSIYAD | pup sonmg - .7 a7 =7 'ty L PBO. o e o | oy | | ma | wr | e | ows o e s |5 : CHRONOS DUP 300 me + TCS. a 940 azx w o1 s o oy o oy o oy e (2 |y |y | po | me | e N o et 2 e iy K3, A A v e gt B VWS, DR W5, (e i COuTare (2715w, e arrmsra ekt e o sy, ABED: i, AR bk, P e FOO: i, ol i, MR o Ao, W Ky, W ory e, QW ey s v, TCBtopal i, i LU i o, . e, g et h il el Pt 12 i, Yo, incdd 1 o ke e, ek e il chasem atn, ‘Dinstua for Cancal and Exonormic Review, 2021 Pages IAKinbibttors anl Monoconal Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Return to Table of Contenty Metd-to-Moderate Popudation ‘Atotal ot 21 references mek our Iclusion creria for the ki £>-moderate population B Of these, we detiied bw phase I, Flscebo-sontralled RCTs of nxoitink crearm®” and on phuse b piscabo-and actva-controlled (opical riamcinolon acxtoritle) RCT of ol cream %5 Whis e e trias af craborolsfor ths cation ware kientHiad sinca ha prioe CER Repert in 2017, W gl RCTS of thls agent met nclston crters In our previous review.® Dfirances I trisl Populaions, outcome definkions, and length of folow-up 0 not permit s to quantiatively compare aitcomes of triaks of nsoMink cream with crisaborole or topicl cacineurhn Inhbfars. Exiionce Tables G1.50-1,53 contaln the key s dealgn and baseline characteristis of ach tral, whie a summary s presented below In Table 3.2forthe rusoltinb cream triak. TRUE-AD1 and “TRUE-AD2 were dentical phase Il mufticenter, double-bind, vehice (placebobcontrolled ACTs ‘conducted In North America and Europe among 631 arel 616 patlents 212 years ak, respectively, whia Kim 2020 ws phass b muHicarter, double-blind, doxing-ranging ACT canducted In North ‘America amang 307 patants 118 years ol Tha tiis had sinlar besalia characteraics[see Table 3.2, and the primary endpols of TRUE-ADL and TRUE-AD-2 wers the proportion of patents achieuing IGA [scoe of 0/L with 32-point Improvement from basellne} at week elght. In conrast, the primary endpolt of Kim 2020 ws the percentage ehange from basellne In EASI score at week four i petiants trestad wfth noxaFtinks cream 1.9% bufca 3 cy campared with plscab, Adkitioral ol are wallable In Sacon D3 oftha Bapart Surxiamant. Tabla 3.2. Ovarview of Trcts of Rssolitinds Cream ot S | |t | e | e [Tt | o e | 2 {20 Iwaae) ¥ S04 Vo mesos [ e [own (o2 [ma [w [ Rt Ve poor it [mens [ e [tees |1 w3 |ws | = Aoy el AT [ s [ea [mo [ma [ MmO | gk T T T ot ramber, Rt i, PR o et e, U s ', TR el el et e, . i, - = ‘Dinstutn for Cancal and Exonormic Review, 2021 Page 10 IAK Inbibttors anl Monocional Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Return to Table of Contenty 3.2, Results for Moderate-to-Severe Population Ths ke cliical benefis and harms of srochinb, bariclint, ralokinurmat, and upadachin in moderate t>severe atoplc demmatls s well as key network meta-analysls (NMA} results re described InSection 3.2.Data synthesks and quanticaive analyses, such as addhional NMAS, are: describe InScxtion D2 of the Repert Supciement. Addons rests we presemied In Secliona 02 ‘and D03 ofthe Rapart Susslement. Clinkcal Benefits Abrocttosy Abrochiet ubetamialy ncrasaad the lksilhoee of achbeving EASI 75 anel1GA raapones a3 tasa ‘depondant manner comparnd ta plecabo. Aeeults for other EAS| throsholds and cttier patiant reported cutcomes wera generally conrlstent with esult for EASI 75 and IGA. In comparieon with duplmals, dutcounes were sirllr on most maasures, though dutzoxmes with ahrociint 200 g wre sctemdiat bettar and Heh aprowed wars st 2 weeks. Thaugh fuw sdolescarts weare Il In thesm trtals, they speared to ke seilar outernes campmred to adki. Long- torn doty wry Bvitad, Inthree monothersy sl of abrociinl 200 g, 61% t 65% of paberts achieved EASI 75, ‘eomparad wih 10%-15% In th placebo arm o those triale #34 EAS) 75 was achieved by AT- 455 of ptients with abeocitnl 100 m. Tests of Sstcal Sgr¥icance comparing abrocitinl 200 g an 100 mg cosing were ok reported. EASI 90 was achieved by 36%-52% of patfemts wth ‘abrocitinib 200 mg, compare wth 4% 10% ot paients with placebo. EASI 90 was achieved by 19%- 26 of putients with abeocitindh 100 mg. 1GA resporse, defined .an 1GA score of Dor Land an Impeovement of 2 panta o mere from basaline, was achleved by 38%.4¢56 of patiarts with ‘abeocitin 200 m, comparec tn G-I with paceb. Inthe abrachinl 100 mg ars, IGA response was achieved by 24%-309% o patiem. G el camparac sbrocTinth 200 mg, sbrachinih 100 mg, dupfumab, and plscaba In prents sho neatectwith topical cortimsterclie IGA responsa, as definec abas, and EASI 75, buth measred atweel 12 wers the co-primary outcomes. 1GA response was achieved by 48Y% of patiemts with abrocitinlb 200 mg. 37 with abeoctthl 100 mg, 37% with duplkumab, and 14% with pacebo. The ercentage of petients achieving EAS1 75 With abrocti 200 g was 70% compared with 5% with Sbrocitnb 100 mg 5% with dupfumab, and 27% with plcebo, Resporses i the sbroctnlh arms were statftialy speriar to placab, but sathical lgnificance wak ot repcried campared chpllumal 2112 wneks. Howeer, bt 16 weeks, i were na sttistically siniicant dffarances Tn ‘Dinstuna for Cincal and Exonormic Review, 2021 Page 11 IAKinbibttors el Monoconal Arilaiesfor the Treatmat of Apk: Dermatls - Evidance Raport ‘Return to Table of Contenty EASI 75 anc 1GA respanse between tha abrachinih arms and dupilumab apart from the IGA respanse belng greater for the abrocitinib 200 g am [see Re0art Supplet D3). Intha manatherapy trish, marm patients mxperiancad a 24-paint Impravamart on the patient reported Peak Prurits NumericalRating Scals {PP-NRS), 2 measurs of Hching, with abrocitinib 200 g ancl 100 mg than whi piaceb (SS-643 and 38%-50% vs, 12%-26K, respectively) % ‘Concordan withthe EASIand KGA resuks I the til versus duplumab, ot week 16 more patients ahleved a #4-polrt Improvernert with ubructinl 200 g, abrocitb 100 mg, and duplhuma (63% ‘and 42% and S5), comparad to placabo {29) 7 Measurement of PR-NRS at twe waalcs was 2 kay aacandary outzome i this traland abractinla 200 mg {495, but nat abractin 100 mg (325, was statisically superior to duplumal {275) or this outzame prowiing some esicisnce that resolution o Ruh may occur more qucidy with abroctin 200 mg than duplumab. (Qther atient reparted outcames shawsd siilar frvorakie st compared ta pacebo. I two ‘monctiierapy trials, patients had grexter recuctions from Kaseling on the Dermatology Lfe Qualty Index (DLOJ) with abrockinib 200 m (0 20-10) and 100 mg (-7 10-) than placebo (4; peBOS for ‘compartsons with both doses of abrockirib, where a 4 point dference is considered to be. dinkcaly muaningfuL 45 I thoos tals, patants fad grester reductioes fram baseline on the Patient, Criarted Ecrams Massura {FOEMS), safreported mussurs of symtom sevatty, wht ‘abeocitii 200 mg (-11) and sbrochtinks 100 mg -7 ta -3}, campared with piacebo (4 P05 for oath comparisons with piscebol, where » 3-4-point Improvemens ks considered clnically eningful ™ The Scoring Ataplc Darmatts {SCORAD), an instrumant mmbsining objective measures of area andItensity whth subjective symptoms Inchxing tch and sieeplessness, was also ‘evalugtad i the trils. Results showed there were greater reductionsfrom beselne wth abrocitil 200 mg [-56% to-70%) and abroetinlh 100 g {-46% to -50%), compared to lacebo {-23% to 29%; 'Pcream verss topicalsmalliants s (pavebol, patents receving rusoltin cream had Improved oitcomes at the two doses studied. A single phase Il rial of e Rini cream Induded a toplal teroid comparstor. Wil outeomes sppeare tofavor kot cream compare to topical triamelnolore acetonide, na tests of staisicl agrficance ware ruported, and H was ot compared with more patat topical corrasternide. Side effects of oxaitinb cream ware simllar or bette than vahils {placabo),though lang term sufaty remaia. wncertal. Insummary: = We conskder the evidence for the net heakh benefit for it cream compared with ‘topical emollles o be compmabie or betzr (°C+),demonsirating a Moderace certainty ofa camparabia, amall o substankial nat hasith benaft, wth hgh cartainky of st laast ‘comparable nut hesith bereft. @ W conskder the mvidance for the nst heskh baneft for it cream compared with thar tapical medicatians t be innfclent (7). ‘Binsituta for Cincal and Economi Review, 2021 Page 29 IAKinhibitors and Monocional Antibatlie for the Trestmert of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Cormerey New England CEPAC Votes Tabie 2.7, New England CEPAC Votes on Comparative Clinica Pfectiveness Qcetions Cuaastion ¥ [No ‘Potient Popuidtion for questions 1-4: ATUI: WALk MOJEre -severs Gtoph ermats Whose: chsese s either ot espomded sxequately o topica theraple, o for whom toplcat theroples have roe haen coerated, or e mecdcaty inadvmble. Usual cone o such potients ts fied a3 sz af pioal emoifisnts an gvokdance af sxscerbeting octors. Given the auTety avoloble endence: T+ Tha ouianca adecqarte £ damanstrat hat the net healkh baneft of abrachinlb e to Ul care s superior to that provided by usual care akone? Ta Eha witance adecuate £ damanstrabe et the et hewlh baneft of Exrichinls ot usal are b supariar tothat providd by usual cara ione? s the evidence adequéte t demansiate that the net heakh benefltof upadacitink dded to usal care I superio to tht provided by ususl sre alene? 1 th evidenca adequats & damans—ate that the net heakh bonefttof ralokdnymab added to ussl cae s superforto that provided by usal care iane? ‘Patient Poplation for Quettions 5: Adotescents and Atalls with mid-tz-moderate atoplc demathe. Given the currently wvaliie eviience, b The Evidence siequate to demorstrate | 12 it tha net haalth banaft of rmobtinlb cramm b suparior o that proided by Eopical emollents lone? Based on the evidence Inthe clinkal triaks an ungoing concema sbout long-tzrm safety whh aral 18Kinhibtiors,the parel vates wara it st the et health beneft of abroct il karickints, and it In adults with moderste t2 sevare wiopic derrartis. The pane vated that tralokinumab had adequtts evdence of net heath benett n thisserdng. Far adchescant and adult etiants with -t moclerets atoplc darmatits,the panal votad thet I crA k8053t a1 of e st b compred i oyl el ‘Clnsituta for Cinkcal and Expromit Review, 2021 Page30 JAK nhibitors and Monocional Antibodies for the Tretmert of Atopk: Dermatiis - Eddence Report ‘Return to Table of Coanty 4. Long-Term Cost Effectiveness Methods Overview We adapted the Markov model from ICERs 2017 report on dupllurnabfor this evaluation, with the adaptation Informed by key cilcalrals and pior relevart economicmodels 2 Cost and utcomes ware dscxuntad ot 3% par yuar. ‘The model focused on an Intertion-to-reat analyss, with a hypathetical cohart of adut patents wth moderste10-asvere atopic dermatitia being treated with abrecini, barkdtiv, tralokinumab ‘and upatackinks comparad to duplkaab, ar emollerts {represanting standard of cars). Model cyclelargth was 16 weaks basad an comeman respanss evaluatan tire pants, pior publhed ‘economic medel, and dlinical data. ‘Wa tavalopad s Murkav matlslwith heskh sstes busad on traatmant respors. Trastmant reapanse was measure by the Ecsera Arsa and Severty Index (EASI) score. £ Heakh states ware ‘ategortzad Iy the percert decrsasa In EAS! sxore from bogaline after a patent begins an Interventions: 50% 74% decrease (EASI 5], 75%-29% decrease (EASI 7}, S05-99% decrease (EASI 50, o less than 50% decrease (no response). Patdents anter the model in the non-rssponder state and then may remakn I non-respona or transtton t0: responder sate (EASI 50-74, 75-83, o 90-100) I the istcyck, Onoe n aresponse State, patients were not alowed 1o transition between responder categories. Patients could trantion buk to the nor-rusponder stata u they diacontinued trestrment, for any reason. Patients ‘could also trarmiton from any heaih state o daath. Putlerts ramaired 1 the modal il the and f the tima hortzon of e years or dexth. We asume thar atopic darmatitis dsaca and ragtrment did ot afect mortaiy. ‘Binsituta for Cincal and Economi Review, 2021 Paga31 IAKirhibitors and Monocional Antibotle for the Trestmernt of topk: Dermatii - Evdence Raport ‘Return to Table of Conerey Figirs 4.1, Moded Sructre ————— e Standard of Care (Baseline or No Response] = gy & N s% . / » Desth Responder EASl Eczams Ara Swerty e Schamaticncte: Sandard of care dcatas opical amlntearl rat opkeal cortcotckl], Prtntein the candard of cara ta, atharat basal oo ahar dicontinu g tharag ara acuvad 1o have EAS ssormof s tans Key Model Cholkces and Assumptions. Balow i it ofkay model cholcar: @ Exchtharapy was Inchuded at nn dsaga, whch b ether tha most commonly uaad docage ‘orthe mosteffecive dosage (X two doses have equl effscts, we modeled the lower dose]. « Wemodaled one e of active therapy to focus the cos-effectiveness analyses onthe vatabla clinkal data for tha Inarvanfions of narest. @ Tha madal ueed 16-weak cyclas and inchuded » hahcycls corracton foral cycles. « Base case costsInduded direct medtcalcosts by health stata, drug costs, and any costs assoclated with adminstration o monftorig, @ MortalRy In mach haaithstate was busec on age- and gandar-spactfc US mortalty rates (ol cause). ‘Binsituta for Cincal and Economi Review, 2021 Page32 IAKihibitors and Monocional Antibotle for the Trestmernt of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Cormerey Duetn o wsumed dfferences in mortalty acros ireatmerts and o asumed time: \ariston an trestmants banefits star the massurarment o raatment responss, wa Uasd 2 5-par time horzan for the hase cats modl and tmstad the hartemn duratian n a scenarka anaiyss, « Allhestth states were weighted by a sngle st of health state utliy values from pooied rarwfacturar dutn to derive qualty-acjustad ifa-yasrs (GALYS). « Cartx and ouncornes were discourtad annually 2t 3%. « Change I peak prurtus rumerical raing scale (PP-HRS}, mpact o skeep Rems wthin the disease specifc patient reported ountcomes POEM, SCORAD, and ADem ), and Impact on ‘anstety/depressien (HADS) were assessed Inthe ekl review and were conskdered u part ofa cart cansaquunces anahais oepsida the cost-uiity indings ram the mode. ‘Binsituta for Cincal and Economi Review, 2021 Paga33 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Cornerey Qur modelInchades several assumptions strted below. Tabla 4.1 Kay Model Amumptions Tomrpton TrarEaa o U raponas stta e 47 e cyle. e e ey vabiaod far rmporan st spproaimtely 16 weeke. Patants do it dhsgs s el shar tha e e e ot ke “Thir e Atad data on saainad changas eesan reporentorm. o remekiomig of oo, oty f T md oo e apublen 14 it who e el for raatan bt nevertrestad “TrereF el ewdencetht tesimert ot arope. damathi aitasthecoure of thecondlon ahar rtmanthes xsiad Patarson aly topcl tastmant who wa Faapordas [achava A5 aferth st eyl rathon 8 -t b bl 80 Bacartuston rtenfor placabo et n the vt civicl - et I the placabo o o ha corarad Ginial- ‘il wars sk 10 s, and th e rTenca vt the plooto e nmpect miirorthet o petets restd whh opkas, We 3 ot consher tacontaton ratas o s here ptants warsalowad s topia cortcostarolds. Rruous rempersiers, decartiestio et 4o ot vy by racponcer el “Traraa ribed rdencesupporting afurrtal lconsinuion by rapans evlor over e, ‘Ao darret dimen s roeoets 4o mck- Mt moralty “Trera iibed rcence suaseing an et o mortalky. Wa acame the masaed prtert Popuation ks atens o whom AK i bitors et mortly ihese e 55 e of age it s cardovmscie ok acon). Treatment Population ‘The modaied hase case analysis utlized a hypathetical cohar of patints whis modarate-to-severe aopic dermatis Inthe U, belng tredted with abrocitn, barctinlb, tralokiunab, or upadacitinib, compared t dupiumab or emallents resvesenting standard of care). W pooled ol data rom these treatmants o derhe demagraghic detals for the cohort, which Inchaded a Fraan ape of 35.8 years el 4% o the cohort being female. The patient populatian 2umad to e patiants over 50 with Incraased carclvascudar sk, ax JAK nhttars wil Bhaly ot ba ‘approved Inthat population. ‘Binsituta for Cincal and Economi Review, 2021 Page 3¢ IAKihibitors and Monocional Antibatlie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conemty Model Inputs Transition Probabilites We utlized the resufs of the NMA of placebo controlled monatherapy rals t Inform the trestment specfc ranitions 10 each responder healthstate I he first model cycle. The overall ercantaga of responders was a1 fallows: 735 far shrocinl, 4% or barkdtib, 46% far traakinumat, BOX for upadschint, 545 for dupliumab, andl 21% for sandard af care. ‘Tabla 4.2 Inflal Reaponse Heaith Stata Tranution Probablitie T TR T | oot e ‘oo e T e T2am% T TAE 2060 T650% e okl a T2% A a5 Upwiectints e e S 798 Duplumat 153 561N 3150 @ Bantidotter | 3o% &% s3% . A s Ara ey e ‘We utlaed trestment specific per-cyc reatment iocontiouaton rutes for the firt yeur after Inkial traakmrtand then for a ubsequent ysars cvar the il time hortzon whers data was avalatia. Par cycln cacortinustion rates wers dertval from lang-term fallou-up data for patents who achioved 2 minimum of EAS 503t ther Inhtal 16-week exaliation. Treatment dlscontinuation for any reason resulted I transtioning t the nor-responder health sate. Longterm ‘dsconinuation data for atopic dermatits patients were ot avallblefor upadacltinib; Inthe absence of data previded an the dicontinuation rae for responders after 15 weeks, we ainrned o Fata agual o the highest ratm within the clas. Table 4.2 Discontinuation Rates. e Vaart aarss ) Foroiis EECd . AR COHPARE e T Taax BREEzEADS ok, o S0 Az T Ta o BREERE AT ] Dl ™ % T ADSO0. oMU LerTYAD oie ot | A = EamAIET T e Avew Svery e ‘Binsituta for Cincal and Economi Review, 2021 Paga35 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Conemty Health State Utiites ‘We dertved pooled health sate utities for each heaith state (Baseine, 5% of subjects among any of the clncal trioks, therefeore we did natinclude odverse eventeasts In the modeL Table 4.7. Direct MedTcal Health Scato Cocts I i T Sours o) o racponder 10,5003 | Do prawied by o R 0% e Sagwnar ERi%r mEsH Gt S Trlning e Mg o O vl foston e 2300 [CrreRET el prciEioner i o750 | CrreR ot S [oTe Gk ol rieiogs ey S sl A s n 202800 ‘Binstute fr ikl and Exonomic Review, 2021 Ppe JAKInhiitors and Monodanl Anbadies for the Trestment of Atopkc Dermatii - videncs Report ‘Returm to Table of Corgam 4.3. Results Base Case Results ‘The tota dlscountad costs, qualhty adjusted e years {QALYs, e years (LYsl. and equal value of It yaara galnod {avLYG) ovar tha iv-yuar tima horlzon ara presenud I Table 9. We nata that therm aru ot currntly wallsble pricesfor abeocti and tralokinuab, and ths the cost timatns aref Incremertal cat-affectivanass atio ara bassd on placsholar prices. Ina cohortof patients whth moderate-to-severs atapk: dermatkis who received asingie trestment beyand emolllents for up to 5 years, barictinlb had the owest drug cost and totalcost, $26.900 and 205,200, respectively, compared to upodactiel ot $151,300 and $219,700 43 the hghest drug and total st respactivaly. Abrocitin gensrated the highest QALYs, 355, followsd by upacacttini ‘and duglumab, whth 3.51.and 347, respactivly. Abroctnl’s highar CALYs was dus o having the scan Highest percart of overall rsporciers i Iower Hlarotinurtian rata versus comparators. ‘Binsituta for Cincal and Economic Review, 2021 Pagedd IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Conemty Tremes | DOt | TomiGat | AL | D | ¥ | POEM | SCOWD | Aberm | WADS amamn | Yoars | Mt | Gdouplt | tloepi? | B | (dapraadon vy (gt | et =4 T SRA0| SomAw|am 4w WK (W[ [w[m ) 0| swsso[sm [ (WA [ (W [m[m T | $A500| o0 |am 4% [ n[am [am [w [im Upedacine: S| @w|sE |4 [m(MA (WA [55 [W gt A L LY = andardof | wan(am |4 o5 |00 [oB |45 [0 Core(Toplesk ‘ADurm-S: Acop DS Tmpac S, A ok ve i, -1 ek i R g Scle, FORM: Patirtriated Ecoum Maesire, GALY:qualty.adatad He-yer, e aquaheaks M gear paned, SCONAD: Seoring tcpk Damati: HADS: hospral 3ty and deprastin scal; *udnga placabolderprica ‘#orage changa It PRD corefrom pocid basal e ver e e horon Results of the cost-cansacuience anafysls, which refiect the average changs In each patint reported ‘outcome (PRO) score from a pooled basele over the 5-year time hortzon, are aso reported In Table 4, Incremental resuts can be found In Supplement table EL1, ‘Binsituta for Clnkal and Economic Review, 2021 JAXInhiitors and Monodanl Anibodies for the Trestmart of Atopic Dermatil - videncs Report Page4l ‘Returm to Table of Congams Tae 4.10 presants the Incrementalresuts from the base cass anaiysk, which nclute Incramental ‘costeffectiveness raos for Incrementl cost per LY ganed,Incremental cost per QALY galned, and Incremental cost per eviYG galne. Given no madeled gains In e years across the evakusted theruples, the costper e year gained b nat reporied. Tabla 4.1, Incramartal Couts Efecthvarass Ratios for the Bese Can Trsmet | Corparver | Gk ALY | Comtperlie Coprwi?e eaved | Your inad T 830 i) g3 = S e " Srig00 Trlokdnumak® | soc A Iy Susam Usedactude [ soc 10400 Iy Sas 00 [Dupliarnt S S0 h 00 abroctis® | oupkirab Sna0 ) £309.400 i ‘Duphuras | Lack oty Lacx - T oty Lot Eflecnn Tk | Diphira | e oty La 0 T oty ot . Upedaciials | upkrab Siama0 [ T VIYG: equabvaie - yeur gined, GALY: iy adnted i v, SO Srndvrd o Gre- “Using s placeboider pice Mot The coat per ALY an cos e LY ationwe: the same v thatthe trestments heve nck been shown wimgienlfe. ‘Binsituta for Cincal and Economi Review, 2021 IAKinhibitors and Monocional Antibatlie for the Trestmert of Atopk: Dermathi - Evdence Raport Paged2 ‘Return to Table of Conemty Sensitivity Analyses ‘We conductad one-way sensithity analyses t kenty the Impact of parameter uncertainty and key itvers of model outcomes. Across all modeled comparisons, the healthstate utiity values were dentifed usthe most Influentlal model parameters on the Incremental cot-effectiveness atios, followad by the thug cot, Intil traration probabiltes, nan-respandar irect msts and Clscamruation rate. The Raport Supplemen cantains tomada diagrams for aach ofthe madaisd compartzons. Protmbileic santty amabyses ware aiso be parfurmat by ointy varying il modal paramtars over 1,000 dimudations, than cakultig 95K crecbla ranga estiratesfor sach modal outrrme based on the results contalned In the Ropart Sunplemen. From the PSA simultions, we estimated the probabiity of acrug being cost-effectve across a range ofIncremental cost-effectveness Fathos. {850,000, $100,000, 150,000, and $200,000 per GALY), presented In Table .11 versus standard of care. PSA results Indicated tht Inchaded theraples hud 0% stimated probabibty of being cost- ffactive varsus duplumah 2t an KCER thrashold af $200,00 o lex. W aho paformad trashold ‘anafysesfor g costs acroesa ranga of Incramantal costeffactivans ratios (50,000, §100,000, $150,000, and $200,000 per QALY avalable Inthe Rscort Supclemert, ‘Tabla 4.11. Probebiiz Senstubty Anabyal Cost par QALY Galnsd Rames Each trusbment vercs. $oc ot i Tt | Alvcian | Bt | Traicenaat | Upiacind | Dol o ™ [o% E % = ™ [ % =% 3 = e = 3 % ™ [ =% Ed Scenarlo Analyses We conductad five scanario aratyses for the repart. Frst wa ceculatad a maodifed socketal perapactve try ading productiiy los assartrted with midarate-to-cevers api darmatti by heaithstata. Second, we axtendad the time hortzon 0 Fetime, but maintainsd the sngls ine of treatment, T, we adste the modl for abrocttinibto be Inally evakuzted at 12-weeks rather than 16 weeks t reflect the JADE MONO-1an -2 cliical riaks. Fourth, we ad]usted the model 1o fefiet outcomes for combination therapy with topleal cortcasterolds. Finaly, we adjusced the Fratll for traokinumab atints achleving EASI 75 or abava sfer 16 nfial waeks of thrapy ta rackice dosing racquency from evary 2 waaka o avery 4 wasks 2 refect arms of the ECITRAS dlinicl il ‘Binsituta for Cincal and Economi Review, 2021 Pagedd IAKihibitors and Monocional Antibatie for the Trestmert of Atopk: Dermatii - Evdence Raport ‘Return to Table of Conemty e total dlazountad costs, quality-adusted I years (QALY, s years (L14], and el valve of IHfe years gained fev1Y(G) over the fiee-year time horlzon Under the modifed societal perspecsive are presented In Tt £4.2 In the Report Supplemert. The drug costs and patient outcomes remalned the same compared to the buse case, and the talle shows the bese cas totalcosts for comparkn. ‘Tha totalcoat from the matified societl parspactive varcus the hase casa Incrased by 10-26% for the Intarvantians and 3% for standard of carn. ‘Tablo £4.31m the Repors Supplernent presents the Incremental resuk from the modHied socletal erspective scenario analysts, which Inchude Incremental cost-effectveness ratos forIncremental costper LY gained, Incremental cost per GALY gained, and Incremental cost per e¥LYG. Incremertal ‘costeffuctvenuss ratios from th modifed 0cletal parspectve varsus thu buse case whan wpiying the tandard of carm camparator dacrazsed by 75 t 22% acras the theraples evakatad, but did tlead ta theraples crasing cost-efactivenees threshoks .., $50, $100, or $150,000 per GALY], with the exception of duplema which becarme cost-effective 2t the $100,000 per GALY threshokd. ‘able £4.51m the Report Supplemnent presents the Incremental resuk from the Wetime tive: horizon scenario analysls, which Inclode incrementa cas: ffectivenessrtfos for incremental enst er LY galnad, Incramerta cost par GALY gained, and ncremental cost par svYG paned. Incremanta cost afectivaness et fram the Hatima tims horlzan versus the base case five-year hortion whan appiying the standard of care camparytor decreased by 4% £ 13K across the theraples evaluated, but i not lead £ theraples crossing costeffectiveness threshokds e, $50, $100,or $150,000 per QALY ‘Tao £4.5 I the Repor Supplernert presents the effect of changing tha Intal moce cyes for abrocitinlbfrom 16-weels t 12-weeks t bette reflect the JADE MONG-1 and -2 clirical raks, This soenarko had minkmal efect on OALYS, ife-years, or equalsalue ffe-years. Ina fhe year tine hertsan, this switch would decreese drug cost ani total costs by 14% und 0.9%, espectively, and decransa CER varmus SaC by 1%; ICER varms cupifumal wai Incraase by 0.2 Thata autzames ‘arm based n 1 placahalder price for abroctiksand willba upcatad. ‘Table E4.21n the Report Supplement presents the tocalresutsfor the combination therapy sceriario ‘anatyss, which Inchude drug costs, ot cost, QALYS,Ife-pears, el evLYG. Drug s and total oty were higher I the combination therapy scenaro fr all theraples, wih Increases runging from 5:26%. Total corts dacrwesa by 25 for those bn standard of care. QALYs rcraased 24X acrasyall tharaples and Sa€ 1 the combination therapy scenaro. Incremental casteffactiveness rewits (Tabie E49) were all nomialy ager {3-14%) I the comblnation therapy scenaria when compared 10 standard of care/piacebo bt remaned Inthe same arder of cost effectiveness. Abroctinib was the ol therapy 1 croas cost-effectiveneasthreshold exceeded $150,000for combination therupy, asuming s lacehokler price). When compredt dupfumab, both berlitiib and ‘Binsituta for Cincal and Economi Review, 2021 Pagadd. IAKihibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conemty alokinumat remained exs costly and axseffective, however duglumal swhtched to domirats upadachinib (dupiumab being ess costly and more eflective than upadctinib] Inthe combination therapy scenarto, ‘Table £4.10 n the Report Supplement presets the ress of scenario that akimwed S0% of patintx who achieved EAS1 75 or abave on traloKinumab 1o swhtch from 02 10 04 week dosing, which refiees data from the . Thi soenarl had no effect on QALYs, Me-vears, or equavalueIfe-years. In & five-year ime-Horizon asmuming concurrent TCStherapy In both s, dinug ane ol costs would decransa by 1556 anc 6%, respacitvaly. The ICER weni dacruase by 20% compared to SoC, hovwever ralakinumat would rermain s costly and s effactive whan compared 1o dupilumat. Bacaute thecinical il forming the analyas alowed patients t use concurremt TCS therapy,thesa resuts are mast comparable o the scenario analyss of combination therapy. Threshold Analyses. ‘Anmual prices necassary 1 reach cost-effectivensss trestiokls of $50,000, $100,000, and §150,000 er QALY compared 1o standard of care are listed In Table 4.12. Tabla 4.12. QALY-Besed Thrashoid Anabyals Rashs T | A | R i A SAB wa | P porqALY Toodwls | SR | SLAGY a0 = O ) 5D Trdcknurety | LB | LA 640 30 Sigan Tpetecint | Soiso0 | teaa [Duplnah | Se1m00 | 30,100 GALY: Gty a)aind -y, WA: whobmale sy i pric “Sase okl ricn Modal Valkdation ‘We usac saveral appraaches t valkists the model. Wa prowided praliminary mode sructure, methods and ascumptons to manufacturers, patient groups, and clinkcalexperts. Based on feedback from these groups, we refined cata Inputs sed i the model,os needed. We varied model Input parameters to evaluate foce valldiy of chenges I reits. We performed model etfication for modal cakulations uaing ntarnal reviewers. Spacicaly, wa tusted all mathermatial functons Inthe model 12 ansure they were canstant whth tha raport {and Report Supplamart natartls) and usad extreme and nulInput valuss t ensurs the madel was producing Aidings ‘Binstuta for Cinkal and Economi Review, 2021 Pageds JAKInhiitors and Monodanl Anibatdiesfor the Trestmart of Atopic Dermatii - videncs Report ‘Retum to Table of Corgams ‘consistemt with expectations. Firally,model valkiation wat st conducted i terms of comparisons 10 oter medel findings. We searched the Rerature to Kty mosels that were simiar to.our ‘anatyss, with comparabie populatians, settings, perspective, and treatments. Uncertainty and Controversles ‘A5 with any modeling exeruise, thee are imitations o be consklered when evaluating these findings. First, we extrapolated cliiea triel eficacy beyond the length of time that the traks were: ‘conducted, which msumes continued effeciveness (slong wih sdherence to treatment). Nex, we anumed that levas af EAS rmponas are ecsocirted with dffarances In heafthraisted quaby of . However, thare may be differanialeffacts af tha rastments modelad on conditors such ac Itch and steep that are not completely captured by generk: quaty of e Instruments. However, avalable data dkd not support the us2 of treatment speciic utiies. Additonally,there may be Incremental effects of some of theae treatments on aulRy of e in ub-populations of people wih atopicdermatits,such s those with co-ocrurring isthma or chronic thinoainusts, which are net explicty captursd in thecurrant mode. ‘We only had disconeinuation deta beyond one yesr for duplumab, and azsumed that the discontiuation retes forthe othar trastments wers the sama 23 yar 1 1n yuars 25, However, e ote that wa salactad s 5.year e harzon for the bese case n part > reduca tha Impact of thess ‘assumtions. Furthr, stoglc darmatitls specific discordinuatian rates wars ot avalable for upadacttinb and we therefore assumed that the dlcortinuation rate was equal tothe highest rate whhin the clss, We also assumes that patient respanse to treatment ws flsed ater 16 weeks, allowing neftherfurther improvement nor waning o effcacy, other than capturing dscontinuation. T msurmption wes basod ontha lack o data tamonsirating chanpes I althar daction. We exchuded SAES that occurred Iness then 5% of thetial populetion. However, we note there are some rare SAES from the phase Il AX iibitor s trials that nay Imaset Bath costs nd patient heathrubstad cuaty o fa. Finally, the NMA analyses that Informed our effectiveness estmates I the model were derved rom phase I ane 1 RCT that eommpared the treatments of Interest to placebo with only the added e of topical amollbarts at 16 wnakx. W prowided results for the use ofthes products ‘combiarion with sopicelstarids as a srareto arapas. Furthvemare, the NMA's produced ‘estimates with wids confidenca Incarval and thers may be additiona! rcartainty regarding the comparative effeciveness of these tratments. ‘Binsituta for Cincal and Economi Review, 2021 Pagads IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermatii - Evdence Raport ‘Return to Table of Conemty 4.4 Summary and Comment Using a Marka model, we compared the costand sffectiveness of four emarging therapies for oderat tn severe atopi dermattis o skin mellents an an approved blologk, dupliumab over ive-year tme hortzon taking a health syetem perspective. s Important 1o ote that the JAK Inhitor coss has been amoclaerl with sorme rare but serious cnkcal sdverae events whichaare not ‘capturcIn the currant model but wo camy the potaintilto kmpatt both costs and autzames In thoss patlents wha axparienca them. ‘Whtle o ices sre not currently avatable for two theraples {sbrocTtink s trlokinurat, we found abroctint ta produce the most QALYS (3.59)of heraples conaidered anc barkitinl to produce the fawast(3.23). Comgarad to SoC with mlllent ordy, aichinta was coet-affactva 2t $100,000/QALY threshald, abrocitnb and trlokinumab were cost-effectie ata $150,000/0ALY threshold (using placeholder prices), duplumab was costeffective 2t 2 $150,000/0ALY threshokd, ‘and upadackini would need to decrease s WAC per dose costfrom $176 1o $113 In order to be: ‘coutseffectve at $150,000/DALY threshald. Compared ta dupdumab, buridnl and trsiokinumab ware fous 0 b beus oty an I effctive whareas abrocitnd (uaing a pacaholder price) updaciinb did ot mest commanly cted mst-affctiveneas thrashol ‘Binsituta for Cincal and Economic Review, 2021 Paged7 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conemty 5. Contextual Considerations and Potential Other Benefits Our reviews senk to provide Information on patersil ther banef affered y the Interveton to the Incividual patient, careglvers, the delivery system, other patients, or the publlc that was nat valabe Inthe evidenoe base nor coulk be adequately estimated within the costeffectieness model. These elements are sted i the b below, with related information gathered from patients and othar siskshakdars. Following the publc Mbaration an thix rapart the appraisal ‘committan wilvote an tha degree t which sxch of thesa factors shou affact overall kukgmants of fong term alus or money of the Interventionts)n this review. Tabla 5.1, Contaxtsml Corkdarstions. ool Comiorrio e et Ry of peed o rasroat of il | P, caragr, hvoeac gt and e part uerta bemed o the sty ofthe et e fornee hezwetc gt o ptiegs whh Couchtn e treated ok demacks, escecaly those wits mor severy dgase who arn it unesporatv o falratof g haragies. Wagriwde o e Fetime mpecton Atopkcdermathl b a chrod corction thas uualy begha 1 Indhddin et of the condition ek | chilhood and cancotfue theoughoLt the cours of petents I raaed raadl flacing phpical, pychosoetl,and rtional sk A et affct cls dovedopmert oo szhevrent e pestymance nthe workploe. o iy ot o | Though il of ooy e b e o Sl kot e e s Gemmactshowed few rous sl cfec,oral K nbkors when utn o tharconttons inchude bisck b warrings o sefos nfactions, malgruncs, 1 coting cvetar. ‘Binsituta for Cincal and Economic Review, 2021 Paged IAKInhibitors and Monocional Antibatle for the Trestmert of Atopk: Dermatii - Eddence Raport ‘Raturn to Table of Conanty ‘Table 5.2, Potarial Other Banefits or Dicadvantages Pt Gther bt o Bladrariagy st Wovte oot sty achlors mefor o goks | N theregio o Sk ettt Fprov T wppemrore, el tn acucation, vk, ol B | ymgtoms nd complcatonsof ok et oy hlplmoecve Uty of Mo acroe 2 rargeof dfarertauteomasicldingeocl. baractions Wit farl, Vi and cthar rebtions sdcational e ‘Whether abructil, it radokmammb a"d upedachind Wil improve sccaon o work cuteomus. Caragiory cualiy of Mo andjor bty 35 | For cikiren and o cscon whh rtopk dermeti, e oure schiow rajo Ho s rlsted o ocurd e nvotvs faly mambecs and ottar araghers. The ‘aucntion, work o faaly fa 1Mpac of asoic daratai ad the darmansaf reamart fllnck odyan theped, bt ke e cornghes. 2 e, e roples o s deret offr the el o mproeg the bty of e forthe caegiers s well o fo paents. s SRy s e sttt The el o riew rel therapes o ot s traatmest s the oty of regien | and upacackn 0 inprom ouomesfor et wh o ‘domathi ma e tacraase the complecty of care., T heed for ‘Copca harapla thetar h-conaaming 9 4, e srapes S gl s et e it meadctcr tht cre debvered by ecton all Inrease the compieaky o e, Though ‘oral AKInhors ar Bk o ba g alor whth topicl theaphes ey ar iy radice the camplasty of a atent’ agirun et Forthome respancing toan el every e wesk heie, ‘asokinimab dosig dacessadto every b veaek n s potats could putaial flc i werd acbarsnce et e o High o of rasmntsfr atop armatite, epecaty ewar agants, ay acacertota wtng ekt st Toaae rarvrtiors efir nowl ‘Aaroctin, barkdte, talkirra und upedecHND reprecert achaslas of acion o appenach thet wl | riew hersgestht reflecs randatiora esaarch o which nproved Sl rzemet ireest ey rdersaeeing a1 mocharkems of s Havaod o etira e v ther svettle heraples. Sreamens s i ‘Binsituta for Cincal and Economic Review, 2021 Pageds IAKInhibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatii - Eddence Raport ‘Return to Table of Conanty New England CEPAC Votes Ak the publc meeting. the New England CEPA dellberated and voted on the reevance of pecfic potential other benefits and contextual considerations on [udgents of value for the ntervertians udar review. The resuls of the voting srashown bekaw. Further etal on tha Intant of these ‘vatas o hul provid comprahanstve i an lony-4srm valus for maney arw provided i the (CER Valus Asssssment Framework. ‘Whan makdn Judgments of cvarall kng-Aarm valua for moner, whaet b the elative picety that ‘shoukd ba ghv £ ey affacivs traatrmant for sty darmatita, on the biis o the follwing. ‘conmtpatys! considarations: Contextual Caralderstion Vory | Low [Averspa| Wigh | Very Low | priorty | priorty | priarity Priorkty “Acuity of need for st of s Individual patients based on the severtty of the condition being trested ‘Magnitude ofthe fetime Impact on Indhdual patants oftha condticn being treated For the acuy of need fo trsatment, the panel voted tiutany effectve ireatment shoukd be ghven rvarngs o high priceTty dus o the severtty of the dicesa. The magritude of ftime impact an Inchvidual prients racabvect » mafartty vt f “high prioety; the pansl amphasized the chronic ature of atopi dermatkis which can startearly I a persons e, oten In adolescence. ‘Oinsiuta for Cinkcal and Exoromit Review, 2021 Page 50 JAK nhibitors and Monocional Antibotle for the Trestment of Atopk: Dermatii - Eddencs Report ‘Ratum to Table of Corgam For queetions 12, considering the mveage affect of th new syatarsic theragples 3 3 ey, whet are the rletive offcts o the new therapies versis usual care use of wopical emollents and mvoldance of exacerbating factors) an the following utcomes that Inforn Jucgment of the versl orgtarn vabua for moey. Potanta] Ot Barmlt o Wojr | Mnor | Wo | Minar | Mer Diradvartags Mapien | Hogth Fatents ity w edieve maor e | 0 goals rekted b edhucation, work, of famityife Coregivers” qusihyof s andjor iy o acheve major e goos rekated 1 ecucation, work,or famlly e 7 Soduiy' goal of reducing heatth T 1 7 ¥ 1 Inacuities ‘Whatare e rave deatthe | 0 T T % T AR nhEtors o m s versus upharab an bty abity o ranaga und sustain tratmert gren i compleis of the regmens? ‘Whatare the relatve effects of T o 3 3 T ‘aalokiumab versus plumab on patients abiltyto marage and sustin treatment ghen the compleates of the regimens? ‘The pael ot thathe new systemic theraples would have a minor or major posftve effect on both the patients" and thelrcaregvers’ qualty o Ife. At the same time, the panel conchuded that I 1 ificult 10 assesa these therapies’ Impact on sodety's goel o rediicing heahth Ineouites ~ igh prices mnd sy aczesalimitfons might negetely impact certain pogulatons more aeverely than others. Whan talking about acharance snd patiants’ ity t sstain a treatmant ghen the ‘complesttis ofths regimens, the panel uated t1at the aral AK Inhlbitars may Fave 2 minar paaitive effect s oral theraples. When comparing rakoknurmab and duplkamab, which are both gven by subcataneous Inection, he panel voted that there would b o dHerence, or a minar positve: ifference, on the patents’ abity 1o manage the reatments. ‘Binsituta for Cincal and Economic Review, 2021 Paga51 IAKihibitors and Monocional Antibatie for the Trestmert of Atopk: Dermathi - Eddence Raport ‘Return to Table of Conanty 6. Health Benefit Price Benchmarks Health BereftcPice Benchmaries H3°Bs) for the anrua costof reatrment whh the Irterventions. when compared to standard of care alone are presented i Tabie 6.1 below. The HBF for a drugis defioe asthe price range that woui achieve Incramental cast-affecttvaness retios betwaan $100,000 and $150,000 par QALY o par vLYG gaied. Because ofthe assumption thet stoplc dermatits and assasmec tharapins 80 not haeva an Imgact on mortalty, cakuiated QALY Gained and Y5 are squa Inthis madel, Using the broadest st offgures dertved from thess thresholds, wo ‘amive at a HBPB forabroctinifrom $30,600 ta $41,800; for barkdin $24,400 {no discount needied at the $150,000 threshold); for ralokinumak, $25,700 b $35,000; for upackachini, $30,400 10 $41,500; and for duplhura, $28,000 to $25,500. Discounts from WAC to reach thrashokd pricas for abrociin anel tralckinumal ars not apalcabln ax thay ars curently buted an placahakier WAC Peces and shoukd be upedstad whan WAC piing s sscabisherd. Tabin 6.1 Anrum] Gant-Effctivaness Heith Barie Pice Benchmarks for Abwoctinls, Bartinks, Tk, Uipececitiath, ani Duptharab vercs Seandard of Care Tt Doy | A WE | Ammivwt | feralPirw | Dl o WAC Measmra 0020 T | $20200Trakol | oo Tt ) A 050 L0 | W LS %0500 1800 | W e S50 B 950 [ KD 16K S50 ) 990 | Ko 16K T e o 95000 | WA e S 95000 | WA pasachins ] S S50 SR ma ] o 6150 | sxma Dipineh S =50 R g ] B A ol gt T o o W e o GALY 1 Nok apeiabl () e plcoboldar pics wars Ty ‘Binsituta for Cincal and Economi Review, 2021 Paga52 IAKihibitors and Monocional Antibotle for the Trestmernt of &topk: Dermatii - Evdence Raport ‘Return to Table of Conarey New England CEPAC Votes Tabie §:2. New England CEPAC Votes on Lorg-Tern Value for Money st Curret Pricas unsian Lowlangterm | incarmedista | High ang-term wlve formaney | lorg-tarm valus | vakue for money tcument prcas | for moneyat | 3t cumant pices urent prices Given the wallibie svkdencean| 7 ompartive effctivanes and Incramental coetaffectivanass, and Eoeaidering othar benfts, disatvantages, and conteutual contiderations, what I the long-tsrm ‘e for money of reatment with berfcttin versus usualcare? ‘Gven the mallsble svkdancean ompartive effectivaness and Incramental coet-affecttvanems, and Eoeaidering athar banft, disadvantages, and conteutusl contiderations, what I the long-tsrm e for money of reatment with upadectinlyversus sual care? ‘Tha panl voted an s thuraplas which already have n known price x they ars approvad for athar Incicatians. The majorty of the panel votad that Lariditins epresants sther an “Intsrmecdate® ar “high" value for money at current prices. The Incremental cost-eMectiveness ratlofor barktinib was $71,600 per GALY gabed. T malority af the panel vated that upadachini represants < valus for monay at current ¥icas. The Incremental cost-efectiveness rato for Lpadactinib ws §248,400 per GALY galned. ‘Oinstiute for Cinkcal and Exoromit Review, 2021 PapeS3 JAK nhibitors and Monocional Antiboies for the Trestmert of Atopk: Dermatii - Eddencs Report ‘Returm to Table of Comamty 7. Potential Budget Impact Overview of Key Assumptions 1CER used resufts from the cost effectiveness model t estimate the potertial toal budgetary. impact o each dug that aweiks S regulatary approval feroeltin, bericiil, trakkinumab, ‘and upatocinb) for moderute-bo-savere atopi: dermatits. Wa used the WAC, an srtmute of nst rica, arthe three threshokd pices (st $50,000, $100,000, and $150,000 per QALY fr sach dnag In our estimates of butget Impact. Conslstent wth th cost-effsctiveness analysi, sbrocTink was. ‘asigned a pacebolder net prios equal o the average between barictiib and upadachints annual et prices. Simark,trlokinumab was essigned a laceholder net price equal 5o duplmak's ‘annual et price. Pleceheider prices wil be upcited In futue verskons ofthe report as achual pricing nformation bacamas eralible. 7. ‘The alm of the potertial budgetary Impact anafyss i to document the percentage of petients who ‘coul be treated st selected prices without crosinga potental buiget npact threshold that i e with ovarall growth n the US scanomy. Far 2015-2020, the f-year annualized potential budget Impact thrashold that shoud rggar polcy actons 0 manags access and affordabilty b ‘alcutatac 1 be appraximately $819 millan per yeur for new drugs. ICER's mathoch for estimating patantin budget mpact are descfbed n datal inthe Fapart Supplement Saction . Far this aralyes, we calcubrtd the bulget Impact of rew treatmans. {abrockink barfitint, ralokinurmat, and upadacitinlt) ghen these trsatments’ displacement of upilumab plus usual care (assumed 105 mis) and usual care alone (30% mb) and by assigning 109,200 new inchviduals to each new treatmert. per year for ive years). 7.2. Rasults Raport Supglement Section £ dsploys she averags annual per patisnt buiget Impact rcings 3cross the ive unit prices (WAC, dscouned WAG, and the prices that achievethree dferent cost- effectiveness threshoi) fo abrociti, barkcinks, raokinumab, and upedackinb. Further, Baport Succlamant Sectan detata tha cumdtive par-petint buget Impect asimates fr abroctinl, arctin, trafokinumat, and ugdaclin. Figures 7.1.~7.4 lksirate the patential budget impact of brovdtib, barlchin, traokiuamab, and gt trastrmant of the slgible poguiation, kused on tha raspecties five different unk prices QWA discaurted WAE, and the prices thart achieve three diferent cost-efacthvenacthresholds). Upon remaving the pacaoller picas and across all faur treatets, the rarige af tha parrantage of thase treated without crossing the potential budget Impact anwal threshold was between 8% ‘Binsituta for Cincal and Economi Review, 2021 Paga54 IAKirhibitors and Monocional Antibotle for the Trestmernt of topk: Dermatii - Evdence Raport ‘Return to Table of Conanty ‘and 79% for il prices evalatec (WAC undt rics o the maximum price to ahieve $50,000 per . Figara 7.1, Budgetary bepact of Abrocti® o et e |~ s soumaony SEREEREE e sy = o - e - o Parcantagn of aients Trastad WhkoetCraeing Pl Threshob ach Yoar Pl potannbudga Impact, QALY:ualt-acotac osysar, WAC: wholesl wpiskon pice "Bna on lcancknr e Figire 7.2 Budgetary yact of Barcitinly smom ssosmvaur S0 2., =m § o Tusom s mom ® £ m - o - o Porcaseage o Petent Trosod Witcut Croming P Threshckd Ench Your PBic ot gt g, GALY: .ot yar, WAC: whobecs uzplaton pkn ‘Binsituta for Cincal and Economi Review, 2021 PagaS5 IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conenty Figira 7., Budaetary pact of Tralokdaumat® _ « et o sssima ", SRy ot . Pacahar e e el e N o - ikl s smomuar Soom o @ = ™ - oo I o Porcartage o Pt Treste Whbeu Craming PO Ttk Bk Yo PBicpoteril gt Impeet, GALY: vty o e yeor, WAC: wholea scplsbon pe ‘Binsituta for Cincal and Economi Review, 2021 Paga 56 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Comanty 8. Policy Recommendations Folowing s dellberation on the evdence, the Comparative Efectivness Publc Advisory Councll ‘engaged n @ moderated dacusdon with palicy roundiable about how best ta appy the evidence: ‘on tha usa of oral abeoettnth, baricfini, and upedaciti, topical it craar, and subcatanects tralokinumab. The palicy raundtabls merbes Incuded tras petant atvocates, two linkcl experts, twa payers, anc hres rEpresetatives from the crug maker(s). The discussion reflected mitiple perspectives and opinions, and threfore, none of the satements below should e taken a5 consensus view hed by al partidpants. All Stakeholders ¥ Roketolders have o rsponstseRty @ad mporteat rofe 0 piey n encuzing tht effective new. ereatmeent options for patienes it etopl: dermatis are neroduced i o Way that wSi help reduce Aeokh knenulties. Safl and effectve treatment for atopic dermathis, especkalyfor those with moderate tosevere disease, remains a igniflcant unmet health care need. Eforts are nesded to ensure that new theruples for azpk dermatft such s ol abroclint, berctin, andl upactint, topicsl ottt cruam, andl subctaneots tralakinumab, Improve the hualth of patarts and famike and o ot agaravate adting haslth Inaquitias. Chrical evparts and patlants hghilghtad that tha high ‘costof new theraples may wersen disparKies In accessing cars, TH may be dus 1 lack of eakh Insurance thatlimts acoess 6 speciaists and the new theraples thatthey prescribe, or hgh decuctibe paymments even for those wth Insurance may resultin steep out of pocket eosts. The ‘ot of care s o the only fuctor that mey conrbute 1 health inequities. Our cinlcal experts oted tha the anpesrance of the skin L u key cartriutor t massuresaf diase severty, and Inchiduals with darker s types may be sesemed 25 having |ess severe skin Imvpivamant. Since ‘educational matertas often Inchade photos ofIndiiduals with atoplc demmatiis who have Mighter skintypes, those with darker skin may be more Ikely > be misdiagnosed. o ackrass these concamn Manufecturers shouls take the folrsdng sctans; Follow the precstismt of respanlbie pricig 3t by Sancfl/Reganeron with duglumah and 58t he prics for new treytments foratoplc dermatits I ai allgnment wkh dcied bonefts for patiens. ‘Binsituta for Cincal and Economi Review, 2021 ol IAKirhibitors and Monocional Antiboties for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Cornanty @ Tuke sieps necemary to Indude & more diverse patent popuetion i cirical trabs, Incuding taguate numbar af patiants with sthr and racil backgrounts whe have darker sin types. Eavan aboudtak the falowing sctions; @ Ensurthat benaft designs devaloped in on|unction with amployers and ather plan Sponsars do nat create requirements for outf-packet spending that creats malor barlers 10 appropriate access for vunerable patients Cllmeal spactaky st atios shauk tak tha folowing sctons: « Develop and disseminate edcatonal materials and create measurable guals o ‘demanstrate thatciians are aware of the challenges of dagnosing atopic dermattts In Fatiants wih darkar ki types. Payers “The ange mumibser of patents with varying leveks of severtty of stopl dermatits, combined wth the. potential fo i effacs.and the high anrus pices for riewar ganerstion trastments, wil lad Favars t develop pricr autharteation ¢rtarts and tn consider ctharlmits an utlzatian. Perspectives on specific elements of coxt shiring and coveruge critera for oral sbrocitinl, arichink, el upadacti, toplcal ruxciinl cres, s subetaneous tralokinumab wthin Incurance caverage palcy are dicursad bekaw. Coverage e @ Aps: Age crturts ara ksl t follow the FOA abl for sach drug an wil not be expanded 40 cover aafar apes I the casa of cuga ok approved for adohescants or chiken. ‘Simlack, aithough thers may be greter uncartalnty n aytcames for Youngar patients, It ‘Ssem unfkaly that payers wiluse cErica ral eligfhiiy cteria o rarrow coversgs the FDA approvalIndudes treatment of adolescents. Payers should have eMident mechanksms for linkcians to seek coverage exceptionsfor patients wih serlous et need who are aar the cutof far the age nscessry for covermgs. @ Chukealsighhiy: There b o tear consanaus an how o oparatianalla 2 defitian of the FDA Indication for reatment of patents with “moderate tsavere” atopic dermatits. The severty ofatoplc demmattlscan vary substantily over time and, rom a patient's perspective,ean incude a complex comblnation of intensiy of e, kocatien, body surface: ‘Binsituta for Cincal and Economic Review, 2021 PagaSa IAKihibitors and Monocional Antiboties for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Conanty ‘area Invohvarnant, ncl deres ofsdn Impalrmet. Some payers wil alow cinilan ‘anestation, whereas others wi adopt crteria based on cinkcal ralelgbily. Given the. “ariabllty of patlent phenatype and lack of familarty amog cinclns with scorng systems wsed inchnical iral, It s acvisable for payers o create a broad, dinkally relevant defntion Inclusiva of multipl spacfic massures of disasa Itarsiy, 1.2, “ary of the followhg: BSA 2 10K, 1GA2 2, EASI 2 16;" ar “affectad BSA 2 10% OR involvement af body it that we. fficult to rext wth prolonged sopical corycasteroid therapy {e & hanch, fer,face, neck, scalp, genhtal/groin,skin fokds) or severe Rch thathas been unrespansive to topical theraples.* @ Inaddan o, defiton o savarty,peyers ara kaly to recuire tht pients hava recatad an alaquste trtalof topical therapy, eg. 30-day tral of preacription toplcalcorticostarakd ‘and/or topical cakinurin InhibKor OR the use of thess macications s ot madicaly ‘advisable (a5 occurs with epeld Invoivement), Payers should not requirs that tis il of topical agentis) be Immediatey pror tothe requested prescription; medical records indicating prir tril ot topicaltherapy be suffclent. @ Potersial rtart recuiring pior usa of phototherspy or systamic of-bal trastment whth ‘agents lln methotrmusta s coversd Tn tha sactian on step tharapy bekow. * PoRink cream, f approved by the FDA, wi Hkely have an Inciction for reatment of “mikd o moderate” atopic dermatit. The linealcierta for coverage mdy be based on linkal il eligtlty (BSA = % wcluding scalp OR 1GA 2:3)buk wil aso ety rauireprior sa of topicl rarticoatarcds o caktnari Inhibtare. Ancther ndicaton caukd be allowing the use of amiini cream In parients whh severs atoplc darmtii fo arees that danat clear adecuately with systemic theraples. « Exculon aterk: There are o spedal medical comorbidtes a thia time that would serve: a5 exchasion erter for these treatments. « Durstion of coverage and ranews!ertara: Inhial crvaraga will kdy bafar a priod af 0 12 manths, which s long enough fordose thration, sssessment of s effects, or cssase progression. « Clnical experts and payers feft that It woudd be appropriate 5 require atestation for ‘cominustion of tharapy. The timing of such rarewal may depare t some axtant upon ta spociic tharapy. For example oral AK kidbitors sppear o have 1 cucker st of acsion than bilogics such as duplumalar raloidnumab.. Patients and clinkians.fet that requing ‘subission of outcome measires 0 support contiustion was not needed. For blokogks that are ghven by Injecton, patients reparted that they would not want t catinue use In ‘Binsituta for Cincal and Economi Review, 2021 Paga53 IAKinhibitors and Monocional Antibatlie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conanty the aboance of Improvemant. For JAK InhEtors, Bven the potamtialfor uncomenan byt serious sde effects,Iong-temn use Inthe absenoe of considerable beneftt may aso be wnilety. Mostcilcal experts suggested a three- o - month perlod prir to renewal 10 be appeoprinte. @ Provider raetictfore Clical axpertx agraed that 1 i rasanabls o rastrict peascriptians for upllumat, abracitint, barkdtink, tralokdnumab and upatactink 0 dermatoioglts or allergy specTalists. Some payers may convider allowing prescription by ganerallst phyicians ableto work In consutation with speclalst. The new therapies for moderate 1o severe: atopic dermatis require knowledge abour evaluating and treting paients that most primary care dinrs are untkaly to hava. Speciakty clinctins are better sitad to ety Putients wha ars mast Haly o baneft, provida suffclant informatian for patients to make 2 ‘waikinformed decio, and manitor fo response and sds effects. RinoRink cream may Ibe covered wth less restrictions on prescrber quafications, bu because t may be used In youngar patents some payers may sl wish to it prescrbing, ot leastIniily, to specialits or generaist clincians weorking n consutarion wth specialits. Stap Therapy ‘Payers should onfy use step thercpy when it pravides adequase leubitty 00 meet the needs of dtverse patients and when kmplementation can meet high standonds of transporency and eicency. Clinkal exerts and patent representatives stated that delayed and restricted ocoes to reatment e o step therapy requirementsfor patients with moderate 10 severe atopic dermattis s ‘comman. Whila L pasikie to taiior stap therupy In a chnically esperble fashion, t s oftan ‘atminlstared with documantatian bursens and radeqarts procedres or excaptions that make StaD therapy a 50urcs of grea frustration and the cause of BT oUtcomes Ko ome patients due 1 the discontinuation of medicine/missed doses. A partcar ared of cancern raksed by patiets Involved recuirements to e step through previously aled theraples when Insurance chinged. Poyers estobshing stap thervpy wich fess expeeiv, off el syeteric ageess enelfor phototherapy should atiow petients and ke to choos? from nwuiple ptions rathe than equine patients 0 try mukipie options. Currently aaliable spectatty society guidehes are out of date and uptated versions are expected the coming year that may help shape palices regarding appropriatestep therapy. Clnkal experts at the KCER meetingstated that It may be reasonsble for payers £ reque patients o step through a o1 epenivm off-abel systamic tharapy, but thesa tharaphes have wal-known sdversa effucts ‘Binsituta for Cincal and Economi Review, 2021 Page 60 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Cornerey ‘and Ambtec sfficary daa that maies . clinicaly nappropriate o requira patents to stzmpt rials ‘with 3l options plor o obtaining coverage for one of the newer agerts, Prior agents Inchude ydosporine, zathioprine, methotrexate, mycophenolate mofetl, and Interferon gamma. Cyclosporine muy be u ressonable st dne agen:for some patients, bt the rsk of renal tocty racnirus paiants to swlich to anothar irastmart ahar &-12 month, 5a petient shaukd not be racgirud oty tha agent afr havin an Inadeckar respanse to anather systamic agent such as methotmexate that may be usad for ongrr tarm use. 1 s reacorable to ncuda phototharupy as an option for fire-shep therapy, hut ack of svalabity In Frary ocaians makss It Fappropeiate for peyar s requir patlents n try phototherapy befare recalving coverags fo ather options. The only seption would be a health pan/system thas can rovide good acoess to phototherapy at an out-of-pockes expense comparable to medication trectment options. 1 oteiple ogents for severe stopic dermetils are Spproved, poyeTy shovsd mote Ve ot foast ome Blolopic dupfumeb sad/or cralokinmos) €nd st east one orsl JAK InKiBRoF given bow. fforant these csees are in their oneetof acion end their ek prefl. Cinklan experts emphusiad thet the hetaragenalty of siaplc darmatiis and the challangas n dflning and Fraamring dlsaaus sevarty mugpart the need for heving sccess t rangs of ffarart tharaplas. ‘Spacifcaly, cllncal expart i ot faai It woud ba apprcpristn t use stup therany that makes only ‘one trestmant svalable 35 the st step agsnt across biologics nd oral JAK Inhiitors. Some: etients only have severe diease on a seasonal basls, making continual bicogle treatment otentiallyless desable than periodic use of a JAK Inhibitor. Smlry, patens with asthma or o ye-round severty ara battar cnidatas fo biokog traatmant. Clrcal experts tharwfore strongy urged thatat leect cne agant fram bath casses be avallable within oy step tharapy poliy. Far nsaltib cream use in patiens with mild to moderate aboplc dermatit, polky round table particpartsfatthet siepping thraugh othar toical tharsphes such as corticosternid o calinevrin Inhibtor was raasanabd, Sorme clicalsxparts et that shhos rusmiRinks raam may ba used for ‘Youngr prtents 25 2 steroilsparing maclication, rcuirng stepping thrugh 1 mors potant topical sterold may not be appropriate. Manutacturers, Payers and Patiemt Advocacy Groups ‘Sappor prcing em rabote efo efforts that wil cracte better rewaresfor el ad econamic Veton bl stz elpiog potients occes nd GForS the Croptmenty they need 11 widaly racognizad that the high pricas of ew prescripton madications Imit scoes o atents ‘wha may banaft fram their . Curmant pricing for madicatians s complex and tha practics af wsing rebates and other mechods to obscure the pice ofa therapy makes It cHfcu o assess whether the pice belng £k I Inlne wth I effectveness, Manutacrurers and payers during the olicy round table highfighted the potertial Impact of value-based pricng as helping to promate: ‘Binsituta for Cincal and Economi Review, 2021 Page 61 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Cormarey ransanency,affordability and promote acoess ta new therapiss. For example, upadachinia has 3 uch hgher price aher estimated rebates than otie eatments, and t s possible that ths drug can compete with a igher prie largedy becase s manufacturer can te fomulary placement 1o rebutes provide by other drugs made by thet same manufucturer. This phenomenen, commonly Kazwnaa “rebarte walls” may Insome cases provide an overall owar et cust i the payer, but t: ray ordy drive up the bubble betwaan tha st price an the it price for the benef of pharmacy benett managers and/or wholesalers, I aiso crstes trus Larries £ compttion for new ‘agenss that have fewer Indications or which re not made by comparies that have ather products ‘whose rebates can be bundied together In negotiation. Unforunately there are no ezsy sokutons 10 the role ofrebates Iy the curvent system, but policy round table partcipants agreed thet the foderal gvarmmare, plan 3ponsors,and otber policy makara shoukd work togethar oy ta develap ew appraache, such 25 nclcation spectfic pricing, that can be pibtat to st a patiweay toward an ot the dominant roke of buncted rebtes. Speciahy Socleties Updote trwotmant grialioes o patiants with opi dermotiths o reflect cureat tractment Options I o form that i eoey to Cerpret o uss by clicioms, patient, and payers Clincalsocietes shiould et thule practics dlines o managing patents with mld fa. modarats and mademts to Eevens Ftmplc darmatis toInciude newar therapies Such 26 abroctik, barickink, dupikamab, wralokinumab and upadactinks Payers bass thelr coverage decishons and Integration of dizaton toois to a great extent on dinlcal guldelires. The American Academy of Dermatology ast updater 1t guidefinesforthe trestment of topie dematits in 2014, The loint Task Force on Practica Parameters for Allergy and Immunolagy, mmprised ofthe Amaricin ‘Acadarmy of Allarg, Asthrma, and Immunclogy, the Amarican College of Alargy, Asthma, and Immunciosy, anci the Joint Councl af Allergy, Asthma, and Immunology Issued updsted trestrmant uideines for atopic dermattts In 2012, Current guldelines do ot Include newer approved agerts for patients wth atopic dermattssuch a5 dupllrnab, approved by the FDA In 2017 or ciabarole: eream, approved by the FOAIn 2016; pudebines lso do ot discuss newer therapies that ave not ‘Yt rncetvad FDA uppraval such ms 113 receptor artagorists an JAK Inhitars. Polcyround table partickpants hghilghted that gufdelines shoukd ot only provide Information on ‘optioes 13 e sed by ciirians and patients for shared decklon making but aio offer pragmatic aivicw nbaut how to seect spectfic Hharapfas for specfic aubgreupa. Payers mxprassad the nesd for updrted guidelines from cinica sacieties wih ditalle gddance ta permit meaningid stspped therapy approaches that permf reasarable clical excsptions, For sxample, guldelines shoutd isinguish use of agents n adolescents versus aduhs where there may be cHferences n the. wilingness to accept smal but pocartialy serlous risks and the need for rapid onset of ‘Binsituta for Cincal and Economic Review, 2021 Page 62 IAKirhibitors and Monocional Antibotles for the Trestmert of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Conanty Impeavement. Manufacturers and Researchers Ectobieh kg arm rogisties that con be used 10 aesess the SoRefts and harms of chroals oee af orad 44K Inbib¥ors o patients with sioplc dermatts ‘Cancerns abous uncammon but potenially sariots ks oforal JAK Inhlikoes such a5 setoue Infections, cancer, blood cots and cardlovaszutar events when used for other condhtons have led to bated wamings, Whether these harms wilaso be seen when used In patients with moderace 1o severe atopic dermatits requires rger, long-term fllow.-p studies that esess ok anly the chrabilty of asporsa bt thesa Infracuent rsks smang IndiEkas using oral JAK Inhtars versis other bilogic tharaptes such as uplumaks. Even tha topieal K hibior, rucifinll cream, hax topical absarption and may warrant ong:teem Flliw-up, espacill ince It may be used In youngsr Inchviduals. Even H s ot assoclated with systemic txlchy, sopical ruxolin cream use might Increase the sk f s cancers. Comtiact rearce thr dhnctly compueres ek work trmatrent ot amd saqueaticltrrtment focthoness Muitpln stakahoklers expressed concarns abaut tha ack of nfarmation directly comparing new raatrents ani the neac for acthe comparator sk, With the patential fo hayving mukiple newar therapeutic options that work through different mechanisms for patients wh mikd to moderate ‘and moderate to severe atopic dermatls, there I @ great need for pragmatic research trias that ‘compare diffrent medications usthey will be used by patients and dliclans in real worid settings ‘Approprixta haacto-haad tials woul] Ifarm dachlon making by Fatients and cinkdrs, Trish that ‘compars multpl truatmant optiors, sequences and combiations ars nesdad to Kerty ‘comparative effectiveness, durshily of beneft, and aokerse sffect. For example, rals shoukd ‘compare the net benefis of diferen aral JAK Ihibitors o the toerabity and acceptance of oral versus Injectabl theraples for patients whh moderate 10 severe dieae. Sopport the deveiopment of Inproved meceures f secae ssverity and aoteommes tat e mesninglvi to patients Cllncal superts ierefad tha ack of standare finkions of dhaase severiy In stopic dermatiis s challenge tn dsmying homogeneous patient populstions for Inchusian In cincal trsls. Wo ko heard from patfent advocacy groups that endpolnts used i il rals do not ahways measure What s st Impartan o patients and familes. For example, rany endpolnt measures focus on the apearance of the sk, sorething that my be Inpartant for an adolescer ar young sduk, but ‘Binsituta for Cincal and Economic Review, 2021 Page 3 IAKirhibitors and Monocional Antibotles for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Conemty may be less important foralder padlents. Thaugh thers are measures.af fch,sisen, and Interfererice In qualky of e, these autcomes are nat yet combined In ways that rfiectthe heterogenefty needed. Moreover, they are arely transisted o Uty measures that can be Incorporated nto cost effectveness analyses. Putlent groups can take a leading role n collecting raslavorld dats, s wall 23 ollborating with resaarchars, manufocurers, s regulstars s define & core st of sevarity and cutcorma masasures sl Ehan In pramceing their uss i ol dlinica rsh. ‘Binsituta for Cincal and Economi Review, 2021 Page 64 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Conanty Supplemental Materials ‘Binmtuta for Cincal and Economic Review, 2021 Page 65 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Corarey A. Background: Supplemental Information AL Definitions ‘The primary autsomes I the pivotal tials stucded Inchude Investigator assessed responses: L. Ecawnir Aryo Severtty Index scorw (EAZ:* This Insrument rapreserts 8 modiicaion of the ‘@eneal schema used Inthe peariask ares and severty Indeu{PASI. Th totalscore for the EASI ranges from 0t maxkmim of 72 whh higher scores Indloating @reater severky. Totalscores regwesenta sum of severty scores from four body regions (head and necl, upper extremiues, trunk, ‘and lower axtrambtes). Tha scors forauch body reglon Inchades n assassmant ofsavarky for tha four signs of erytherma, Incuration/ paguiation/adema, excortatons, and ichendfcation. Thase are ‘each aignsd 3 52w of 010 3 (None, mikd, moderate, severs,respactivly). Thesa are added Lp for each anatomic reglon and muhipled by the percentage area Invoved and a proportiondte body surface ares asslgned to each of the four body reglons. The percentage ares Invotved for each of the four body reglans are assgned u propertional core from Do 6 fwhere O o enuption, 1= 10K, 2= 10.29%, 3- 3049, 4= 069, 5= 70-89%, and & =90-100%) Tha proportionate body surfac ares amigned t ackdts are 3% for the head and rack (205 fo chkien], 20% for the upper ExtromYies {same for chiran), 30% for trunk {same for ¢hidren) and 50% for o extremiies (30% for chikdren). Outcornes are assessed a5 the change In EASI esponse from beseline and are categorred as the percent Improvement: s niotad below. The EASTS response i Poast commonly used a the priary Quicome end point. @ EASHS0: 2 parcentage Improvement of EASI cora from busaline that 2 50% « EASKTS:a percantags Improvement of EAS! score from baselne that s 2 75% = EASHSD: a percentage Improvement of EAS! score from baseline that s 2 90% 2. Invesdgatur's @Sobat Assessmen (A} This ik reported outcome messure provides an overal assessment o the severty o a ptfent's toplc dermatis . pecifc e o, There are iferent versiors ofthe Intrument with the mest common using u - or - polnt rating scle. The. 5palnt acabe runges rom (cear), 1 {amest ), 2 i), 3 (moderate}, o & (severe). The 6- polrt scale rangen om0 flear) 1 flmost clearl, 2 i, 3 [moderatel, 4 fsvere) o 5 fvary ‘savare. In marsy rals the primary reaponse autzama or IGA response s defined 5. scors of 0 or Lonthe IGA. The KiA response can aiso Inckude an Improvement from baselne of 22 polnts. Other cutoffs used I studies Include 23 or a4 poknts, ‘Binsituta for Cincal and Economi Review, 2021 Page 66 IAKihibitors and Monocional Antibotlie for the Trestmert of topk: Dermatii - Evdence Raport ‘Return to Table of Cormanty 3. Aaak Provitus Mammerical Rating Scole (PPARSE™= Hh (or prurhus} represents 3 ksy symptom for patlents wth atopic dermaits and can be Intense, persisten, and deblltating. Thisscale was developed 10 ascess one dmension of prurts, s severhy. It a single sef-reparted fem designed 0 Mewsure the severty o prsfis ar peak prurtus, or ‘werst’ ek, prer the previous 24 hous using an 11-point scale. The Fam asks: O a scale of 00 10, with 0 baing “no heh and 10 baing “warst ech Imaginabis” how woui you ate yaur et the worst mamart during the pevious 2 hours?” Impravament from haselioe can b reparta using a umier oF diferert it points Inchilng 22, 23,ora4points & Scoring Atopic Dermothis{SCORAD]™ Develapiad and validated by tha Eurcpean Task Forca on ‘Atopic Dermatitis, SCORAD s compasite severty ndeux that comblnes objective sympeoms (extert ‘and Inensty, and subjective crteta (prurtds and siep loss). The extent of topic dermatis ks expressad aathe skin surface area invobed. The intersty ncludes B specific symptoms: erthema, ‘edema/papulation, poalng/crusts, excoriations,ichentfcation and dryness of the Involved skin. ‘Thuse are rated from non {0}, mii (1), modarate (2] or sevare (3} far esch Ham. The wbjactive ‘symptorns are s Leing 1 visual araloge scal where s o i or o sespdessnias) and 10 5 the worst magirable hch or sleeplessness). The SCORAD Index ranges rom to 105, with higher scores Incating worse severky. 5. Dermetoiogy Lijy Quety Index (BLGYL™ The DLG s 2 10-am, valkistsd dermatoioay spectic ‘qualky of e assezsment Instrument used Incincal practios and clirical ra t assasmes s domains Inchuding: symptoms an feelngs, dally activile, ekue, work and school, persoral reltfonships, and adverse effects of trestment. Nineftems have four response options: “notatall” “u it %a lat,” “vary much.” On ltam asks about whethar work o study bas beun preventad, and then f yar’] to what degras s the skin condHian been a probern { bt it or “nct 2t ). Incfuldual ams are summed to cbtain a otalscore that can range from 0o 30, whth hgher scones Indicating warss healt-roated qualty of He. Suggested Imerpretation of 0Ly score for -1 Inclcates no Impacs, 25 Indiotes small Impact, 6-10 Indiates moderste impacs, 11,20 Indicateslange impoct and 2130 Indicstes an extremely lang Impact on heath related iy of I for the skin condltion. 6. Chien's Dermatobogy Life Quaity inéex (CLDGIS™ A version of the DLCI questionralre: deskgred to measure the impuct of skin diseuse an the ves of hikiren ages 4 o 16 years. 7. Actiont Orlented Ecooma Meaears {POEMY Thissimple, valdated questonalre assesses: patient’s symptoms and Impact ofatoplc dematitsinchlcen and ockts. t asks about sympgoms overthe prior week and nlxdes seven questions about ich, deep disturbance and whether the skin s weeping/oaaing,crackac, fisking cry/rough, o bleeding. Thse ara rated fram “na dys,” “1:2uye", *3-8 daye”, 56 caye”, o “every cny”. POEM sconas anga fom 1o 28 with hgher ‘Binsituta for Cincal and Economi Review, 2021 Page 7 IAKihibitors and Monocional Antibotle for the Trestmernt of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Cormerey Scores Indcating worsa cloeasa severty and the minimal il important dfference has been reported tobe 34, 8. Atopik Dermatiti apcxs Scole (ADerm- 1k e Includes thrae kame (dHicuby Faling asen, vel of Impact on sipep, burden of waking up ot righe) £ ba complatad daly, assssaing Impact on sleep averthe previous 24 h, and seven tems (Imitations In househoid activies, physical activiles, ‘sockal acthtes, dffcuky concentrating. feelng self.consclous, embarmassed, sad) completed weekly o asmess overall mpact ove the past 7 eya. Responses re on an 11-point rurmerc raing 3caln frum @ “nok [precantf 10 “exremely [prusant]*. Resporses ars on an 11-paint numarkc rating cala from@ “not [present]” t 10 “mxramely [present]”. 5. Dermatits Fowtly ipact (restiomelve (DA A dicase-spectfic messure o moess the Impact o stopic darmetts an the qualy of Wa of parant and famfy mambars o effacted chikdren. 10, Hospted Anzdety cnd Depression Scole (KARS]: Likert scale uied to detect states of undety and depramiar; aruduty und depremion subscales euch with 7 heme. 1L Wark Productity and Actidty ispatravent for Atoplc Dermatitis (WPALAD) = The WPAL, & validated Insrumers b used o mewsure inpalrment In wark productity and dalty actvtes. The uestonraire convlts af x questians assecsing the pest 7 ays: amplaymart st fyas/nal, work ‘e misse dua > atopit derarts (aursl, work time mise dus athar rassons (haurs), actual work time fhours),Imiact of atoplc dermatits on work productiity whk at work 0-10 polnt scael and Impactof atopk: dermatts on acthvtes outside of wark (0-10 polnt scalel Four scaresare derived: abeenteelsm (percentage of time mised from work due 10 heslth), presemteeiam {percentage of mpalrment whle 2t wark due ta healh), wark productivty oss sgsregate of absarkaniam anl prasartmelem) and sctiy Impakmant (percentaga of Impakment In daky acthfies duo to heaith. Higher scores ndlcate a higher levslof mparment. Higher scores nltate ahigher level of mpairment, ‘Binsituta for Cincal and Economi Review, 2021 Page 62 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Corarey AZ Potentlal Cost-Saving Measures In Atopk Dermatitis IGER Inciuies I e raports Information on wastsful or ower-valus services In the same clncal wrea that could be reduced or elminated tocreate headroom In heakh care budgets for higher-value Innovative servces (for mare nformation, see htizsu//lcer reviewore/lnala2017-20137. These Services are pnes that wond not be divecly affecd by theruples o atoplc dermatits (e, arnghvar/famity burder], asthess sarvicas wil be capturs In the scanamic modl. Rether, wa ara a8aking 3arvices Laed Inthe current management of ataflc der matts beyand tha potertial et that ariss from» new Imtervention. During stakeholer sngagmant and puibic comment periods, 1CER encouraged al stakeholders to suggest serces (inchuting reatrments and mechanksms of care) curersty used for patients wth atopic dermatitsthat could be reduced, elminated, or made more efficlet. Nosuggestiors were received. ‘Binsituta for Cincal and Economi Review, 2021 Page 59 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Cormerey B. Patient Perspectives: Supplemental Information B1. Methods In developing and exacuting this report, w rsceived veluabls Input from Indhickal patierts and atient advocacy groups throughout the scoping and evidence development process. We recetved pubilc comments on ovr draft scoping document from the following patient advocacy organizatons: the Naticral Eczema Assalation, the Infernationsl Eczema Councl,and the Allergy and Asthma Natwark. We also conductad a focus group wih three patiants and three caregivers thet was ‘amangail through the National Eczama Asoeiatan. Thesa Intarviews wkh pacarts an caregfvers helped to lusrate the dversty of experisnoesof patients Aing with atoplc dermatiis, as well . ighighted the health outcomes that were most mportant to thefr, ‘Binsituta for Cincal and Economi Review, 2021 Paga 70 IAKihibitors and Monocional Antibotlie for the Trestmert of topk: Dermatii - Evdence Raport ‘Return to Table of Conenty C. Clinical Guidelines Amerlcan Academy of Dermatology Euidntivercf conefor e ocogament of atupkc dermotti™ ‘Tha American Acadamy of Darmutology |uied updatad and expanded dinical gadalinus for the tragtment of atopi dermatii In 2014, based on the Il gldelnes that were publihed In 2004, ‘These gidelines were developed by 2 working 6r0up of experts I the ek! wh used an evidence- based approach to dlscuss dagnasls, ssessment, safety, and efficacy of avadabl treatments for atapic dermatits. Treatment with Topical Theraples Norpharmatoiogk: trastments ara racammentisd 1 maintai and prevert: fares, Thesa Intarventions Include melsturkzers, athing practices{le., Iited use of nor-so3p cleansers, subsequent moisturtzaton), and wet-wrap therapyfor thase with moderate to-severs atopic dermatits. Wet wrap therapy can alse be used in conjunction with toplcal cortcosterolds during Tlarea. These methoda serve 1o minimize the severty of stoplc deratiis wnd reduce the amount of pharmacalogicIntervention needs Topical pharmacologie trestments are recommended to treat atopk dermatis b patients that do. ot ragpond t the sbova ntarventions. These Includs topks! rticostarokis {TCS) and topical caldaurtn inhiktors {TC1, bth of which are used for the rastment and maragement of it ‘and adolaszent stopic dermatis patiens. TS are racommendec for both activn and malntanancs therapy In paients that have not had success In controling symptoms with non-pharmacoioglc Interventions. TC!are recommended as a secontine therapy I TCS has falked o cortrol smptoms. ‘While cther topicaltreatments exst forthe malenance of atoplc dermatits symptoms, they are ot recommended lines of therapy. These tapial theraples Include antimlcrobials, antiseptcs, and anttistamines, Trestment with Photctherepy and Systemic Agerts The American Acatmy of Darmatology recommencs phatatherapy a a sscar-lne trstmant for atopkcdsrmatiis n chikdran and acits, 2 well 5 malnterance theragy In cases of cheanic dlssase. can be used as monotherapy or In comblation wth other toplcal therapies. Whle tls considered a krwisk treatment, It s Importart o conskder adverse events when used in ‘Binsituta for Cincal and Economi Review, 2021 Paga71 IAKihibitors and Monocional Antibotie for the Trestmert of topk: Dermatii - Evdence Raport ‘Return to Table of Conanty ‘conlkncsian whth ather crugs. Photatherapy trestment s cantingent on several patant facsos, Including avalablhy, cost, skintype, and medical hiscoy. Tha prescription of systamic agants for stopic derais patiants warrants smvaral corakderations: relatad ta lsazaa contraincations, cuaiRy of I, and sevarky. Systemis trewtment s Pecommensec for patles with moderate-to-severe topc dermatts whase disease ks ot ‘adequatetycontrolled by topical egimens and phototherapy. The recommended alfdabel systemic theruples Indlcatzd by the gukdeines include cydosporine, szathioprine, and methotreatz. Mycopkenolte mofet] and intarfaron gamma are asa Trbcated 2t sharnetve cffabel therapies for sopkc dermatits. The iimal sffnctive desa of each systarm: therapy shoul] be used when treating patints. The guidelinesalsa recomment against the use ofsyssmic corcostarokds a5 there are conoems with assocated short- and long-term acverse events. Use o Aeunicivs Tharapies I s recommended that patient educetion sfwiy be Inciuded In comventionsl therapy. The use of TES or T cars s b use #a pravan renpas afer the icwma has bean sabilzed Jolnt Task Force on Practics Parameters for Allergy and Immunclogy Atopic Dermatitis: A proctics parumeter update 2012 ‘The lont Task Forcs on Practics Pararmeters or Allrgy and Immunolosy ssusd an updats In 2012 t0'thelr 2004 tredtment guidelines for atopic dermatis. Th tas force wes comprised of the ‘American Acaderny of Alergy, Asthis, and Imenunology, the Ammerican College of Allergy, Asthena, ‘and immunolagy, and the foint Counct of Allergy, Asthm, snd Immunlogy. I these suggestiors. for practice the ol task forca presarts recormmandtions for st ine manugerment and tremtrment of atapic darmaris, as wall a1 gukdancs for Levars cacas that are morm cHfcuk 5a rast. eyt Ling Mansgument andl Trestment of Atopic Dermetitis 161 racomrmendlthat cinkians trext frants sing a systamtic approech, and tha Ittty of ranagamant an traatmant shouid ba detarminad by severty of the dissass. Retommentie traatments Include 5k hyoration, topical ant-nflammatory medications, aiprurtic therapy, anttsacteral measures, and elimination of any emronmental factors that may be exacerating Iliess. Some ofthese common Iants Indude soaps, olletries, wools, nd chemicals tat tend to rggar tha Ratvacratch cycle. Food alkrgies may ko ba consklerad as triggers o Ifants and chikiran with atopic dermattie. Regardless of the severtty of lness, I I mperative for diviclans o educate patients and famly mernbers on the chronk: nature of the disease. Treating cliniclans should review disesse. ‘Binsituta for Cincal and Economi Review, 2021 Paga72 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Corarey exacertating factors with thelr patiats, a5 well 25 the safety and s affects of amy preazibect medcations. ‘Treatment of Savere Casas of Atopic Dermatlis Far sevar casas of atopic dermatit, It I rscommendad that patlents am treatad whth systamic: Immunamodulating agents,such a5 oyclosporine, mycaphenolate mofetl, azathogrine, terferon amma, and cortoosteralds. Wet dressings i also be used In combination wit topical corticasterokds. Hawever, I Important to note the potentialserfous dverse events smocited Wit thesa crugs, e tha sk and benafit shouk ba cussed with the patient. Photathersy can alen be utifsod s muars of reatmant, pariclarly arrou-band UV, whith has bean prevan 0 b mast fectie n the U.S. For extremely severe cases of stopic dermatiis, hospializton i recommended, s this coukd potentially remove patient from environmental allergens and essen the effects of lsease assocated stressors, such as sleep deprhation. Investigattvn approeches to treting and munaying stapi darmett are not recammencind, thara I curmamtly Insufickrt data o prove effecttvaness. Eamples of thesa Imervarticns Incuda Intravenous immunogiobin, omaitzmab, and ndmat Natlonal instiute for Health and Care Excellence (NICE) ‘Dupliamab for Tresting Moderate 20 Severe: Recomumendotions™™ NICE released recommendations for se of dupilumb In 2018, Dupllumab b recommended s an oo for trating modarate to severe atop dermatiti n sdults after not respanding o et lsart ‘ona cthar aystemic therspy such a3 cycusporkn, mathatrasats, szatiopring, and mycaphanalats, o thes ars contraincicated ar not tolergted. Responsa shaulk be assessed 3t 16 woeks and therapy should be stopped Hfthere has not been an adequate response. This ks considered at keasta 50 reduction In the EAS!score {EASI 50} and o least a & point reduction Inthe DLGY, both ‘compared 10 pior o startig treatment. The recernrendtion notes that skin coar should be: tmka ko aczunt and chnical adjustmarts mads I apprapricts when mseasing tha EASIsinca 1 Fray affec the score. Far tha DLCY, acjustents can be made f spproprite tn acwourt or any ysical,pevcholngica,sansory, orlearming dsatities, o communication dHActie that could affect patfent responses. ‘Binsituta for Cincal and Economi Review, 2021 Paga73 IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conarey ‘Borichtnis o Treating Moderate to Severe: Recommendations™ NICE released recommendations for use of baritin In March 2021, Barietiib has silar Facnmmendations as for duslumab; adults with modersta to sevara stoplc dermits not respanding to et aast oreather sstamic tharapy uch as cyrlmperin, mathotrete, austhicprine, ‘and mycophanciats, or f thesa am consrainclcated or ot talergtec. Rasponse shaud be asiessad #rom B weeks and barciink shoui be stopped I thers has ok boen an adecuate responss 3t 16 wesks, using the same aferk asfor dupilumat ‘Binsituta for Cincal and Economi Review, 2021 Paga 74 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Eddence Raport ‘Return to Table of Conemty D. Comparative Clinical Effectiveness: Supplemental Information D1. Detalled Methods PKCOTS Papuation Tha popultions of focus for the review ware: L Adults and chlldren with moderate-to-severe atapic dermatiis whase disesse has elther not responded udequately 1> toplealtherapies orfor whom topical theruples have ot been tolarated ar ars mecdcally Insdvisabla 2. Adults el chikiren with mil5-moderate atoplc dermatits ‘Addiioraliy, based an the avaRabily ofdata, wa Inciuded evidance stratHied by age [chikiren: <12 years, adolesoents: 212 years o <18 years, and aduhs 218 years}, duraion {<16 weeks and >16 wesks), and dsease severky (mid, moderate, and severe). Anterventians ‘The interventions of nterest incuded the follorwing JAK inblbitors and monecionsl antibodles: Moderzte-to severs aopic dermatts (Popuation 1): ‘abrovtieib (Paer) Bartchinib (Olumiant®, EN Lith) Tralokinumab (Lao Pharma) Note that sach of theas theraples may ba ed akone or wth topical theraples (including ‘emollents wth or wfous a topical cortiosterokdor cakcineurin iibkor} il to moderate atopic demmathis (Popuation 21 « Rualtink craam {incyta) ‘Binsituta for Cincal and Economi Review, 2021 Paga75 IAKihibitors and Monocional Antibotle for the Trestmernt of &topk: Dermatii - Evdence Raport ‘Raturn to Table of Comarey Comparators For moderate-o-severe atopl: demnattts{Population 1) we compared the iterventions to: © Duptumab o Exchother » Topical theraples(incuding emalllents with or without a topical corticosterokdor cacineurn Inbibitor) ‘We had Inttall Included methotrerate 2 3 comparator,but afer addional Iutfrom clnical experts and ather stakeholders we have not Inciuded comparisons WRH methotresste n the report dus to dferences In study design, populatians, and outcomes. For mi-to-moderate atopc dermatis {Popution 2} we compared the tervention to: = Topical emollent therapy alone « Topical corticatersis . Topicalcakineurin nhlbitors « Crisaborole eream Outcomes “The ounteomes of interestare described Inthe sk below. Patiertrepcrted prurttusar ching Exema Arew und SeverTy Index (EAS); 50,75, and 90 or reltv changs from buseline Ivestigator's Global Assessment [GA) Sleep Scaring Aopie Dermatis (SCORAD) Scorm Patiert-Orianted Eczama Msasura (FOEM) Dermatolag Life Gualty Index (DLCH) Chldren's Dermtolagy Lte Gualty Index (€LY ‘Andety and depression te.g, Hospital Aredety and Depression Scale HADST} European Quakty af LYe-5 Dimenaians (EGHSD) Memsuras of productty (a5, Work Productiiy and Activity Impairmant Questannaire IweAl) « Othar prtentreparted symptam ancl ity of e maasuras ‘Binsituta for Cincal and Economi Review, 2021 Paga76 IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Comanty Achersa mntz (AE8) Serious adverse events [SAES) Discontinuation oe to AES Thrernbotic everts nfctions {seriaus, skin harpatic) Hamatolagicl sbrormalttes Matgruncy Abcause mortalty Timing Treatment-emergant adverss events (TEAEs) = Non-melnooytcskin cancer Evidence on Intervention effectiveness was derived from stucie of gt least four weeks durtion. ‘Binsituta for Cincal and Economi Review, 2021 3 IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Cormerey Data Sources and Searches Procedures forthe spstemtic nerature review assessing the evidence on new therapies for atoplc dermatttsfollowed establshed best esearch Mmethods. X35 We conducted the review n ‘scardance withth Preferred Reporting Hems fa Syatematic Reviews and Meta-Analyses {PRISA) pialies S The PRISMIA guidulines Incuda 3 checklist of 7 e described furthar Table D11 Tabla D11 PRISMA 20089 Checkdist =1 Tme T T5_ [ erafy tho rupot a5 spstrvatic revi; e s, or bt ABTRACT irmtad ey [ 7| Prvido rucired saroeey i sl ie: ockgrouel; oo et murces; sk leloty s, sty and nervertors; sty appaa nc synhoss et esuts; Wnfaios oochudors nd mplaions oty fings: syvamaric rodew raieaton rumisr, WTRODUCTION T 5 osaioe o vl o e T o ont e o s aremy ‘hjoatma "4 Prou an axphc statamant ofgions bang aSirecead it refaraa 10 paripart, tventors, omgorty outcomes,and sy desgn [PCOS). amrioos Fromeoted 5 Iciate Varevewprotoce wie, Fand whers Focan b sccemad ., W regitraton ‘s, . rvalabla. o rghatraon ormaion rchuckg rageian e TR e[ €| pecly iy Saraciis o 4. ICEE, Mgt oTTolowuplnd e ‘oo o5, oars conekiese, g, pls o st e et o eaglhly, g ratoraie eforation aoeras | 7| Dasrib ol kraton soureas (g b wth dutas f comraga,contact i sy vuthor o endy kel uin I he e s e bt semhe, T T et ll rori e vtngy o St e, Tl 7y B s, ichthett cou b repevted, ey i[9 [ St the rocm or sectingshafbn L, reoring ARy, FRaT spte i rovicw, and, Fapplcabie, et i the mera-analpsl o caiion | 16| Dok of e fraston fom e .5, ko formey == neperenth, In duplet) nc sy prszsenfo bt e infining et trom Iresigton. o T Uk el ey for i s e sough (o8, PO i soursasand any asmumtions e skmpiication . T T3 Desclbe methak v oravmemin ok o o f et s Tk Indbadind wacbos pecticntion ofwhether s was dane e the sy o utame v, ndhow i Imaron s o be sed it uny datasyne s, [ oy mossres | 13 | Stae theprvc el sy menres (.t e, erenis sl Spviseof rcatta | 14" Dot i reéhonsof g it e rmdis f s, i, ncuting mesaure o conabeeny (e, 12 or cach mete anaiv. ‘Binsituta for Cincal and Economi Review, 2021 Paga7a IAKinhibitors and Monocional Antibotie for the Trestmernt of Atopk: Dermathi - Eddence Raport ‘Return to Table of Comanty Tk oo acrees | 15| Spscfy iy ssscoamert f il of b the oy e the e vidence e {85, publcatin e, et mperting i st “RaibimaTenain | 15| Desabe meiods of adbcna s (= srafh o SEETR SIS, e sogeon, o, cringwhicvars e sl Resuiry Vo T | G e ot sl e o SRy e A e, et rmor o cxnlom e ey g, Wesly ki o o, Shudy 18 | For mch shudy, preen characterixtios for wiikh dia wers exiracted fe.g., study. it Sim, P8, o o] ad e o . ek A | 5| Prsan ok Dk e .0 4, e, oy ST o e essament (e e 12). ‘st of Indivicuad | 20 | For el outconves considard (banefts or harma, present, for asch study: (3] e bl ey o e, o) et e el deahy with s frest ot i of s | 71| Pt e of meh ot rmdpt oo, nding s omva st mesmres of osbiency. ik s srots [ 22| Pt e ofay masarort of Pk of e ot o e e T My | | o i of addora b, € dor o, arovey o o aravs, et egron e fem A5 becman Sy ol [ 28 | Simarte B fings natig T e of iz o aadh prbienty e o e o 0P (14, et psddr, e, et ey mabm). Tinkatons 5| Dl s sy e e . Tl oS v b {ng, cmphta el of i st et bk —— T e praal mpreain of hares i e oo rden, i fo s e oD Torine 77| Do o of e for e ek e e opar .. supply of daa. ol of undars fo the psamatc reiew. From: Wahe , Lberel A, Tetaft, Alurwn DG, The PRSMA Group [2008). Prefered Repar g o Syt Rl nd Meta-Arayoe: The PRIHA Stzament. Los Med 66 1000087 o107/ jumal pmad1o00087 ‘We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Certral Regiter of Gontralled Tils o relevant studies. Each search waslimfted % Englh-langlage studles of human subjects and excie aries ndexed a3 guldelines,leters, ediforiah, namative Festiwe, casa reports, o newes ema. W Incided abstracts from morferenca procesdings it from the systeaaic Iteratur search. All aarch strategles wara garerated utling the Population, Itervention, Comparator, and Seidy Desln slements dscibed abovs, The proposed search srategles Included 2 cominaton o Indexing terms (MeSH terms In MEDLINE and EMTREE ‘terma in EMBASE), as well as e text term. o aupplement the database searches, we perforrmed manua checks of the reference s of Included trials and systematicreviews and Inviked key stakicholders t share references germans to the scope ofthis preject. We also supplementad our review of ublished stuces wth data from ‘Binsituta for Cincal and Economi Review, 2021 Paga 79 IAKihibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatii - Evdence Raport ‘Return to Table of Conarey onfarence procsecings, reguiatory documents, Iformation submkted by manufaturers, and other grey Rerature when the evidence met ICER standards [for mre Information, see [psc//cer= ool Where foasie and desmed neceasry, we o cceptedda ubmited by Frarafacturara -zanfidance,* by accordanca with ICER's bl gukdelns on acceptance snd 5 ofsuch dacn (s lcer-reviow orghme-ofdn-confidencedta/). ‘Tabia D1.2. Saareh Stetagy of Madikna 1596 £ Prasset with Dally Updata and Cichrana Cantral Fagistar of Gontrolled Tila(intarventions]® RS WY ‘e ol st ‘o6 oo st e - pak araly T Tortorsaraorsars et rtroted PR cortrobeddivca g randomieedab et S waTaGrErHes ompareive Rudfor. o GG AbA, of CYTGL b, of TR TABA, o TG R TRA compartoab. o camparson.ab . of comparathe bt f eflectieab, or fiectencmabi, or st oevab Tad 1T Torts o k] Fumamah. e Tren ik 23 to g e ca raprts o commant o Eangracias o larl o #ar o T B 2w o B o Durmattia, op/ oursderaiip. o o NS ‘e Darmatia or darmatte g ToBaBa® CECCECEEEEEEEEER ; & 2] s[s[s]=[s[e[x]e]e[ s 6]H] ‘Binsituta for Cincal and Economi Review, 2021 Pageda IAKinhibitors and Monocional Antibotie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conemty i Rorocting or rockinb e, {abroctin or TA0965642° o pOASGSOAZor "o 4965AL" or MESBAZLab. Eop bk o e iRl or " 2RCE0" o IcBGERCHD o b 20055 oy SOOPION"or ARG o olumin)stab. Fip upodedtinky orUpeENTHTD. PAdactin or 'abt A6 o 3bABA o o o “Upa D PR o UpAdacin Fydrate” of Fupadacmi anrawsian, i raokimamab or trakoknmab v Traiimat o Ao a8 o et T 5 Rl o nackbih.rg. s or"och C10424" o IcBOTBA2 o TOVEA" or SLOAZHof W or v o ‘b malete”or oty phosphat' L ab. oD xSt o e BorBa il Smiez Fwa e “Buarealast updrad on May 3, 2L e[e[2] * [2]e]s] Tabl D12 Saarch Stratagy Medine 1996 to Prasort with Daly Updote and Cochrana Cortral Fagistar o Controlled Trias (Conparstons)® ey w5 e ool ke o e el wn oo s/ 2o metuhec- k- snwtely multcartar 2. ToZoaawses Fandorisa ot . controed v vkl b, Borfor Worllr Gar B ariar 15 Compraiive KUyt or Tareabl. o NP . or oAb, o PR A o compartsn.abt. o comparsonab . ofcomparatha bt r efectieab . or ictwnessabt or . orvabt T 17 Borta Slel=ElRIE[e[ ==~ ][ =]~ BE ‘Binsituta for Cincal and Economi Review, 2021 Paged1 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermatii - Evdence Raport ‘Return to Table of Conarey o s haranash. Dt Bran k230 nghth bnggr Tom ot or comnend or ararmses il o e Rl EE 2w o e ‘n Darmttia, op/ e T s Darmatia or daratterp. TorAwBea phmatrp. plumad o e o eg G o egnfor e SRS o aa 2818 e aaborsiemp i o an2728 or wn 2728 1A 38 o Y17 2021 Stands e[ e]ss]o[e[e]= e[ e[s]s] =] s o] e[~y Seachlaetupiriedon ey 3, 3081 Tabia BLA. Coctwans Darabase of Systemetc Meviews® amararp. T Gt ok e Torzoraers whroleg. broctins or TRAGSSRA1" o POMSESALE or Tl BSIAT" PGz b . TRl or " GAROS0" o IciX28050 o Wb 200ST oy SOOHIDR" or A Iohor clumbrestab. i Topadackinh or "abt 45F o 304 or i o Upadaci eyt o padadin Fydre or uadacinb arrawtab. ook ool or "CESSA"or cld o “crr S A S[elel & Te] = [=[<[=[[=[=[~] e ‘Binsituta for Cincal and Economi Review, 2021 Pagedz IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermatii - Evdence Raport ‘Return to Table of Conanty TR or ok CI04BY o IbO10424 ornch 1042W"or S 082% of Ml or Rk o “nowiin malssts” or ol phosphae’) ah. o Timethoptrts or eI i o oA SororBwsor w o Bor Bor MorSororty upbarsbrp. TRapbamel o Gt o g BEF o rgnf o ' TR’ o R Ee b i or vz or v R oo ordcomerai o opkal SRt or okl s ki S DobwdoRuna S n SO Bors ST ok Wy 38, 3T & s[s[s[e[x[e[[e s s R]s]s Tablu DLS. Saurch Strtngy of EMBASE SEARCH (intarvantions)® e OR ecam oo Bt R Hiok e Dot /p OF neurodermas Gt/ OR it TIORRORRORN abroct s OR sbrocinb. broctlct b OF Y O-SESAT-TLb OF IOFDGSAE . ON T ABGSiAZ Tk DR FMOEeoi i “Barinb/ep O barktind. Tarkfebel b O och UZ050 2 O 28050 ,20 Oy S003 108 Ak OF R ah Upstackibap OR pedacing pacockis o O et 45821 2 O v G et el G i st O upaktints ot st nuTAb s O inkumab ko abab OR ct 35 b O ot 34 b O A TRl O ik inoil b O ich GLBASH L2 O i 94245 OF o 457 1,25 O Wb On Jard 2, U ruac i maleat’ s b OR ualkind photphate 5147 R 9,01 3 OR ¥10GR 111 0% 23 OFLFI3 06 FL4 GRS Sanons e O a8 O gl M O e e OR Bl ochortany o O et s’ e e BEEBEEREEEBEEEREREERE ‘Binsituta for Cincal and Economi Review, 2021 Pagedd IAKihibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermatii - Evdence Raport ‘Return to Table of Comerny procpecive 2UBY 18 OR prespacive sudy- allowp'fde OR Tk’ Casaconrol sty 4 OF cant ool . b palr alp O kgt anapd rossava sudyfde UN cross var ooty eohortedlah eaca®and oot 30 O 420 OR 21 O 23 O F23 O 24 OR A5 GR 728 GRLER7 eompare i Wheonan ek W 5 on 0GR OR A mmom Taonae T Carima s DR oA a7 OR il Ao e N W o wsnoTEr 58D [nghabifim 89 N Imedineim “Serehlastuptad on May 26, 3L B(3( (8| 5| 2( (2| 2(5( (| 8[| 2( 22| Tabla DLS. Sesrch srwtagy of EMIASE SEARCH (Gormparetonst® e e OR SR eops et f OF ik At aLrod el /4xp OF RS Gt OR armtits TORAIORKIOA M Hphurmatfz OF duphumat uphmaet s R dupbent €, OR v 587 OF v £, OF Y SRS A O mz b o OR b ‘xrcartlab OF s iah OR'an 2738 A,1D OF W7 E7F .20 OR AT, wonw ormoR EAD D oo O o4 OR gl B 5 O e 1 O e v o “oohort syl e OR bert bl Tongtudiea tudy e OF Torgdral idy. orospecive tudFia OR pruspactiv sudy” ollow p'7de O obowp' “ime conia ey e OF oot el it ki s OF atshaplt sy ‘Binsituta for Cincal and Economi Review, 2021 Pagadd JAXnhiitors and Monodansl Antiboies for the Trestment of Aopkc Dermatii - Evidencs Raport ‘Return to Table of Cormanty B|a[e(o |8 (al(( 35| 5 (x(%[x=(=* Cromover sty e ON cromovr ooty Taohort b e e o T 15 ORV 434 OR 915 OR 38 O F17 O ¥ GRA15 GR 720 DR omparsiah e eraw i I 50 NG [vnkrl eperkmen; OR el o OR case reporf6c OR urmen o OF “Muman tsuede OR onburnfde R practoe el fde O stk /e OR hupter . OR edhoral/k O Teter/Rk O ot O review't O ot aurvey At 53 NG (Farialop O herbuvan'/asp O sl oprinant ) WO urar7m] 2 AND (17 oy RINOTImedivelim 34 AND [rghab fim !!Ei! B (5 5{E(2(3(5(2(3 R 532 Tabla BL7. Saareh Statagy of EMBASE SEARCH (Systemati Raviaws|® Tast updrad on May 8,351 A ety ON i’ O o g O “atopc darract'f o Of ropl damathi” o et p OF ks “dermatitjexs OR dermutts abroctindfaxp G sbractnd ‘abrochtiet,th OF ' ABESAZH1b OF IDADESHE i ON 4565847 Lah UR FMSGSBAZAD kit OR bkt ekttt b OR o C2A05 i R TR O Yy SOOI O okt paductnisljom OR upadscting padackiirlah O et 494316 OR ToqLab OR Wpadecin P Wpirvie LD OR padedinb. byditeab O ' upadactnts tarste a0 mioinumat/am OR Ealodhumab raboinumatrlab OR o 3542 OR cr 354 b OR i ziab “raoRilyerp O ik s i 2 O e CLBASA'H2 G Wb 842A,8b O 1 £34128 G BIafetab O oo OR il malese’ s OR ramlKnk phosphut b okt 08 mthoraats ‘amincptaiv b Of o, ah R res ik UR et b OF atmap i ab Of ol b 600 47 0% 0 OR #5 OR410 OF #11 OX £12 O F15 OR 414 OR 415 OR#15 OR #17 HEEEEECHEEEEREEEEEE “duplumalfes OR duplvmab ‘Binsituta for Cincal and Economi Review, 2021 Pageds IAKihibitors and Monocional Antibotie for the Trestmert of topk: Dermatii - Evdence Raport ‘Return to Table of Conarey BapRA s OR upboen %2 OR et 668 A OR regnd 4,2 OF e 5365 %20 OR s “erbmborae fep OR rbaborcle vt ah O stz OR ot 73808 OB ‘ar 728 f R e oA e eseieuri mhbrrh s ah O opka s OF togial enolBert . ON “oplel carteosaroé§ab 150 420 0R 921 0K 22 0R #23 0B 44 waunes 28 00 1.2 ca00/ut s moma rronis 29 AND et rediow]/ i O et sembvai ] 304D /i 3 NOT Imadiaim “Bardalast updtad on May 28,351 !HE!‘EEE“EE g Figurs D1.1. FRISMA Flow Chart Showing Resufts of Lkeruture Saarch for Abroctinlh, Baridtini, ‘Tralokdnumab, Lipedecitilt, and Rt cream ‘Binsituta for Cincal and Economi Review, 2021 Pagada IAKihibitors and Monocional Antibotie for the Trestmert of &topk: Dermatii - Evdence Raport ‘Return to Table of Conarey Study Selection We petformed screening a both the abstractand fltext levels. According to th Incusion and xciusion rkera described earller, asingle Investigator screened al absiracts kientifed trough lectronic semrches. We di not exclude any study at sbatracklevel sreening due t Fmuflent Informtion, For example, an abmtract hat i not raport an cutzome af Interast woul ba ‘aczate for further eview In full taxt. We retrisved the chatlonsthat were accaptad curing ‘abstrachievelscreaning for ikt appraisal. One nvestigator rviewed full papers and prowided Iustifcation for the exclusion of exch excluded study. Data Extraction and Quality Assesamant We used crteria published by the S Preveriive Servces Task Force (USPSTF] t assess the qualky of ACTs and comparative cohor stude, using the categorles *good,” 1ai,” o *poor® (Table 0.1 and 23,5 Guldance for qualty ratngs g these crterl s presented below, 2 4 a descrition f any modfications we made t these ratings specfic o the purposes of this review. Good: Meets ol crter: Comparmie groups e assembi ol and maintalned throughout the #0u0; refie and ald measurement instruments are used and appled equafy o the orous: nberventions are speled cut leary; i impartant cutcomes are conidered; and cpercpriste tention & ped o confounders in ke I ko, otention o treot sy i used for SCTS. ol Studtes weve groded "ol wny or aifof the fobowing problems oczur, withaut the fatol fiowe ‘aated inthe "poor™cotegory below: Generolly comprrable grougm an: csembled il but some ‘question remains whethar some (hhouph not maor) dffereeces ccrurvad with followup; mewsuremant instruments @ ocosptatie {uthough At ths est) ond penarafly apphd equot; ‘same but ot ai-mportant outoames ore consiered; and some bt nat o patential corfuunders are ddressed. itention o treat anatyss s done for RCTS. Poar: Stdtes were graded "puar* f any of the folowtng utni fiows exdst: Groups assembied Imhtady are not case 20 being compaable or maltained thioughodt the study; unrediabi or hvald measuremen instruments me used ornat appded equoly Grong groups (induding o masking ‘autoame nssezsment; an key coafounders are iven Gite o o atiention. For ACTS, ntention to trat anadyats e ocking. Nota that case series are not eansidered under ti raing system —because o the kick of ‘comparutor, thase are ganerlly conskderud o ba of poar ity ‘Binsituta for Cincal and Economi Review, 2021 Paged? IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Conemty Asssesment of Level of Cartainty In Evidence ‘We used the |CER Evidence Azing Matrs o evaluate the leved of certalnty In the avaliable eviderce ot et health beneft: among each ofthe Inerventons offocus (se2 Flare 3.2, of the Regor). Asseasment of Blas 5 part of our qualty assessment, we evaluated the evidence base forthe presence of potenial Pubiiation bies. We performed an assesarent of publestion bas for abrocttn, barictinb, upmdactin, rakakinumaby and usobtindb cream using the dinkalirials gav datubase of i We acarnethe sha o kerfy studies cormpleted more than b ysars o that woud ave met our Inclusion critart and for which o Ancings have been publihad and did not find any svicenca of pubiiation blas, Data Synthesks and Statistical Analyses Data on reievant outcomes wers sumrmarized In evdennce tables {506 saction D3) and syrthestzed ‘quaativety Inthe body of the review. In addton, we evauated the comparative efficacy of bracitint, baridtink, upadactilb, wralokinumab, and duplhumab for adufs 18 years okd with oderate 0o severe stoplc dermatts by means of network meta-analyss (NMUA}, where feasible Basad o it avalibily, ur NMA evakiatad IGA, EAS| 50, EASI 75, EAS1 50, and PR-NRS 24-oirt Impeowement outzames st 12 and 16 wasks. Netuark Meta-Anafyals SupplemantalInformatian ek (Section D2) contains. detalled descrition of the NMA methods. Due to Inconsitent or Iimited data reporting. other outzomes were only descibed namratvely I the body of the report o I Section D3 ofthe Revort Suoplemens. ‘Binsituta for Cincal and Economi Review, 2021 Pageda IAKinhibitors and Monocional Antibotie for the Trestmert of Atopk: Dermathi - Eddence Raport ‘Raturn to Table of Corarey D2. Network Meta-Analysis Supplemental Information A Methoos We evaluated the feasiiiky of conducting quankittive syrthesls by explorng the dferences in study populstions, sty destgn, miytic methods, and outrome amesment for exch outcome of Intarest. Triols deemet]suficently similr In tarrs af populatian, Intarvantion type, hration, and utcome tefinitions were Incutsd In the NMAs. Whia mast trial that met the NMA elfhlly rtert envolle patismts 216 years ol the pharal ks of abrociis UADE MONO-1 and JADE MONO-2) and the pivotal fas for upadackinib (MEASURE UP 1, MEASURE UP 2, and AD-UF} enrolled ptients 212 years old. I order to analyze il ias In @ comparable fashion Ina sigle network, we sewrched for subgroup evidercesiraified by age an these trils. We received ‘confidantis datn frum the manfacturas fo tils whara tha subgrou deta by age ware not putiicly prasentad. Based en data aval developed quantiative, ndect compartsons of broctint, barickink, upadactin trackinumals, and dupikmab using « Bayes/an necwork mets-analysl {NMA) for IGA, EAS 50, EAS 75, EASI 90, ant PR-ARS 24-paln Imprrvemart. 2t 12 and 16 wesia In atients 218 years ok The primary endpolnts of the abroctinbtrak, JADE MONG-L, JADE MONO-2, nd JADE COMPARE, were measured at 12 weeks, whie the remaining nfaks’primary endpolnts were measured at 16 weeks. KGA and PP-NRS 2¢-polr outsomes were analyzed as dichotomous autcormes {“yae” ar “no”) uing a bisomial lkalhcod and lag ink. EAS| autcomes ‘ware aralyzed a1 crdered catagorical data with s o four distinet groups: e, EASIGS, EASISD, EASI 75, and EAS1 0, repraserting reduction in the Ecasma Arsa Severty incex (EASI af s than SO, t oass 50X, at least 75%, and ot beast S0% respsciively. Using the EASI outcomes reported in studles, we created munually exchisive groups by re-classiiYng the dota os <50, 50.74, 75-85, 290, ‘Therefore, & multinomial Ikelivood model with a probit ik with method from the National Irathtfor Haalth amd Chincal Excalance Dechion Support Unlt was used. 30 Ghven the expected dferences In the dinlcal eficacy oftreatment n the monotherapy tils and ‘comisination tral, separatz networks of the monotherupy tiak and combimation s were. develapad. Wa axplored both randam- and fivecaffects modals for each nstwark and compared the goockhess of it to thacata. W Eonsklerad the modal with the knwert deviance Information crtarion (DI 0 Fave the hest” fit 1o the data. We used flmd-ffects modsl for the NMAS of the ‘combination al, aiven the Imiued data avallabi for each netwaork. Adjustng for placebo respanse I an NMA design i frequently performed to controlfo ciferences n population characteristics and baseline isk. We considered placeha austment for al NMAS and reported Fesults whare the adstad NMA mocdl prowidai 2 battar it of the date. The mocil with placebo ‘Binsituta for Cincal and Economi Review, 2021 Pageds IAKinhibitors and Monocional Antibote for the Trestmernt of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Cormerey ‘atjustment was considered a bt ¥ the regrestion cowficent was statistical sgnificamt and there was reductionIn between-tral heterogenelty. Blormtal NMAx wers canducted using the IndiRect NMA pltform {CRG-EVERSANA, 20207). Multinamial NMiAs were conducted using JAGS software (version 4.3.0] via R sing the Fjags ackage. For al analyses, we sed norinformative prlor distributions for all model parameers. We Inhfaly discarded the ist 50,000 herations 45 “burn-¥1" and base Inferences on an addkional 50,000 Heratiors using three chalns. Convergence ofchalis wes through vimal exarninatlo o the Broak-Galman-Rubln diagnostc and Historical plots. Lasgua tablas ware presentad for the trowtrment affact (1R of aach drug varmus each ather and placsbo, alang with 95% ¢radiia Inmnals {95%Crll. Table 02.1 I5s the NMAs we conducted and the detalsofthe mode, and Table X sty the tias Included In our NMAS as well a5 easons or exclusion oftrials. Tabin D2.1. NMAs Conchictad & Prassmiad Cne Tt Wiodd Haraber of i B W orotbersgy ol | FRJIomRTM probitE VS b) Gomblnation ank b6’ = o) Moraiberagy | BierGrtn BT A b)Gomblnuion onky be RS eird | ) Moncitcraey ety | Bnorei et Tk A b)Combinuion anky B ‘Binstuta for Cincal and Economi Review, 2021 Paga90 IAKInhibitors and Monocional Antibatle for the Trestmernt of Atopk: Dermathi - Eddence Raport ‘Raturm to Table of Conanty F u m m o O u s 2 5l zle w|alm|u wn(ma walm W[ alma w | o [w]w w0 | [w w | aw wm[ %[ m]alm = [m e m[s m|n W [ [ w5 [m u LR E ) 2 (= (@] 5w @ [m[m | [m[w]n = B0 (2| & | o [om [ @ 30 4= | |0 [ [ma | a0 [0 i@ 50 |5 [ 20 | [ 2% | o0 [ [ o | mw [ 3w [ e [ a2 om0 | ow =0 LN eI S I BN D = [ » | m e A ot WA owsoma | [ e | = u [omssme u [asm o [owamngaew | = [ w0 | Table B2.2, Netwoek Metz-Anabyty gt for Monotherspy NMAs {AN dyte ngart arg In ackfts e and ckden) ot zna w1 ey e 02 e a0s s wior Paga91 ‘Binsituta for Cincal and Economi Review, 2021 IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermathi - Evdence Raport - w| | mme | ® - - owsmryoew | |5 [ m | @ o=@ (% e]e il el - w i [wm wmlalulals als T, T e, U R PO sl i, 0 o ey S, i, T it Uk i, Wk ‘Tabla D2.3. Network Meta-Aneiysi Inguts for Comblnation Therapy NS {Alldeta inputs arela dhilts 15 and okder) ™ - am v | e | % = - [Ty s | v [ [ [ [t [ [ [ e e e e e e e e o I w[w o mA [ ms wmn = o [eomestE [z [ [0 [ [ [wo [ 2w [e 2| w DB eS| w0 [0 2w | | o7 20 [ w0 [ [ v [ smar 1 [raisngsrs | om [ |3 [ 1o |00 [ 3w [ a0 i [0 [ L) 2 20 (2 [0 [son o [ [ @ (e[ @ o [PhizeTs o [ w0 [w (9 [ m |5 ] s TS v mm malalala]s Semmtbyitt | % [mors w i (wlwm s (w8 0ol et | m | o [ | @ | = [ [ L] TSIt | % [y, 35 [ (w5 (oo [ (s [nn [ T, T P U7, P, i, e T G ey o e, T rminat L b, W ek ‘Binsituta for Cinal and Economi Review, 2021 Pages2 JAKInhiitors and Monodansl Anibodiesfor the Trestment of opk Dermatii - videncs Report ‘Returm to Table of Corgams ‘Binsituta for Cincal and Economic Review, 2021 Pagasd IAKInhibitors and Monocional Antibatle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Conanty Figuee 02.2. Netmork Fure. Combination Trisk ) ‘Netwnrk Mot Aesyals Result: Movurthercpy ACTY Far the EAS| NMA, the uradjuctad modal (DIC: 165) wax ascociatac with Improvec it compared ta theadjusted model {DIC 203]; the estimated regression cosffiient waa nat sinificant n the ‘adjusted made (-0.93; 95% Cri:-1.18 t 0.54), and the Ierstudy SO with was Increased In ragnitude from .05 (95 Cr: 0.002-0.16) 100,007 {95% Cr: 0.004-0.18) with placebo djustment. For the IGA [DIC:231) and PP-NRS24-polnt improvement (DIC: 243} models, the raijustad modals ware also anacitac with s battr it reltive o the acsind model (e Inturctucly S fallowed a imlartrand ss presartad for EASI moda]. Tharefore, wa precantad the resultof the unadusted modes for il outcomes. EASLI0 25 el Reaults ware smlar 4o EASI 75 and EAS! 90 presana T the bocly of the raport. Al mtervertions shawad statstically signifcartly grastar EAS| 50 reaporses than plcabo: baricKink 1 me (Tais D2.4). Upadacitinlb 30 mg wa more Heely to schsve EAS| S0 compared chpllumabs. However, there were no statsically signficant dfferences with abrociilb {both ‘Binsitita for Cincal and Economic Review, 2021 Pagasd IAKInhibitors and Monocional Antibatle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Conanty ases) and upacachini 15 mg campared t cuplumab. In comparisan, dupikamab shawed a ‘staticatysignficantly greater EAS| 50 response than tralokinurmab and barlctinib both doses). 16A (14 o] Reuits wers simitar 1o EAS! asporas. Allimervertans shawnd sutistically ‘fcantty bghar effcary an IGA, a3 defied Inthe tials, comparsd 1o placebo (Tabia 2.5} Upacacitinlb 30 mg was more likely to achieve IGA response compared o3l Interventions, However, upedacitil 3) g was ot statfstical betrer than abroctini 200 mg. Addhionaly, there were no statisiall skgniican diferences with abrohinl (both dases), upedadtilb 15 m, and barichinth 2 mg compared 2 dupfumabs. In campartsan, opllumal shawsd statistcally skgnfcartty grastar KGA rasporan comparad o trlckiruma and barichh 1 mg. RN ooiot imorovezt 14 sk Whie s dirically mearinglul Inprovemen n PP-NRS Fanges from an Improvamart of 2--poirts, the svaltablacata forthe Inarvantions s imost ey mmprised af a4-polt Improvement. Apart fram karickink 1 e, the rmaling Intarventions howed staistcal sgniicant regponsas compared to placeb (Tabie D2.6). Further, there was no statitcaly significant cfferences between abrociin {both doses}, barickink 2mg, tralokinumat, upeadadtin (both doses) compared to duplumab. ‘Binsituta for Cincal and Economi Review, 2021 Pagass IAKinhibitors and Monocional Antibotie for the Trestmert of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Cornerey TR ST e QRO - QLIS ACTY 0 ARG 4 0] SPOGET IPUCTOUDYY L SR NVT P 202 e Huouca3 pue (@310 103 WA S 0130 AR LoD 105 15V3 40 SETU AN Y 2 BIEL TR ST e QRO - QLIS ACTY 0 ARG 4 0] SPOGET IPUCTOUDYY L SR NVT 608q 202 e Huouca3 pue (@310 103 WA U L e ooy Py e L A ALy -1 0§ R AR 2 AL Netwark Meto-Analysls Recults: Combination RETs ‘Chooe of Modei As roted above, we presented the results of the fied-effect model or the ‘combination therapy NMAs give the limited number ofstudbes avat e for thi netwerk. Madel M nforrmatian prasented n Tabla D27 shows that the fuad effact mocdes it acualy wellor bettar comparel % e raniom afect mocal. 0844 Bt n gEneral, the resuksfor the combiration therapy NMAs, provided more onsarvativ astirates ofthe rlative sfficacies of these rugs varus piscabo, athalugh thay followad 2 iilar anking arder 2 the monctherapy NMAs. Allarvantions showed staitica elgnificanty greate responses than placeb on al utcomes (Table 02,9~ 02.13). Table D28 presents the expected propartions of patents that achieved EAS1 50,75 and 90 for each Intervention. Tablu B2:7. Model R Wformation an Combinaton therspy NMAS ol | i st | Random o hodl Rt i o Dwina formaton Carn (oK) LD 5 ot eaon s s 90 poral | 643 @3 o ] Dodnee fmetion Gheron K] Y ] ot o Devarce v 5 ¢4t pora] | 195 ) Rk rovern v nformation Garkn (oK) ) wa ot Bekiunl Dcvree . T3 pokesl | 34 W ‘Table 2.8 NMA Rt Proportions of petieets achbeviey EAS 50, 75, and 90 thrashalda I Cambination RCTs. Trestmert BsE Tess TEsio0 Medlon proprtion 25 G = BAEEAL-0AT | 024{022-0) |i0(woe-0a) Duhamb 300me QW _| 078 (073-0.84) | 051 054 048] | 0391032048 Toroekb Dmg | 073 (ak-TAL) | 036{0A7-0m3 | L34 (Li8=04%) ‘ororkik J0me | 083 (077-048) | 05610500741 | 044 (55 —058) b Iy DapsEeon_|oAifis1-0m) |an@ik-ox Trlomumab X0 | 043 (053-07%) | 0421033-0521 | 0 MI5—030) Tplackink fSmy__| 041 (077~ 08K) | 087 £59-074) |4 L3803 Upsdckinb 30mg___| 091 (07-05%) | 080(6.75-0a) | 00052089 ‘Binsituta for Cincal and Economi Review, 2021 Pagasa IAKinhibitors and Monocional Antibatie for the Trestmert of Atopk: Dermati - Evdence Raport ‘Return to Table of Conemty Tably D29, Relythes sk for EASI 50 1n Combingtion RETy In Adulty w10 azs a5 (7703 warpzrams [imp 3 a2 2 1015 115 1o Lo ot et e 4 7300 595 ol B o 1 0 g om0 i i i ey 5K e ot ot e, RO s, DA i, DUP, o PR o, T e,k paocen, 2, oy o oo ‘Tabla D2:10. Relativa Risksfor EASI 75 I Combination RCTa In Adus PrYTS 1m0 s 20 10 1m0 11y wojwre [1osporaz |1wpss1an aanre) [1naoensn [1seeie 1o ssopmaen [impzmaon [1mumsaon [ssumion [1namioy [0 13 12256) [10(125219) [1021126200) [ 150510 | 10eioeis aspsram [anpisi [1npesn [1nenen [1nnsse o e e i i o e S5 bl o o o s oo mesatoes g, o Py gyt o el et o e . A i, AR R, s, PR e, T oy, UPK kil A, sy s ek Tabin D2.11. Raathn Risksfar EASI 30 n Combinwtian RCTa In Aduft ‘Binsituta for Cinkal and Economic Review, 2021 Pages JAXInhiitors and Monodanl Anibodiesfor the Trestmert of Atopic Dermatii - videncs heport ‘Returm to Table of Congams Tably B2.12. Ralethes Risksfor BB respoms n Combingtian RCTs In Aduts oo i o7 am e 221 2o Py ses m1 an, s amam) 1! am PEY 1 1mi Eoch bt et oo 14 730 595 o B o 1 Bt T a1 i i e ey SN e ot ot e, RO s, DA i, DUP, o PR o, T e,k paocens, 2, oy o oo Tabla D2:13. Relati Risksfor PRLNRE2A-polntImprcvanent in Combination RCT3 in Adufts 1 1713 an1 200 LupE: 23 L) e [supsae [1osemiy [P0 1o nsem [Lsamis [1esniin |1mpee) mjzsan [isioasn [1mpsasn [1masem [1orpmiry [FTT 2arisars [aouianase [1npseang [1mnmes) [1emses) aspwien [awpusm [17g01m [1upmen [1wnasg o e i o S5 bl e Forth o e s o s g, o Py gyt e el et o e . A i, AR R, s, PR e, T oy, UPK kil A, sy s ek ‘Binsituta for Cinkal and Economic Review, 2021 Paga 100 JAKInhiitors and Monodanl Anibadiesfor the Trestmart of Atopic Dermatii - videncs heport ‘Returm to Table of Congams D3. Additional Clinical Evidence T section stars by peowling acktional clilcal evdence fo patiemts with modergte-t-severe atopic dermati presented by drug. Euldence Isirst pesented for adults and then for adolescents ‘and chdren. Next,we provide addtonal oiical evdence for patients with miktto-moderste stapic dermatlts n short4erm placebo-controlied traks of achdta and udolescents. At the tme of this report, o lang-tarr wwdance for st cresm was drtPed. Moderate-to-Severa Population Adults ‘Two placabo-controlied monctherapy triaks of abrocttinlb enrolled patients 212 years old UADE MONO-L& 2). 55 Resufs of the subjroup of paterts 218 years okd I these trias (74%-45% of the ‘il population)showed that 615 85 of paients achieved EASI 75 with abrochinib 200 mg, ‘compared 10115 125 I the placebo arms of those tials. WM A% n this subgroup of atients, 395455 achiavac EASI 75 with abeociib 100 mg. The parcantages of patiants Inthi subgraup. that achleved IGA respanss with abrockini 200 g were 38%-46%, Z3%-30% whth abrockink 100 g, and 7%-10% with placebo. ‘Aa eccrbar 1 the rupart, o trisl compared abroctinls 200 g, abeociilb 100 e, duplurmab, ‘and piaceto In aduit patents aso treste wth topicalcortcosteroids (IADE COMPARE). ¥ Whille: Fesults 2t 12 woeks are described I the report,resuls at 16 weeks are presanted here, The percentage of patients achleving EASI 75 wth abeocitils 200 mg was 71% compared with 60% with ‘abeoctin 100 i, 66% with dupfumah, and 31X with plicelso. ™ The percentage of atients ahieuing IGA with ahractink 200 g was 48% xmpared with 5% with abrocHil 100 mg, 39% with dupfumab, an 13% with piacab. ® Thare wara no stathticaly sgrficant dferences In EAS 75 and IGA respanse batwoen the abrockini arms and duplkenah at 16 weeks. & ‘Wa idantifind cne o e tia of broctins (ADE EXTEND) ™ JADE EXTEND f an cngoing, apar- abel extention stuly that evakstad continuaus trestmant wih atrochtints 100 mg or abracink: 200 mg In aduts whth moderats t severs atopkc dermatils wha had particpased n previous ‘abrocitib trfas {WDE MONC-L, JADE MONG-2, JADE COMPARE). Resus at week 48 showed the fesponse rates on KGA (200 m: AT, 10D mg: 295) e EASI 75 (200 mg: 625, 100 mg: 46 were: sustained. ‘Binsituta for Cincal and Economi Review, 2021 Papa 101 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Raturn to Table of Cormerey ‘We ket twa ong-arm il of baichinia (BREEZE-AD3 and SREEZE-ADS). BREEZE-AD3 wes four-year birdad extanion tiaIn which petants who achievad t nast 1 partal rasporus IGA 30008 0f22) 2t 16 wneks It ariginating trais ware ntinued on baricitinl 2 mg foratleast 52 Weeks for 3 otal 68 week of continuous treatment. Week 68 resuts obtained from the arufucturer o5 acatemiciconfidence suggest mantendnce of EAS| 75 and IGA resporse ot 68 weska, 444 'BREEZE-ADS I an ongolng, 52-week opeHabel, single-arm extension study that evaluated the fong term eficacy of coriniious treatmen with barictinlb 2 mgin adults with moderite tosevere: stopic dermatits clssfled m nor-esponders or partial responies at week-16 n BRECZE-ADS RET.S The uas of tapical coticostaraids was permitiad aftar Week 16 In BREEZE-ADS and throughout BREEZE-ADE = Recus shawsd same Improvement In EASI T, 1GA, and DLOISS. responges ot 52 weeks {EASI: 495, IGAS1K, DLOS: 45% ] compares to week 16 (EASE: 40, 1GAZT, DLOIS: 45532 Inthe two placebocontrolied monatherapy traks of tralokinumah (ECZTAA 1 and 2], patients were: followad up for 52 wesks S Aftar the 16-4wask Inlal restmant perads o ECZTRA 1 and 2, paiants who achioved rasporaa (KGA scara of 0 ar 1 ar EASI 75) wers rerandoeizec n rakinurmab 300 ‘every two woeks or every four wesis, o placabo for 36-week mairtenance period. Resuhsare presented In Tt 03.3 below. InECZTRA 3, the pacalbo-controlied trial of talokinumals conducted In pasents treated with topical ortcosterolds, patients were folowed up for 32 weeks:™ Simlar to ECZTRA 1 and 2, patiemts who achieved response (Kih score of Oor L or EASI75) a 16 weels n ECZTRA 3 were rerandomized and followed p 10 the end of the study. Reslts are preserted In Loble 033 below. Inadditon, we kentifed ane 268-week angoing, open-iabel, single-arm extension st of tralokinumab (ECZTEND)™ ECZTEND evaluated the efficacy of coninuous trestment with trakinumab In sdults with moderste 0 severe atopis derratis who hed particpated I previous tralokinumab trsk (ECZTRA 1, 23, and ). Intaris rusdts et weak 55 showad tha respanse rates on 1GA (41.75), EASI 50.79.7X, EASI 75 (S2.8K), and EASI S0 (51.1%) wera sustainec ™ Sufery overts ware consistent with wt was obsarved In the argiating rigk. Upsducltints ‘Two placebo contralled monatherapy trials of upadactinl (MEASURE UP 1 82) and ane placebo- ‘controlied combination tral (AD-UF) of upacactinia anroled patiants 212 yaars old. © @ 1n tha ‘Binsituta for Cincal and Economi Review, 2021 Papa 102 IAKinhibitors and Monocional Antibotlie for the Trestmernt of Atopk: Dermathi - Eddence Raport ‘Return to Table of Conemty monatiierapy triai, the EASI an 1GA responses It the subgroup of patents 218 years okl wers consistent with what was abserved I the overall population. At week 16, 72%-79% of patients In the subgroup of patients 218 years o EASI 75 wth upadactint 30 me. compared 10 13%-17% In the placeba arm of these trals™ In this subgroup of ptles, S9%-63% achiever EASI 75 with i 15 mg.™ The parcentages of patiants n this sibgroup that achiaved IGA resporise with upndciinib X1 mg ware 51315, 2EX-50K whh upadacitill 15 g, and SK-3% with placebo.™ Siilarly, I the combination trkal that compared upedadiinl o placebs In ptierts wha rested it tapical eoticostarakds, the EAS! and 1GA raspancesIn the subgroup of petiurts 218 years ok ‘ware canststert with wiat war cbsarved In the avaral popuition. ™ At weak 16, tha parcantage af atients achleving EASI 75 1 the subgroup of patents 218 ysars ol with upa dackinib 30 mg was 775 compared with 68K with ugadactin 15 g and 26% with pacebo.™ IGA respanse was achieved by 56 of patients with upadactinlb 30 g, 41 wth upadachinib 15 mg, and 1% with Flacebo™ ‘Wa ldentiied twe ong-rm Phaca I trial of cuplumat (UBERTY AD SOLO-CONTINUE an LIBERTY 4D CHRONOS]. In UBERTY AD 5OL0-CONTINUE, upfiyma was compered to placsba. LIBERTY AD. ‘CHRONO Is comblnation tralthat comared ckplumab pus topical cortocsterokd & toplcal ‘coricasterold alane. 11 bothtrals, patents who achieved response (KGA scove OF 0 o 1.0r EASI75) 16 wosks Intha orfghating trals wera rarsndamized to thplumab 30X mg woakly, avary twa ‘waeks, every four week,or avery aight waeks, ar piscebo for 16 weea. Aftar completion, patarts ‘ware followsd up far up tn 12 wesks o anealld In an apa-abel extansion [OLE). Rasuts of UBERTY ADSOLO-CONTINUE and IBERTY AD CHRGNOS are presented In Table D33, ‘Binsituta for Cincal and Economi Review, 2021 Papa 103 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Comanty AdRions! Outcome Tatbes: Table B3.1 Key Outsomes In Plocebo-controlied Monotierapy Tials In Adufts o] | - e[| O [ i | ot =TS TR oo T e e [ [ 57 N | ne s2vade [0 | ioo 180 oa0 | 365 —n 5 o i3s T30 | to [ 50T Honwag o oea T [ | ses soewano- [ e s2unse [iaa T 443 a8 Tooa T3 T n ) 53T ioa T35 {00 [t o JAmomon 1 T es Tot [ e o7 Contabam | 2300100 my wesks =6 | anr | 250 [ 208 | 500 | oz % i Tiea Tos Ta T iss 0 S, o S [ [ w1 [wainy sownss [0 | o3 o Tila | ias | —gao £ o T T o e e T T s weman: [Bin s5umcie 34 |53 T ea 88 a7 % BT e Tas T e 0T T ST T T T T wemis [Mains thunso a7 T3 T3 T 150 T % i T es i Te T T e T e TE T e Py P80 Bwes vy Ty [ aa [7a [ oo T e ina s ins [aas | peo |t i P8O 6wee® [ ny | 114 [ ss [169] 35 40 Tt TR e [ | o e [ oy sounse [ 00 wv0 | o smo | o s o 80 [ 30— onsiEL a0 om0t e | e sewnd |8 ioo s30T 200 | 55| —n e 30 Tsa | a0 ["e0 ensing w [ Tme [ ees | s sounss vy oot T | o [P w3 [ wn [0 [we [ s | aoa e Y sowndo |71 | vaa 202 [o10 | o | 4eo Yoy i[5 0T as T T3 55 T—a ot o [P ROREN | e |80 ] 50 [0 5 A | 5 wios o 2o aa s s [ 300 oo e[ ouaw | o[ 4aa Twio [wes [ seo [t inetute o it 3o Eorri e, 2 o 00 IAKinhibitors and Monocional Antibotle for the Trestmert of Atopk: Dermati - Evdence Raport ‘Raturn to Table of Cormerey - N T S0L02 o s [PSE i e T T e e, 8501 S T ey T ST U o T S ot o it ety P o ‘Tabis B3.2. Key Outcomes In Placebo-controlied Combinution Trisls In Adults [Short-tarm) va | am [ [ | v [eamno | | [monr T el ws | n [ as [ os [ma] m e [T o | ms | w | wa o] m coveare el o Wi | ms | wa [ wa [ m woss FT T T T R i i DR | gyame [ B |55 | 5 [ 5 w5 [ s DT PRO+TCS. i s g B3 AT 3 | S s ng 7 sea |0 | s e [on [am oY [roerss [ [Taer [as | 61 | @2 | w | e e R s | P [T | a0 | ma | e [ma | o ™ e e [ [ o w [ [ ] m A s meres | Wk [ B0 Y 0 520 NR oo | amo | i Tas [ we o e [oRoTe [0 e[ 0 [0 [wo [ w0 [0 | at Sinovcs [Fas 7S o | B0 | 5o [ oo w0 o AT velics T the bl ae percerage. BRI 417, DUP 390w G, DUP 200, whd DUP 100 g doses were ‘chuied fomthe NMA. ABRO: abrochi, BARE barctl, DUP: dupl b, me: illaram, MR: o repores, PBO:placabo, TRA:rkoidnura, TCS: opia cortoaacoks, UPA: upasecdl, PR-ARS 4, 5 drange from asain,“reprtad cused maan g rom bsaloe I SCORAD Frcufsae from paiets ages 12 or, rapotad SW parzataga chingefom basane b SCORAD. ‘Binsituta for Cincal and Economi Review, 2021 Papa 105 IAKihibitors and Monocional Antibotie for the Trestmert of &topk: Dermatii - Evdence Raport ‘Return to Table of Coranty Tably B39 Key Qutmses in Longterm Comparativs Trivk o o W T e Temtes | [ O T g | wan [ 2 [ scomo kit TG W | me | | s [ [ W eomar [Tasomgoey | seesie [0 [ @1 | [ ws | e | w 0 m @ [ [ oa [ [ TR g A s ] s [ | w e T vt U T ] m [aa | m [ 5 [wm [ m A g QW o wm = m | ws | m | om XD ma W s | sTson Zweets [ 525 [ ms | s | ms | m | om repondry TRA J00 mg GO - i |ma| @ | ms | m | m oo s oy - ma (e | m2 | ws | me | 2 COHTIME | o 7 [ | e | mo [ aen | a3 DRI TES wmarvao [ i » s | s | % [ u | s NS | et 775 w2 % [ w [ 5 [ o ATl T the bl ae perceriage. s s oy T whu¥s 18 4 okder. DUF 300 O + TS dove wes ‘emAnid rom the tble. DUF:cuplkemst, m: milyam, ML o reporsz, PRC: place, LIW: every o week, QM very four weeks, TCS: opkal cortoatrokt, TU: oo ‘P-MRS i, L5 charg fom baetne, reored LSW percentage chinge rom basline i SCORAD. ‘Summaries of the harms are provided In Secion 3.2 of the Rsport. Tables presenting ey hurma from tha shart-tarm ACT are presarted in Tahns 3.4 and 3.5. For respondars It re-rarclormized Iongrtarm manceisrapy trials (Table 2.6, harms wers uncammoe thaugh ighthy mars patlents ‘on actue trestment dlscontinued therapy ts to ske effects. Additanl reparts of conjunctutl: ‘and herpetk Infections were simtar aman those fecehing active therapy or picebo. For patients 1 long:term combinasin trals {Tabie 03.7), harms leading 5 dscontinuation were uncommon and simiaror gty hgher for patiants recabing placebo. Othar sévarse elfects wera abso simikir amorg trastrment s, ‘Binsituta for Cincal and Economi Review, 2021 Pape 106 IAKinhibitors and Monocional Antibatie for the Trestmernt of Atopk: Dermathi - Evdence Raport ‘Return to Table of Corenty Tabin B34 Key Harms In Pacatiocomtrolled Manocherapy Trise of Adult (Short-tarm) DiC wa | mm |t | 27 f e | 2 fchr | ot | s [ et = =T B w5 ][] w Jm] o soewone- » [ | zwee o [ [ 6 [3] 2 [oa | o0 i3 sTwm s 5 el w | s [ 1] | wa | soewons- ,- sl el B 2 B BV I ) o W o w = el - | wm | ws | o [ S [ | e [ | 5[0 [ [ £ & = T T . 0 M B muczeecs [ ma]| sswwets [ 5o o s T R S T R et O o o - o - o] e e e muczess [ m] sewwets [0 on a7 Tor |0 o o T | e i s T s T e T " & PBO_ Wweeie 7 | Wm [ 43 (41 2 R il e L 2 . ) B6wees [ oe T wm [ 1s |25 15" R s s i | & T = P P ol . o - ST, [ e o T3 = sckine e [ e [ e = 7 o W RT3 = e[S = ST o [Tz 6w [ Zs e = Vesgateo [ > ST e T T et ‘Binsituta for Cincal and Economi Review, 2021 IAKinhibitors and Monocional Antibotie for the Trestmert of Atopk: Dermathi - Eddence Raport Page 107 ‘Return to Table of Corenty bic [ s | v e | [ | [ | 2 |t e = = [rroadl -2 e X N I N - = - = DR300 - L - wno [25 | seee | = [0 [3 [] = e = Tow . Ta2ts | | sowo | M| M | 6 ] % | ® = w5t ‘Alvalias T Thetable ara parcantages. A sdria s, C: AL, g: igrar, NI o raportad, PBO:lacnim, C2W: svery tw ok, SAE: ks scmraverd, TEAE: ek gt s ever. resuts arefrom e apes 120 ki, ronhthtyherstih, ‘cnknctts, conkctis bacert, conjunctt i and conanctihs ey, cnfunci o uapectbed cause, alerg, bacaral und vl conpurett,and atopte aratocorunctes, corpanceal facions, Iaions, and araton, oral harps, e e, sz herpetios,arem kv fetin, i e e, oo et ard hrpen e, ecor herpeticum st e erpes i, s kg, “herpes st o herpes simsies, Pecerma herpetia, Sherpes e, ™herpes i Ifcton, nckding ra e pes, heroes ‘simple. acsma herpecm, harpes i faction, arpes sata,ophehsimic herpe nple. guntlharpes. s phtalic cnd hapes gl ot e ‘Binsituta for Cincal and Economi Review, 2021 Papa 10 IAKihibitors and Monocional Antibotle for the Trestmert of topk: Dermati - Evdence Raport ‘Return to Table of Conenty Tably B35, Key Harms in Placatio-comtrolled Gomblngtion Trtala of Ayl (Short-term) | [ | T S B R|E|E & 0 Salwr ¢ |-l B & ¥ - | 6w e | g w|as| 22 |w| @ | o Yemky TG | s6weeks s w|w| w2 [w] 2 w | o s nafw | ze oa| wm @ - Az TS | t6wents = e wlw[ o [u] = || = = o % wlw| o [ = [w] = B wlm| o |+] w [ m|m i e T el o A, e oy A BT A R ity A s e A by i Xt g o PO, o ey e A s o okt T et e o e P ity ‘Binsituta for Cincal and Economi Review, 2021 Pape 105 IAKinhibitors and Monocional Antibotie for the Trestmert of Atopk: Dermathi - Evdence Raport ‘Return to Table of Conemty ‘Tabin B3 Key Harms In Pacatio-comtrolied Manocherapy Trise of Acult (Lorg swrm] 3 o et i [ [ ] 2 o [t | e . e T Jwmane | o [ [m]m] w | w | m kel | w | w]u] w [ m | w AL T [ ([ e | 13 25| er N o o e W@ T 5 s mi[ w21 o] e | m | ar maz [Trarary | wet (| e | 1 [aa| s e o £ 72 T T 3 gt ] " . a0 [ | e [ ] 57| 7 w [ w [ ot 33 el o tw ATlics T the whle 4 perceriage. s s oy Iy xhis 18 4nd oker. Dugare 300 ma W et QWY doses were ot inchud nth table. AF:veae vers, MAR: baihinb, /C:dcorsinusion, DUF: duplum, ma:milgram, MRt repated,PRO: lcebo, QZW: very o weeks, QU Eeryfur weeks, SAE: uous e s, TEAE: reetmars rmargan strse vae, TRA:takhbnumab. *conhinthltsbactre, conjunctt il and i abeg, canhnctie, conkthits Bechrte, conknctRls i, conjunctia iagc, and Ttopkc bratoconkzis, ‘ecoama herpeticum, rpes siple s nfcton, oral- erpasnfation,opfehaimic haraes e, ‘Binsituta for Cincal and Economi Review, 2021 Papa 110 IAKinhibitors and Monocional Antibotlie for the Trestmert of Atopk: Dermathi - Eddence Raport ‘Return to Table of Conemty ‘Tably D27 Key Harms i Placatio-comtrolled Gamblngtion Trtala of Akt [Long eern) R Torped L am | Tivwpeint | 2 |reaes | | sue | connctts | naman |2 Asfrean - TGN i wa| m | 12 21| a a2 | ¥ respondrs) TRAS00 e @S . — o B8 | 0 |as| aw as | w rpontes) | weels T Gow TS (e EYI T P N = | e repondery) PeGIWs o 0 as|m | 24 2| e o | 2 repondery) TRERTY | oLP 300my o Wt | saees [ W] 2 |4 . .| 7 amones [0t = T T W Alvaluas T thetabl ar prcaragas. AC:swria swrt, C: dicontiniato, DUP: dupdirmab, g Bgram, NI ot reportac, PR lacab, GV mvarytw e, CHYY: avry four wls, SAE: Aok advarse evn, TEAE ek art et carceavunt, TC: oo ot T trohuimc, UPA ipadcen. ottt sy and st il oot g, ot b, hopke. oracoretht, and itk or! e e herpetie, st herpes, berpen i, haree i rection, erpes mate, e Ferpeicum, e erpes e ok, otk herpes i, n cptminic herpes e Children and Adolescents ‘Aditloral cincal midencs for chldren and adolaszants are prassted bekow. For adolescents, ur Iergture search dsrtfed trilsfor abrocHink, upadachtin, and upTumab. Only rial of upilumab were kdentifed for cikiren, and al ofthese Incied toplcal medcations n il groups. Our Rerature search did ok ety any bariciink or tralokinumab s In chlkren or adolescants. ‘5 nated Tn Secton 3.7 ofthe Rsport ral of abroctink Inckaded adolescens and 3dults. ‘Though two plscabo-cantrolsd monatharapy tiss of abrociinb anrullad patients 212 years okd. ADE MONO-1 A7), a il fractian of the patiarts s thasa s wers 212-17 ysars old (15%- 26%) % One trial of abroctinly soley snmile paents 12-17 years ok and Inchuded use of ‘Binsituta for Cinkal and Economic Review, 2021 Papa 111 IAKInhibitors and Monocional Ansibatlie for the Trestmert of Atopk: Dermathi - Eddencs Report ‘Returm to Table of Conanty topical medications In il arm JADE TEEN. %417 While resuits of thess btals In acolescarts are rtefly described n the Report, addhionalresufts and a table of ey resuhs are presented here. It two placebs comtralied manatherapy triats that eniled paants 212 yaars oid IADE MONG- 12, 55%-60% of patients <18 ysas old achleved EASI 5, compared 19 0K-13% In the pacelo ‘s o those tlis. ™4 In this subgroup of patierts, 4% achleved EAS1 75 wh abrocitnb 100 mg. The peroentages of patients achiewng IGA response, defined o5 an IGA score of O or 1and an Improvement of 2 s or more from baseline, with abrociinib 200 mg were 27%-A0%, L3%-27% ‘it abrociinib 100 mg, and %126 with placabe. Inthe placebo controlled combination trialthat solely enrolled adolessents LADE TEEN], more ptients In the abrocitin e achieved EASI 75 ard KGA resporee ot 12 wetks compared o the piscabo wm {ces Tubie D3.5)277 Ak the time of this Report, o lang term datafor abrociinib In sdolescents were Identified. oodockin®y ‘s noted In Secton .2 of the ispars el of upadaciinl included adolmcarts and aduk. ‘Two placebo conralied monatherapy trals {MEASURE UP 1 £2) and ane placebo cortrolled ‘combination tral |AD-UP} af upsdactinih enrolled petants 212 yewrs aki; however, fr patierts In thesa trnks were 212-17 years okd (12K-15K).% ©Whla resufs of thesa rial In atckescants ars vty deacribed In the Report, adeltional ragfts and 2 tabi of ey results are pressrted here. Intha two placabocontrolied monatherapy trsls that envolled petiants 212 yuars ald (MEASURE. UP1 82}, 75K-521 of patiants <18 yaars oid achieved EASI 75 an adacitinth 30 mg, comgared 15 BX-13% n tha pacebo 2rms o those sk In this Subgroup of patients, 67%-715 achleved EASI 75 with upadacitil 15 mg. The percentages of paients a-covere atopic dermatits: a systematic Rusreture review and network mete-analys™ This syttt Itarstura raview and NMAA avalustr the Eomparaive oficacy and safaty of savaral ‘Pyatarmi tharapies, Inchuding oeal IAK nhEstons, 113 antagoristy, and 131 antagarists, ‘nilastants and ackits with ot > severs atoplc dermatits. Tha medlcatians ssssssd Includedt abrocttini, barictint, dugliumab, lshrizymab, nemalizumab tralokinumab and upadaciinib. Investigators dentfied 19 phase Il and phase Il RCTS, publshed before October 2018, 10 Incude n thel analysis, which comprised of 11 manotherepy and 8 cominaton trlls. Outrumes wers analyzed separsiefy for morotharapy and combivation tharaptas L., systemic theraplen plus tupical corticastaraic). Forthe monctherapy t1ah, upsactib 30 mg consbtantly b the highest reaponsa rata on all EASI measures,falrwail by abeocitinih 200 mg and Upatachtin 15 mg. Accttionally, upadactinih 30 g and abroctinih 200 mg demanstrated superiorky over duplumab 300 mg, both doses of aritint, and nemollrunmab. A silartrend ‘was oserved for A resporse; however, no data were identifled for upadacitinb fo IGA response. For the combiratin therapy NMA, both dases of shructinl, dupilumab 300 mg, nermolzumab 30 g, an lebikizuuab 125 my, e the hghest respanse ratas for all EAS massures. Adioraly, ‘abencitr 200 mg damonstrated supariorty ovar bardin, tralpkinumak, and cuplumab. On 1GA, broctinl 200 mg, dupilrmab 00 mg, nemoltzumab 30 mg, and abrochinib 100me, had the ighestrespans rates. Upadactinlo was not Induded I the combination therapy NMA. For saety events,Inthe monotherapy and combintion therapy RCTs, none of the restments had adverse: events that wera statstcaly diffarant rom placabo; buk most truatment arms ba numaricaly higher probabiites of TEAES than lacabo arma. Howeer, the probabify of AE lucing o clscatinuation was genaraly iower I the restroent arma. Thare was o satiicaly sgnicant ifference between the actve treatments an safety events, ‘Binsituta for Cincal and Economic Review, 2021 Pape 124 IAKihibitors and Monocional Antibotle for the Trestment of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conterey Drusker, &M, ot 3, (3020), *Syvtaenc Immuomodulory Treztmynty for Patiants wth Aopls. Dermatiis: A Sysoamatic Review and Natwork Mete-aselyels” Investigators condhuctad 3 systamatic revimw asstssig the affcacy and safety of systamic Immunomodulatory trestmentfor patlenss with modarate-to-severn atopi dsrmatis. 39 RCTs. for 20 dHferens: medications,Incluing abrockib, baridtink, dupllumab, ralokdnumab, upadaciini, methotrexate, and other ITMUNOSUPRressants, antagordsts, and monocional antibodies, were incuded Inthelr neiwork metu-analysis. A totalof 8360 patiens were Inchaded, the muan cmpls atza ar each RCT was 80 (4-315) patierts, and the meary/macian age rangsd betarean & ancl 44 years. Elglilty rtrta Inchudec] patinnts with moderate r-avare stopic: ‘ermattls, 2 systemic Immuromodulatory therapy 3 the treatment of focus, and an outcorme ‘assessment tme point ofelght weeks or more. An NMA was performed for each autcome, Including change from baselie I EASL, POEM, DICY, and fch, withdrauwals due to adverse everts, ‘and frequency of serlous adverse eventa. Data were pooled for trhals wth 8-16.week treatment ‘Hmapoirts, artriss with greater then 16-week trextmart: Hma polrts ware nat analysed. Multple dra doses, Incuding duplkmab 300 g GZW, barichnih 2.mg and 4 mg daly, tralokinumab 150 mg CEZW, and 300 g 7 hed w statstically sigificant reduction In EAS| score ‘comparad 8o placebo, with dupikamab 300 mg GZW having the Highest amourt of cartainty {masn iffarance [MD]:-11.3;95% C: 0.7 m 131} ‘Whert sssesaing chungas In sl signs of atopic denatits smang drugs that araslready used clinical practicn, t was faund thet sl current drugs ware more effective than placabe In dearing apic dermatiis cinical signs, bt with low certalnty. ‘When comparing thesa trugs, duglumal 300 C2W and cyclosparine highv-dose were more effective I cleaing akopic dermatts sgns than methotrexate and zathioprine. Dupllumal 300 g Q2W was the orly drug that demonstated cliically megningful Improvements I both POEM (MD: -7.5; 5% Ci:-11. 10 3.6} and DL outcomes (MD: .8; 95% Of: 5. 10-3.7), with hgh certainty, while abrodiinib 100 mg and 200 mg, and upedactinlb 45 mg and 30 mg had sigifican impravements with awer eertainy. Addltionally,only dupiumab 300 ng 02 hud a statstcallysignficart kmpravamant In the maan charige In PP.ARS, relath to placaba, with high caralrey. Cyclosporine, dupllumab, mathatrecate, and Emsthioprina coul nat be campared tn each othr for the tch outcome dua 1 Ipreciss estimates. Sty could ot ba robustly massad tue o the cvaral low rates of sdvarsa evers. Invastigriors e potarttal fmfeaticns I ther systaraic review, Inchcting hatnraganahy fram Incorporating ralsthat alo vsed background topical medicaton therapy, ughng rals that varied the definkion of disease severty, and the lack of eadhto-head triis I this analyss. ‘Binsituta for Cincal and Economic Review, 2021 Papa 125 IAKihibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatiis - Evidence Rsport ‘Raturn to Table of Conterey Slogeis, ., ot a, 2020], *Syvommic Trastments I the Managemmert of Atoplc Decmstis: A ‘Systemuti Roview snd Meta-Analysts™ An SLR ancl » MA were conducted ta evakata systemc restrmants for madarats-to-sevarn amaple ermatits. Invessigators Wantifet 50 RCTs o 13 dfferen appeoves! traatmants In Europe, as of February 2020, to Include In thelr meta-analysis. The medications Inluded barichini, duplkamab, ethotrexate, upadackink, cortcosteralds, and other monodonal antbodies and mmunosppresants. The total pafent populution wes 6681, 1 majorty of which were in chpilumals riais (3529}, anc the svarag sampin atnfor moettrsh wes s than 100 patiants. ‘Thirtytins wer conducted i aduft populatians. Cre tialwas In adalescents, one trial ssessed theirtrextment In hikdren, and 18 tials had 2 groups Inconsstent with th Investigators defined populations of focus. Meta-aralyzes cout b calcuarsd ankyfor cuplumab, arathioprine, baridint, and yospeein, the other ral’ evidsnce had higher ik of blas[RoB). Ot of thess trestments, cupilumaly ‘fals In acus with a dosage o1 300 mg 02W had the most obust and hghest qualiy evidence due 0 the large number ofrais an patients. Al duplkumab doses I the trals demonstrated supsricrRyt plscabo I EASI 75 and mean changa from basaling In EAS, SCORAD, PP-NFS, POEM, LY {n adchescats}, wnd DLG) (i aduls). Cumulstive safrty et for dupikarab inccated that ‘atversa svmnts fo duplmab and placsha were squal and greaterthan S0 In Incidance rates, Wit conjunctuts and Iaction-5ks reactions bein the mast comman cancerTs. Inveatigators reportad thrt uncertaity Iitad the evaluston af xfety and ficacy of the cthar mestments’ wiis. imitaians Inchaded ik af pubikhed RCTs, most of the Includs RCTs huving 3 high isk of bias,arelatvely low number of patients In most fas, and inclusion of okder trils. ‘Binsituta for Cincal and Economic Review, 2021 Pape 126 IAKihibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatiis - Evidance Resport ‘Raturn to Table of Conterey U PR G oy 20000 - HABELLIS0 HHODY 10 WAIRGAL 10 SAPOYEIY OPOUDH U S VT aneis V207 e uouca3 pue (@310 103 WA o w sopayos: w5 gy Topepdad o W| pwsusions mopen v s o Sacu wpneg O W TR AR WD o 3 R o U =N | e /A o ™ opumnmu o o oo ey | sommsios o W R PR U e o w vopanpo pyrinoy B 29 x ™ ‘i g Ao moi P o x 3 S i v sy SR W T W R O w e e O ™ TREART AR |t i e T T T PRSI O O s e e O O T Ve e PR X % TR meompn o o sy x v SRR X ¥ | suewgen g S T g | e el s s iy o e o) sy | (-] ey s w e S oo Adcumey odu T ool SPOLARIAl PAlIRRa T3 UOTEWI0}U] [ETUa U] G TSSUSAIIE} 1500 WAa1-8Uo] 3 S PRI ‘oo R2UaR3 - LIS ATy 40 URULERAL I 10 SAPORFLIY [RUOOUDRY PR LU AVT ezrodsy 207 3PN AUIDUDIS PUE [ERUID 10§ KA (g o qranupamy. » A DOAN) QBT AN 18 R rni0) GlupeE > (gt ey » SO 50 ] SUOQLIAL204L 0 1] I 241 “9PPUI 0 UMDY AU U0 5a4ed Pue 'SIaImRE) e SUEPYUID ‘SUEHEzERi0 WOTE LIGL Indu) Ay paCORMAD SEM SUORLIBAIIA 1038 UL RIS DRI v TR TEY a0 (e o e A P ik SR pNA ounes o T wat Wy s g s v T AP A R g ool sajeeg 73 ML 1 ) U PO SRS A FYION ) GUELIESS O 90 U QSRR ORERYE SIS MM BRI 008 O THALLID K3 8 A SapL kT {10 SR ST Pl TP ] UCR e I U 10§ U R L. uopejndad jasiey ol 8 mpeS oy peepy wawitru T e =ro o o w g1 4 oRrgod aEan oo Uepenpe| wauoip S P LT oy R0UR3 - LIS NG 40 URULERAL I 10 SAPONFLIY [RUOOUORY P UL VT ezrodsy 20z SN HIDUDI3 PUE [ERUID 10§ MR PAFapt S R e} X3 UL 0 PR PR I 15 Sy e A AR S P 35 PESSER B oA U 82 4 1380 10581 SR U ‘2BeUIAD Y. “SUMSBIAU SHLLBY PUE ‘QVHICOS ‘WIC 343 10y 531008 da315 A PUB [SHN-dd) 31205 BURRY FOLILINN SN 183d 0540 PATESLI 52 GELINIAN PUB 3423, PEFUEIS 0 PRIEALIOS e €9 0 UL PUR S50 [EMALIBINL 4 a6 T3 INEL symw 7 SPRBULIZP o3 3095-01-TRI3POU PN SR 04 UM SR SFIEAE PO ANCLIOBAIA 24 WasoHdal NS O 953U SONJEISA e 43 PUOKS SWIREL 10} WALTES DR P AL 915 U059 LTI U1 ANLIGR IR 43ISO BRI 0 PANGIINE S9m QEUINENG SRASLID SIS0 BRSO AUALIT 8 18 LT UHTAUFYES PR SPIGASCCYD TS SR TUBYau) ‘sodesecs 1K U LN 10 POA91100 4053 O 10 UM UAIOUR BUBTE) R L o (e ‘waning) guunipra 504N 35 SIS 694 4 AR UL KD (OSSR NI PO | A3KT0 0 WO 13 Ry S P LG ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT oct odey 20z SN HIDUDI3 PUE [ERUID 10§ MR S0P P10 i o 4 HALp e AR ope apeizoe 10K S LS PR 450 ] SV SRPAIL] A3 S8 IYHOOS SIS MERY YN AL 183 SHH-dd TAURE 6 4L 1557 0 AL YA, 3P A PO AT Y Y S e MO0 Y S Y v w w w w w wo| oorus| aeumimg | svempen e ™ - ™ - o | wwaren | ssooun | qnyto | et ™ 0 ™ ™ [y | oo | awning |_weives w w w w w oo foorws | apumire | sy ™ w ™ Fi) ™ s [oorvs o | amrgma T M m - P o | ooy o8| et = - wl ow " oo 20 | oosmes o5 | ey, ™ ™ w w0 ™ sew [ogss o5 |_arwema ™ - w - - o | s oo | oy g rarwry | o [ e | v | ey | o | oo s [ ey | ot | ey | oy | saneweny | oo wrs | o | wwo | aws | Vuiwo | pemtnve | mo | roowaven | wwimes: | mvwwmen | masmon | feevemn | mvwemse | smesres | sousmnn [ —————— P L ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT Jevole 202 o D03 put NI 03 SR T ORI O BB B A A 4 L AU B3 ST O AL KIAD 9 M9 G2 UL CRRIBERLCO 34 | SUCREIOIED ULES 46261 o 9 Ut 1) oIS e ) A LIS ST 1 SRS 34} 8 GBI Lo} A3 WL 1 B3 5] LI A [PUBALISD 1 T R UL ST UDFUAAA o4y SAGT PR IR i R U 902403010 o {K748) 100 o4l 0 anfeA[Bro 15 @M9P 01 7 1025 L) PaNOR ONfeA L. P R JOUEIHLLI0 B U1 | 1342 15 {8ATVID BARFAATOE41 813 i) A KBeJank U vk o 4,40 SNl s o, € (9417} POUIER €5l EUORPRE 341 i AN uopepdod PRG3R S DOUIE a0 £209K EURIPPR Ul PGS UASNIEILL b BUAST QU9 PO I UL | OFLO) R0 U280 104 T o oy PaRpISUC0 2122543 ) IR U UORERod E12USB 317 0 AR PRISNIpe-JapUsE puE 9B Ui TSFD40 KRN E SngLme 9 254d T EUIAD UL S 03 I SUORBITIAT IS A0 240017 PSS A § WIS T SR OU B3, LTS U110 34 40 WO D SIIPKUOD SRTAD 4 1500 UL UOJIEII|E) DAAS UOLALIR I PR T ‘e R2UR3 - AeLLIBq NG 40 URULERAL I 1 SAPONFLIY [RUOOURY P UL VT e odsy 207 SN HIDUDI3 PUE [ERUID 10§ MR ) 10 BIPAIRS 674:08 ANAPGIIY 20) BB OPRUIOL T3 Byl oL e 3 UG poued AR KA AL U0 45 0 P 43 ARIRp 63 TS il i VBT i A I U0 K] USRI SR A PANOI TORR RSN AL B, U0 SRR DO [SRSAUR| 500 315 50 PILRUSPY 2136k S9N AUV G185 31 SUORIBKIKO PRSP [8 ROITY REASA: POASPOU WOFD 04 ATYD UOIUPPR 56 1509 Ul SERIEND TARNIBH2 0 SIS RIBUOSERI 0 (SI0LI RIEPAEIS ') AUAELIOOUN oo 1050115 T E0€ IS 1312 1L 32 O SN DN PUB S 110 D KIS0 STRUP RLSIOUSR OL sesAeuy Aynjisues £1 S P LT ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT eEvodny a5z MO HUOUDS PUE VIO 104 QIR THIO K18 0 5, A U5 S PUSCAP YA % A O e i i ) R, 8203 /0 BIvpRS 61604 URRRREN ) UeniBe(] 0PN ¥ E1 SR VA0 K18 0 5, A 43U S PUSCHP YA ¥ S0 O e s i ) W, S P LT ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR VW00 1 ok 3 KRR B U PORSAP YA 301 410 8RT e o1 iy ey, 1K 0 e it g 30) Lme e o0 63 St ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR qeunpdng mtsn (AR 0 tsesberq DR 13 Sty S P L ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT oex vdeg a5z MO HUOUDS PUE VIO 104 QIR VAR K1 4 0k, U B 0 PUSCAP YA Y2 W1 B0 e e i ot R, mng s1ian QURPeRe 30 mesberq e 663 ety T PRI ‘oo R0U0RA3 - WLIBY ATy 40 URULERAL I 10 SAPORFLIY [RUOOUORY PR UL VT el 207 e ucuca3 pue (231D 1 WG Sinw—— urvs-asuem) | seswes = v Ea = Tovud e vwe [ SR oo aw) | s s [ | owos-osw |ewsmz | mmoma T g | ok = e 2] Govud e vl |w SRR w-wrz | oness sy |weus | sowswns |y | moma e ot | e = v o Grewd e vwn e e i | wens e [ | mewssne) [ewms | seama T o) | oruseons = v wa £ bovud e rwe|ws SRR s | s e [ | gescona |weoms | mmama ] ] L] v W ] o o ) fiad R S R T STV QUG P 426315 ARAUEL5 ALK SLEIANTU 05 SSARLRY AUAINIOS OLSIIIEQCi 1 PR 63 YL T PRI ‘oo R0U0RA3 - LIS ATy 40 LRULERAL I 10 SAPORFLIY [RUOOUORY P UL VT exodey 207 Gy AUIDUDIS PUE [ERUID 10§ KA 0 PSS 0% ) P T T SRR 0 RN A WL eereD | srrions = Sou-5 w0 wowg [ g [ oy s | v wos-urg |worens | Gorne-one |suswzs | som ey [ e oy - e " wewd [we Gewn [me e vyl | evers es-usy [oorens | govmsosow |wmoens | seom i —— eoni oy e oy - e w I Trea e e wovs-mrwl | wavos wos-usy [oores | tocos-mme [sroas | som T orwss-my | e - ) & wowg [ wewa [ae R bovs-mems | e ws-arg [oores | st |wowms | som s s wwn | wurms - oW = wrEg et wewn W e o | wowss wwmsmoen |meus | ioovsasson (e | o i SR o W T ST S PR ooy R2UaRA3 - AeLIBY NG 40 URULERAL I 1 SUHPORFLIY [RUOIOIORY P SRR VT ezt oy 20z SN IDUDI3 PUE [ERUID 10} RTAI k|5 x| issss 1 !555325555 2|2 %8 E!!!! 1R | e §5!5§ i!u!s ey | aweemen | R P " IO b iag 1 e300 1373 4 Y K LA 10 NN 63 STy S P RGN ‘e R2UR3 - AeLLIBq NG 40 URULERAL I 1 SAPONFLIY [RUOOURY P UL VT v edsy 207 SN HIDUDI3 PUE [ERUID 10§ MR e pivpuess 5 g Ky ey euw3 153 i) omr e Ema symon mon 29 an sunwvaw [Tremms “potsarion g ——r s T AAROnPOLd ~ UL ARSIV SRS TH WL o i pepe PUR UoRRRRAUpy e s 1 adh oy .51 e R B Aq Rl i s el 0 Knp 30m UL O AP IUBORT 54U PR SO 1Vl I I s UNSITIGId o0 OOM 41 0 oo SU5T 2135 1694 AT SOUIRSD FONIOP DA 18I U 1 SIS0 BB 9 Y 950801 1EIZPOLI Gl 1 5501 RAINPOL PIPPU o ARSI FIFPOS PIYIPOIN ~ T AFARUY CLRUIS seshjpuy opRuRs b3 TR R g 200005 - HApE1LIS0 HHODY 10 WAL, 10 SYPOIY ORI IYT i ot 202 e Huouca3 pue (@310 103 WA “PRENIEAD SHIRIFD U S5O HTZ 01 6L A PISERLII Jojesedwos Qe 40 parpURIS B Bugddde uBLm 9622 S D LM SARR0RIAA 219POT PORPOW S WL SORL SS3URN1IGL-F00 RIUAUG.OU| Py 5,18 190 1503 oL P 0 Ty 19 1501 [EIRALRIU) PP K118 1503 [ XA 30y SOFLS1 SIS 4R LR TP ey e % POl M U TR IR S Smemc '3 AL opa ooy 1 T T AL o R PR e Y % e Vg e | T i3 Tt [ oosizs Svwewedn o v s [0 o0zt SRR e v s [ooweers [ ) & i3 o [ e v S o~ amamn uvn | someLomms | womaLwnws wom— TR 0LImia0 WrIedaiag FEOS PALIPON O 03 TSN THE OHSL 40 PRpUS S KE Y SUOFUAAIRJLY 84 10} SZ-0T A7 P 00| s 8 Bt s mnoedsied F¥308 POUIPOUI 345 041500 101 . UOSUBHLICD 10) 500 X0 950 9500 345, A0S I 4 PUB 250 355 34 3 ALBKICO RS 341 PaUfEWAI $2WC0MN0 Juaned PU 500 SUP UL T3 8L U Pasaud 46 3aR0ads.ad 21305 PAYHPOW IR J9PUN LOTLOY AR Jek S 1900 {5c1] PR 2054 0 en b3 e 22k & 1KTVD) a2 st - 250 PGP 110k L TR AT g 200005 - HApE1LIS0 HHODY 10 WAL, 10 SYPOIY ORI IYT arsoteg 202 o D03 put NI 03 SR ep spaymond 1humn, svnkay pranfe-Y AT VT PeLS i aa ey e B vt [ S pirps o & o T vt [ sewony e T | e T e [ cegiant ] eapn e TN oreT [eeson WIS e T T e o mewes T = v o [ e Sy = T T e g e ‘ULIROS LTV BLULL SRR 453 0§ Eng 2 BRL 15333041 J0 SUOSHALIO 3UF UO S0} G 3P0 | P3P Sk LALTERS O 3| 0 U 03 3 S B3 oy 173U KD 128 514 U] L) 3 I § K3 LU0 SLU PO 43 POPLIED 0 UoTOH eulLL BBy - Z SAfEUY ojeuBos oy oyt s i, ook g i e g YD a2 0 epum 0% o i = 3 SeR S W [ £ DA T A AT TG SRR SempmTRenm [ £ ot T g et e T ormes s L) v Sy 6968 o0c%eE s e | ooreeE 3 ooeees %5 L. ooTrs = e 5 i oorss s oorEss 5 T ooseEE oTEESE E=3 ey SRS SRR | PG IVOes T T iy angedireg RISRI0G POUOM 841 10 SORICY ERUREYIZ-190) eLIRLI 'Y BHURL TR AT g 200005 - HApE1LIS0 HHODY 10 WAL, 10 SYPOIY ORI IYT sroie 202 o D03 put NI 03 SR 93 9193 U P25 SUOUIE euls A9 SO PUE 500 301Ul SSUELP 0P 500 Sup U] SSELP 1ok 10 3170503 O A OU PRY SYRGHZ] G SYGRA-ST LIOW 914D IFLL] 4 ISR SYoa Z] 2 PRI o SURREd GIY 30 R 7 U0 U 90| 4 T 0 WS 81 15 LS oL 38 PRSETENR P R o e VR 2 AMAIFTY PO AEE-ace )l "(PAEN.IE OV PRPRYAUL 0} 4 L3 AR UL PUE SHYNKTD VT 4 feas T 13 P ‘e L3I} -G 413471 Y- 1 PSIAN{SAS 252 Ktm om PUE IR0y 2 P T-ONOI 30VI 5L a0 ). 10K M| PIM-ZT ¥ I QURPGIGY - € SISARUY opReuss opmuans WN3Y 34 U] PALELILIOD 2K qURREPEdN ‘GEwN|dNp 01 pazdWo) “PAENMEAS SIHEIDIR 3 S50008 KET OF $ikr AQ PosEaRP 002se 00 3 40 PIRPURES 13 BupydOe UGy LI Ion IRy STRO-950G Q) SN UOZLION L) U] IR WY SONEI SSRMININLR ~I903 [EUHURIIU| ‘PRURE DAAS S 1502 [ERRUR.OU RUT ‘PANEF ATYD J8d 1500 [EURULRIU| ‘Peulsl A] Jd 02 RILELIADU, 10 SR A L] B A LR UK S U 4 L et o ke 543 N o e smmn, am o porpumg 205 I G = T 3 SR B [ £ DA T A AT ] SRR SempTRB [ £ ot T g et e T ez s v e Sy ovort EL] s e | o 3 eiet %5 L. DT = o] 5 i L s e 5 S ST e E=3 ey SRS SRS | G IO es T T OUIEUR LTI} SR IRITIALT 84 10 SOV ERUMEYIZ-190) LRI ¥ SO P LT ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT v odsy 20z SN HIDUDI3 PUE [ERUID 10§ MR o A1R115 UERAIED 1 ] USERn SRURLR 2 B LI 2o ann e e 4§ P Lms LIPS A LR O LT A PAIEAL LB PO EASNIT 2659 8 0 AR FUORSIP) PANBLD SAURLONT ON TSR0 40 L) AR U L PR I OGE3RI/IE J0 PISPUNS 01 PaSduICD Uty U0 Ao UOMBUIAARO A {NYT:) 5610 ATSLILI [ 950 ST1 S5SNI 2500 RIS ey OB 341 ] 205 PUB SAAEION) 12 S5R.50 K- PISERLON SATVD “SL 6T 300 PIEPUEIS O 3504 10) KT A7 PRTISD K00 16101 "N5-9 WO FUBLEI S35E30] L S EIaUR . 1) OHEUS0S ASRIDIR UOELICD 34 U YR 353 D500 [0 PUE 500 3 “wZUrSREQ-THES 20N 255 24 2110 S0P oBeran 250U A0 o515 (SDLID B UOWIUED B) 0T UOTIRAUOU IO -I3AD 10 . 1103 200 351 o 11643 PILINSS 34 SUCRISEA 35124 L FFUSSUID Gl UORIPPE Ul SIPIIS PAUORLBAOR 30l O U ST ELR-151 IS S840 R € s RS 0 2 IR U PRUIDAR HIGEA0] DRSNS ERy @50 G AR o7 o B L) e T AL K | POSVERE 8.C/A1R € UE S0 U3 SBUNIF L 40 B0 B “{4T02) et muTng pu SONGHHD O ALEER ' O T4 4 0y € VALZI3 ‘BiVCO 30T Bupryau pesceste o snisniy 4 oRIguIED (S21) ISR P 38 o syaRed PO s B e Ao o] B ESP [AKoS TPIOISISOORICI OHI03 Ui AR DORRUIQUIDD - b SSARUY OpRURS a0 g 05 "o SRS 00 BN A wee [owmes [wewss g oo [wews o weo [eoenrs——oeurs e ot vermms oo o o wompx | b | "SR | i ey wamray 1230 rmgdng o erk [ YoM T3 10 0 $¥a SHUL S P LT ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT smoisg 202 e Huouca3 pue (@310 103 WA A B 83 S A B8 SR 14 8 BB 5 T VD B et A S BN 3 e oo 5 o * e ooy o myin | W e [coviers i T 7 e [aarovs () SRR o [ o] ses o i) e[y e F L T o ] ok o ‘opmumag e L UOREIDG M 04 K T WAL DR L3 %z L3 e L] ar = ] e T %z L] e L o G %z o e L] e ] L = wr e e o o e - o SR | SR | WA | o o L Ao ORI 10 TR £ TANRAAR 7 L5 GBI LETIIIELL £3815 peSH ey 7w L9 ML P LT ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT oviedsy 20z SN HIDUDI3 PUE [ERUID 10§ MR w00 patpus 08 T 3 o ) Sy som panawo i o pomson ety s w5 o T ) TR vong e |5 g agera T Hostere = sz e oy oogfoest oot > e | oogoces 3 oogoczs > L] oogeves = msovie > e o s oS > S oovent [T 3 ey WS SRR | PG IO SSs T T OuieuRg AdesnL O (RO 84 10 SOFIY ESURAEL Y3190 eLIBLI ¥ SO Scanario Analysis 5 — A portion of responding patients on Tralokinumab switch from q2w to gdw Ina double-biind, placabo+TCS controled phase il tril (ECTTRAS], patents who ochleved EASI 75 and/or lear oralmast clear skin ater 16 weeks of reatment with tralokinumab every two weeks pius TCS were abieto switch to dosing every four weels. A the cost of treatment would decrease. for thosa taking traokinumah theragy lus raquartly, we empioyed a scenario aralys to assess the potential impact of ths dosing schedula on cart effctivaness mtimuter. In ECZTRAS clincal trial, patients who achleved IGA score ot or 1 and/or a minimum of an EASIZS score ut the end ofthe 16-week trial period were rerandomized to receive an equal tralkinurmab dosa every & weeks {CW) or every 2 weeks (QZW). I this scenwro srais, we azsme no. cHffaramtal utrrimes betwmen the twe dosing arms n the model 2 tratmert respants ot woek 32 was comparable betwesn the two dosing arms (S2.5% maltained 2 minkmum EASIZS In the QW rial arm compared to 90.8% I the QAW trial amn). We assume Inthis soendrio analyes that SO% of atients achieving EASIZS or higher willawisch 10 Qe dosing;we make this assumption based en the mararfaciurer's analys of the cincal el data recagnizig ths 1 an estimte pending resl ‘warkd daa. Bacaina the clnical il Infarming the aralyes allowed petians 1o Laa concurrant TCS therapy, thesa rauits e anly comparable ta the scanario anakas of mbinaton therapy. The reaul for this scanaro, whure sl tients ahieving EASTTS ir highar aftar the sl 16-weak ‘tal pariod stch 2.2 QW deing reg/man, resulted I u 15% dacrazce In rug coet over u S-yuar ime hortzon anctan 85 decressa I tota costs. Versus Standar of cars trlckinumabs ICER decreased 20% to $115,000 per acklkional QALY gained, howerer the therapy was sl s effectve o ess sty than duplumab. There were no changes In cos effectiveness threshold categortation. Table E4.10. Eect o doding change on Traloldnumals costs T | ABmiwoaoRl | ¥ ekt Dot | putiems rw 703 | patarsseasa o s | itrace et S A ) T 0| T SRR S | v v G o | Gt o Bt | B W ot e very T e T, Bcme] e vy o e, St o CHIY In ek i e 16l o4l period an 1 dependent o thel resperme ot 15 weds ‘Binsituta for Cincal and Economic Review, 2021 Papa 147 IAKihibitors and Monocional Antibotle for the Trestment of Atopk: Dermatiis - Evidance Resport ‘Raturn to Table of Conterey ES. Prior Economic Models T result of the rass valdtion showetl that aur model results were simlar o other swalable atopicdermatis models. We Kentfed two publlshed economic evaluations of upllumab for treatment of moderate to severe atopic dermatts 3% No prior economic evaluatons of broctinb, barictink, upedactinl, or traokinumal were fournd. Researchers n the US developed 16-week decision tre fnked t 3 Markov model estimating a price range Inwhich duplumab plus emollients would be coradered cost-effectie compared to ‘emollients orfy (SOC) I adult patients with moierate o severs AD, using efficacy data form SOLO a4 Thelr analyas usad 1 IS peyer parspective over a Natima hortzan. Tha modl Induded twa healthstates, wth patinrts who achleved 2EAS| 75 Improvement afte 16-weak sl crtiudng o upilumab, and non-responders swftching to and remaining on SOC. Afber 4-monkh cycler, upilumab patlents could either convinue b respond ortranshion 10 SOC or . They appled ity velues change from baseline i the model, with 021 for patients on dupiumab, 0.03 for patients on SO, and 025 for hor esporders. They found that dupllumab produced 1.12 more: ‘GALV than SO {15.95 vx 14.53) and $32,069 adtianal nan-chaplumas g cost (§283,449 v $331,538). Although thair model did not ganersta an Incramantal cosb effactvenass i, the ‘OALYS and Heime non-dupikumab drug costs estimiates ars imilar 12 ours, Contazn and clengins astimated the st affectivaness of dupllumat plus SOCva SOC b the Ieaan adutt posulation with severs AD, using a 1-year dacrion troe followat by 3 Ifetime horzon Markoy model = Thlr analyss adopee the halian National Health Servics perspectve, with utity values o166 at beseline for both groups, .35 forduplkumab and 0.78 for SOC after week 16, and .78 for non-responder group. They found that dupllumab generated 2.42 more GALYs than SOC {16.95v2 14.57), with an Incrameta! ust-affactivaness rati of €33,263 par OALY eined. The Fesultsfrom thal analyses are not directy comgarais to tha resuis of the casteffectivanea ‘anatyis prosamtec n this report, e o ciffarant severty of disaasa I two popuiations. However, el Interesting o note that the iy vakues of duphumal used In thelrstudy are lghtly igher than salues used In our model, Wheress we used same utlly values t duplumab and SOG. ranging rom 08110 0.89 for esponders and 0.60 for nar-fespander. Inthe 2017 CER report, we estimated the cast effectiveness of dupikumab for moderate-to-severe. 4D compares to usual care aver a fetime hortzon fram a US hesfth system perspective 22 We found trat duplumal produced 1.93 more QALY than usal care (16.28 v2 14.37), with an Incrumuntal costffactivenitssratio of $1071,830 par CALY gained. The mudsl randta n this anatysl ‘ware similarta thprior ICER report. ‘Binsituta for Cincal and Economic Review, 2021 Pape 168 IAKihibitors and Monocional Antibotle for the Trestment of Atopk: Dermatiis - Evidence Resport ‘Raturn to Table of Conarey E. Potential Budget Impact: Supplemental Information Methods Ve usac ref from the same model employe forthe cost-effactiveness analyses 3 estiratn total potentia budget Impact. Pocential budget Impact was defined asthe total dferertial st of using each new therapy rather than relevant exlsting therapies [.e., usual care, dupikumab) for the. trested population, calulated s Afferentil health care costs Inchuding crug costs) ks any offsats i these costs from avarted heslth cara events. Al osts wars undscountad and estimatad aver ieyuar time hovtzors. The fve-year tinefrare wes af pimary Iterest, v the potarthl for cost affets t accrue over e and to llow 3 more realstc IMPAct on the number of patents treated with the now therapy. ‘This pocartal buge Fnpoct anakaia incudad the astiatad rurmbar of individalsIn the LS who woukd be elgihle for tredtmert. To estimate the sie of the potential candidats popukations for treatment, we used INputs from the US market leacing blologictherapy, duplkmab, across the following age categories 12-17 years olc; nd 18 and older) ™ We note that imftations exst in ning cast-affecthaness mocil Andings within the sdult popultion for estimating the potantlal budget Impact within youngar ages but canddar thoss imitetons to be outwelghed by a ‘comprehensive approach that incudes il llghis age catagorizs. For auuls (18 years and oider), ‘ettence susgests 1,675,000 US Individuals have moderate-to-severe uncartrolled dsedso and are ellghie or trestment % For adolescents {age 12-17), evidence suggests 329,000 US Indiiduals have moderate t-severe uncontrolled dlsease and are elgole fortrestment 2% For the purposes of this unalyas, we s.mmad scross the twa age catagories and assumed thet 20% ofthese putlents ‘wald Inftiate new trestmants In each ofthe five years, or 412,801 patenta par year. Consstent with the ICER Refererioe Ciz, we calulated the budget mpact of new trestments {abrockink, beritin, tralokiurnab, and upadaciin} given thesa trestmarts diplacament af chpllumab and usuel care. We autgrec n squal distriastisn of annually sflgbln ndividatlsfor each of the four trastments (abrocitinl, barichink, tralokdnumab, and upadachinb) = 412,800/ 4. 109,200 new Indvidualsper weatment per year [fo fve years). Per the ICER Refererios Case, we. assumed thatallthe dupiluma users switch over t each of the four new treatments Inthe otential budget Impact malyses. We assumed that appreximately 2.5% of those adalescents and ‘il aligikle I tha US are currrtly taking dupihmab (spprosimtety S1,600) besad on raports thart over 100,000 LS patiarts have starte dupikarab. = Thi assumptian recult n 1 10% ik af chpllumak ant SO i of il carm al0ne upan which mach new reatrment b avaluated. ‘Binsituta for Cincal and Economic Review, 2021 Papa 145 IAKirhibitors and Monocional Antibotles for the Trestment of &topk: Dermatitis - Evidance Rsport ‘Return to Table of Conarey ICER' methoct for estimating potantial budget Impart s desafbed n detal sewhare and have recently been updated 4 The Intent of ur revised approach t budgetary Impact s to document the percentage of paients that couid be trested at selected prices without rossig budget Impact threshold that s aigned with overall growthIn e US ecanomy. Using this approach to estimate patential budget Impact, we then compared our estimates toan upcated budget Impact threshold thetrepresents a potental rigger for polloy medranims to mprove uffordabilky, uch & chnges to pricing, payment,or patent elighiliy. Au described ' ICER's mathoch presetation (1ts://icar-raview.org/mathocioiogy/cars mathodylcaralve- ‘amasmmam-framework-2/, this thrashoie b Exsad o an undarking amumptan that heahth care ‘o5t should ot grow much fascr than growshInthe overall rational economy. From this foundional assumption, our potential budget Impact hreshald s derived using an estimate of (FoNth In US gross domestic procuct (GDF) +1%, the average number of new drug approsal by the FIOA over the most recent tao-year perlod, and the cortributon of spening on retal and fucty- basac drugs o total heath care spending. The five year annultzed potersial budgetImpect threshold that should trgger poloy actiors to Franga aczmss and sffordabilty s calculstad o total apprcadmataly SS18 millon per yaar for naw. dhugs far 20152020, Results Tale .1 flatrates the per-putient budget Impact resuits in more detal, or: @ Abrocitinb WAC ($45,500" per yaar, clarmunted WAC ($41,400° par year), and the pricas 0 reach $150,000, $100,000, amd $50,000 per GALY (541,800, $30,800, and $19,400 per ‘year, respectively compared to usual care; '+ Barichinlb WAC (529,000 per year,discourted WAC ($19,400 per year), and the prices t> reach $150,000, $100,000, e $50,000 per GALY (§33,300, £24,400, and $15,600 per yer, reapactivaly} campared to ususl care; Tralokinumals WAC {541,800"per yeur], cscoumted WAC (§31,100% per year), and the pices 10 reach $150,000, $100,000, and $50,000 per QALY ($35,000, 525,700, and $16,400 per Ve, respectivel compared to wsualcare and; « Upadactinl WA (554,300 per year), diacmuntad WAC (563,400 per yuar, and the pricesto reach $150,000, $100,000, and $50,000 par QALY {341,500, $30,400, and $19,300 par yaar, respectivaly} compared tousual care. ‘Binsituta for Cincal and Economic Review, 2021 Papa 150 IAKihibitors and Monoconal Antiboties for the Trestment of Atopk: Dermatiis - Evidance Report ‘Raturn to Table of Conarey * Bt on lacahckdarprics the wars ssumed for abrtinsand rkinumab. Intarprat ndings wih etin. ‘We nots that dupllumal b canadarad s part of uual care nd tharafors ot displeyed m 8- stancialane rusit. Tabla FL. Par-Patiert Buget mpect Calculatones Over 8 Fvs-paar Tima Hodzon s Rovl PP B e VA [ Dioured | FIOO0/OALY | SIOR00/OAY | Fe0A00/0ALY Waer T " T T g g T £ o £ T T ) Tshirba. | S50 s e s 0 st e e | T £ T T GALY:quatyad)arind T yar, WA Wb ¥ition coc * lcabolar picas wara st Hor abrockind and traobruenas, Intarpeet indings th caurkn, Figures F-1-£4 lustrate the cumulative per-patient buget Impoct caculatios for sbrociinb, barchink, trlokinuma, and upadactns umpured to umal care incliding 10% of ptients treutect with upilumab), ke on the e prices usad whtin the oet-affectvanest arabys. Wa suggast cartion I tarpeating the patenal idgstImpact of abracttini and traiakinumab e ta the placeholler annual et pices assumed. e observed the generaltrn of decreasing year over Vear per treated patient potenal budget mpacts due o redtment dscontinustion over time. Year 41 the cesteffectiveness model Induced an acditonal ol costcyele compared 1o the ather yars. Th same ysar 4 mathod was appiled across wvakistad trastments and for ususl care ancl tharefore, wa did nct amaoth over the yearbry-year cumlstive indings. ‘Binsituta for Cinkal and Economic Review, 2021 Paga 151 JAXnhiitors and Monodanl Anibaties for the Trestment of Atopkc Dermatits - Evidence Repart ‘Returm to Table of Contamty Figure F1, Gumylatio Nt G5t Por Patiart Trazted with Abrocitin for v Yasey at lacehoider $41400 per Your Pice® — o~ - = N i - = = . = a0 . * var1 verz ars Yeurs Yeurs Taceide e were v nepret Sl ks oo, Pigura FL. Cumulatton Nt Cast Pur Pasfat Trazte with arciia for Fiva Years st $18,400 par Year Price a2 JEEEEEE s o i || | H i i Yera Yt Yers ‘Binsituta for Cincal and Economic Review, 2021 Pape 152 IAKihibitors and Monocional Antibotles for the Trestment of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conterey Figure P, Gumylatio Nt G5t P Patiart Trazted with Teaokinureab for Five Years 2t Placeholder $31.100 per Yoar Prics® srosm saamo s i g s s am nam s S . ® Taceide e were v nepret Sl ks oo, Figura F&. Cumulation Nt €2 Par Pasfart Traatad with Lipacachind for Fvm Years 1 963,400 pervemrPrice ‘Binsituta for Cincal and Economic Review, 2021 Papa 153 IAKihibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatiis - Evidence Rsport ‘Raturn to Table of Conarey U0 30 URPL OT W Loy SIUSRIAT ~ AEULIBD ATOTY IO LRULEEL S I0) SNPORLTY [CUOIOUDYY Pt SIUINUI NVT e ooz o o3 put i oy gy w o [ ® | % [ w [ w [ w [ m [ m [ m [eum W o | ™ | % [ W | m | | m [ m | m [ewm W o | ® | | W | m | | m | m | m [ vem T o [ [ m | m [ w [ m | m | m [ o | m [ wo | m | w W m T w T wm | w | m 1 o e S = o = o = <1 W o [ o | [ w | m | m | = | = | m [ W o [ m | w [ w | m | wm | m [ = | m [ w i 5 = o [ W[ m [ w [ m ] m [ m | e o | | w | w | w | m | m | m | m | m | e oo | w | W | m | w | m | m | m | w | | o o [ w | W | m | w | m | m | m | m | | 5 = = = S e | S | it -3 m - s Do | v | e [ v | o | Rn | o | e | i | ety | s | ptema | "2 T | e [Py R S3[qEL SUSPIAT [EUCRIPPY D S P LT ‘oo R2u0g3 - AeL1Bq ACTY 40 URULERAL I 10 SAPOUFLIY [RUOOLDRY P UYL VT surodsy 207 SN HIDUDI3 PUE [ERUID 10§ MR et e e . o e e o e e i ot o o g e O O P e P 7 o R - w | m [ m [ w [ | o [ w [ = e o - W | wm | w | w | w e = = [ pocy. o L o - LY & o B e ot o pocy. o a o - L a o B el ov o = - m ] w [ w [ m [ m [ m [ m [ w [ - m | w [ w [ m | m [ m [ m| m | aw T - [ (m | m m [ m m | T = w | w [ w [ m [ m [ m [ m m | e Rpwedn = == — | e | e s s | b | s |, g | A | 0w | Dy | w0 | | evonmma | vt ( mmaap | (RS | ey | om W | mp | o | mw | S P L ‘oo R2U0g3 - ARLIBY NG 40 URULERAL I 10 SAPONFLIY [RUOIOUDRY P UL AVT P 202 e Huouca3 pue (@310 103 WA prrd ool | oy ((((((( e a0 s el PO oy o sond ohgdontecn | skl o e “wmiovoouars, | SR A wRoes vy e g Eapa Vigmrt | qunsen ey o oy | st 919V v Fondors | g ey U st w0 | VSR Bamop | s S e L T oot | R umecinangau | mER BRRIRT) | Cor qURpaY. Someusa TS g " s o [y s wor G Sonpmoniigun | sk e e | g s | oancs | s o | oz o PR g s, vdom b optyy [ crmampas apousolpms ot n amounpee | wapws | GnTeby| o opeopauty i | op o uihen ooq urumaul oy put st | ujuopenpe oIS ampioatp Rapn. etz v | o mopeypa g | o oo o g T eyt e g i e | 54 e pemama oumum oroupkp | vy umarenausis | sumaeen tupu s 0 ugadonie | AaTbaLa SoeigmaTy | S uGRDL Wkcen oGOt | 1A 0 R e soup o oxon gt aon Eapare i i g [ o | st ‘o v v | e oo | ot Uy LR e e e | 0 Ve S MmOy W | PR 0 AR e | msa| puswaa ‘Covite | % sveep e o et oz ampany. Tocwoedirs g s e P e s i spmnce | v orn Rampmonmym | 1.0 ] e ot por e | iy | askme v | oo vomrs PR G iz, Niowppotns [ magurua-oou | mepwors [ cuaspou wbas 0 jpms ot | wreem oo [ waowo | GRTEN| ad gt Oy WAt | Qb XA UMLRN o e e | ARG OO SV snugump B Sz | s mia | wnireang o Sy wa v s o el el B - seumeey oy 775 seL P R ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 15708y T2 MO HUIDUZHI PUE 1RAUID) 10§ SUNASUICH wimnd 10 Apedoinlecs. wabepe 15 et Hpras [ e R D Wodea “wpedoabooquiang. BI04 RALOW § UL¥A) Sung o/ emE s | ogeomnd + (- B R | A P | oA o0 | GO AP i evarmimn e | “cmanvigem i G| e | smdsman e | s s e | et s | Mo | amkses | T e tvoram | VAo | i | QcSi| | onmon i doups | oo | e pi it | M| AT | maSNND et | e smarprast | vt | mtiass ot e e | 1.5 v o v | o pmans | col egense | woma S 1D smneng s e s SR e o o i DBy B UORNSAP ‘sameyd 0 pecoinbecs e Rt Ny enpne o g i e e e e sy o v g sy mopeigon s - Wik s | son 25 v vy, e i g | S0 Ve Aoty w evvrane ey s | S e amescietmpo weqwpe | vosa| s e g, | g ot | kot e I o s or i, | pind | soep g | e reiema e " ioms | memon | oo 3P Aypeuncuge Axeiogey | Ok J0 W ARoq LN Aduinig jeydcn punasenq | uj UoRDEULPE | (s 7177 SeY aavr i o g | e e | gy | ity o Sen | nemd ] Wi s | e | B | S P L ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT P 202 e Huouca3 pue (@310 103 WA TOSRDE JSU | VSR B LR VIOTSOE e v e | il posd b oqirinda ey Ao Gy | [ PG A i ks museupieie | 30 Ky ks ey Aaneoat| o loweipg | )0 poled AR T 0 ek G ) | I o wnicess, | comampon AR IO | I FREAALD) e <08 Qumpa wes | mvaia A ot ekamApoq urupru 1 vt v e e | e o+ o mngs | ooz aasmve Py oy Toeveamy oxwen € 51 o o @ s oor) e Gt a) oD ey P Sor g oo 3 o GG ) Bucor) a0 o @ g auooiee g gy waus Greoma T g auamep +oqsr s o ) A e o0 s vt e e | Adari e pmy i Ay | Ferpusa e o gl D U AR | G GE B SR 0 s |+ fze ‘v ae m0n oo [ o uopmurg e ks pun | sen s s cpemp | e oy et | 5 A o ok | o8 B onmmypesotuy s | e b sam 00wy g v | O] manpinge womma iR oAy | owmeemyiste 0y | vores .o soseapes 3 oo oo | oy R RSP e ) Pz D Vopeunycp |y umnean o peane bt s e s e e el e ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR RSTRR CETeY o fmup s ey o paraqj 2 s s 20y (worsR S ] vty sopeypau ooencaasioas myiagpus iy s spmusp (oantsan oomma | a2 T oS coptypmay | i st e e wa | cymumpon mmopuyspoment | oretvemd et e [ porwpopom ogdmy | oz qwpagy | jomdep R R e | poq a0 ebeaied) | 0 TAARID] UOROIARRD) sa| ompean 10z e arascucramopen [ s porenpouncs | oo ety | srmgrsay | wewspos v e | e s s | s e pempRy oy st | ek s o pale oy | w0 mogpw praeum | 01 guonay S| aeiomu L 85 e Bakaer gy oo uzous Ryae Rugae o s 0 nado s g Jpras s Salnarb Hurp iz pruguce 8 pasT o demur oy Ragens s somaw, oy parupeeg. munocugy e (ot | ongo . mdum w agoo ‘g o | Bupui uraap o s wemaond 8} o ety roe sovie i Exmpga | 73 4 e gD v 0gyu°3) R o foesart 35 g e s sy | eopemmm | Caotned - B R R G ooy vley ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR ] s e sesagp S g g 1) v el S Sumecr o o s P i sy SR T S P e Ao st | At aas s asays bt e e | s s s | Ema e i | s o | np e s = rRam | oo | - sty | sumnsuonnomoees | “aemeva | v preityented et ] IR Ry R | SRR | IR et i T | r— ovise | amter e | 1y | oS T o] ok [POOON PYONS - - I - s . oty et tid e e | o | e | mween | 0 | P L ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT or vley 20z SN HIDUDI3 PUE [ERUID 10§ MR ] i Sappa o) gm0 0y ey o g s o v smponp Ameppssainauio gL oYy e ooy “Wasopus o “mag g g apsevap s ey e g0 PR O D) simwr o Ay e e e e o] sy | epeeam poen - oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT 20z SN HIDUDI3 PUE [ERUID 10§ MR o o s | A Esages wn oo D (pound PR CHGRN | o e s VTR0 0 uBULES gk | eio)pm 3 B o) oqnie . ogeppin | s o Suougeas wes tmer) st o | ngu e Ay g vy [y s e dpoapue mucpouou o) A a0 R L | g3 R BBEYDA e | 07 QR o Ry sato e | e S sautpcun | g eanR A BuSN | | oczuesus o warkmpeut i — W e o e s | e P v oz onpuos ups 00 | 2.0) HARLLED 2y Rt e | crequmpan e 0 0 Ao | o smsapous ik posoue « | uogious peambesjpepyis | 31 cyown A | i sax oy s g e wn wp by ey | emopeannm " - o etey oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT 20z SN HIDUDI3 PUE [ERUID 10§ MR [y Aduyg wmpes) vor sley oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT 20z SN HIDUDI3 PUE [ERUID 10§ MR ww i Lu>a'ea| e+t s orce “e=omnia ogeoeee v Suzauoue [ ovewmpon | usovammin pusontion | muyqunoinge | g smoy sy oo [ r—— S P LT oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT 20z SN HIDUDI3 PUE [ERUID 10§ MR e o e | oM VS 0 4ITE » won | vawa| wwne Sruspoipke g Rioamtyors g Q. anEow iy .0 forcuusagh i o) avacen | 1207 uoedurs ek o P e Suzaeegs | crmmmpon o u oD | 0 e Supr RpumuITTE WA | ey o o s esany | oy g ooy amees e "Dz 0oy i « | o mapou e Py « peucaron | o1 sy seop mg [ s e e s wp sy | eopemmm | Cateed - ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR Aduyg wmpes) TR R g 200005 - HApE1LIS0 HHODY 10 WAL, 10 SYPOIY ORI IYT o ot 202 e Huouca3 pue (@310 103 WA T o > e e o] sy | epeeam ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR oy s poees e | Sveass Bupeon.d mpuc Do | g ssopope (T s e oS | 4103 PO RO B Supre vopsspuupse | o dmia 0o g ‘ot eyt o 7w vy oy DoAY | VI WISKOF R L sav-zmna (manausagis | oy grzaon s aner poimoin | suwavan i o e P g gy o paaen | 1702 vomkus o U LoD | w1 e mpG W onaymn o AU E B0 | TSOSEVGOION] MVT TS uem| crauspou | anvarmn Mptoyacea oL . | v st o0 e peuuasy | Sz aupenrs | wimser ooy sy e e weun wp vy | epenam | o - TR 30 WL O U Loy SIUSRIAT ~ AEULIBD ATOTY J0 LRULEAL S I0) SNPORLTY [CUOIOUDYY PLe SIUIYUI NV or oltg 20z SN HIDUDI3 PUE [ERUID 10§ MR T e asyrun | rmmiranin e | oy of e i | 1 mtm oo |+ o nws an icpe e i | S i 5 g sosamonaios: | Gi| s | oor e P e oriinl o | M| | S e iog | g g | M oot | - Ehec| rempon S Al | mmou M AT | ot o | Sy @ege | Y BAET st L O o] cxaneerd o e s pascs [ oy et femrpad] e e o e | ey e i sy o e enrou | peueiona | g | o v et e it | e Sivi| e e | At v | e eoumaRroR | Rz | kv | syta o aniario| spsum i vaest | oo nL Sivio | vempen | “iovaren oot ot in, | _ st jortors | seopon o gty | muy aineunes | v ongst s o e oo =y Tom e s onam o ey somcssiont e “JAlopineu. oy e sl s Plaminliioral S Az s s e v v s i s | | B EUIE00) 30 URPL OT W Loy SIUSRIAT ~ AEULIBD ATOTY J0 LRULEAL S I0) SNPORLTY [CUOIOUDYY PLe SIUIYUI NV ourodvg T2 MO HUIDUZHI PUE 1RAUID) 10§ SUNASUICH gz [r s S| weouren oy | e | P T P LT oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT 2 st 202 e Huouca3 pue (@310 103 WA oh o g e micre aipqsimys p asunuprsis wom N o whpous,o mop wopeta ucog epsogtanoumoss | wmspiO. anunpee ey sovon {mem e} foomoympoiusia e wworse | supeeaiesce Povsdumans, “Sueazs o oy 7w | onomis TS oomraran e saineR AT BiseLe [ augee v Ao o sl s | st se i Ao SRR Gngr v | womns g e »an wepmuopinis | oMo Qv tpesRuost . T “wamponsi pacpamnz gt | egrsanzsgn wepsiasucoe s yoam v e | e e Sauruprsis o puopi s o e | o 1.0 i UL o/pR S e | RopEp e o vne o “opiuopus mcpdsany | s wsias e s g e et s o ‘Seppousnu o e wop | mpwang [ pomuner pumst yn weinseis | o ey waie Bupeotuces | oo emes | wpaceor oo o e | oA SRS auumpors [ Sawspou | dneogon, Ao o B, e it s 0| e esarey - o 0w o | oy v o e | Somjum ooy ponc | dep i otz A3 o0 ot e e compripeppen | e o | T wema L P R oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT zoeng 20z SN HIDUDI3 PUE [ERUID 10§ MR g ol ucor s vt ey oo wagmpem no amous o an gl tugoe oy sogtey wpmge [ mmsnppitye umopn mpaonp v e ac} toumpyspaunny s wwaie | aupesmaesme popedusugra s cn oy siou 71k | TRV oy e S L g A oot nquows |~ Sawvasm e o o omomds VoA o e g ye | s dpoq %a%e o ‘wprpopuucs | jousumauigye oemnucsy o0 Sy S S L rerpotu o wealazh wonenuopues | dgeogmu evnompn womslatucoe @ oem 1 o G [ wn comnena Feunpora s wpnpopuLI s oyt oan | i w00 Nepan. ZummeL s yp aussae | ogpau e supes | mouea| mwer vopuuopte oy o epsany | tppeiminma s o sy PR e ofpuR D @ usuodm Aomewna Spampo o) menbapaiy - mgwanp | ppreun oty s | o Axoay wnain spenrues| yomwames | uwedoer uepsapuopns oy o | s cym zpotnse mumpepne [ cmum | ancumen s Mdenped 109w B 0 oo it Ao 0| memnnpy “av.p mpoutep W punopcn | 0y vjo uRudeiGe | umjoum v o papncy | - dapumunens D 3w gy oL EYe Aty e pappasd ey oo | " sy S P L ‘oo R2U0R3 - ARLIB ST 40 URULERAL I 10 SAPOUFLIY [RUOOUORY PR UL AVT eceisg 202 e Huouca3 pue (@310 103 WA n + A oqnth [ [ iy e fomoyppcimana At iaiye | uopmmpn amnunoRs. s o vou e | e dap st sl ncan e Bt sy | 459 .2 g0 i D e et i s ) i BuNIA MR paioe | S amnuonse Cuonropun | oo aese ey v e v s e | e popodumnmns, otespom | Bausarsiemm e Imonems s quumnp g | €y 909 Kare At o P ot o o | o v e UeREop 0 10p0 RANZURUA | Eioppe g +WTD opme. sty dlymepoyn | ym sk su o o ot v v i s LU oA 1 WL imon wepela Bucoe o puopc oposan | oAy wasaie amniponse yumn insye prasm om0 g | Sne Sy EEORSe [y syt Stenupapreskdnazi iz et | e | emme aumets gy wminenis | 1 0 kst [ rean ‘o euncr o cpu) o3 g A9 UBG o wenump | oo s sogRampe 3 | o nes o) wpemuces | yemeans| Lo o Gy pirapes | o e et amnipons | eraamepou Ao e werve W e | wmeanry | mdoLan e | o e smpoun | dapumiaren Fyaza Aot g0 o e e | soumppesepenpuma | " waaveid e | msema B R R oy R2u0g3 - ARLIBY NG 40 URULERAL I 1 SAPONFLIY [RUOOURY PR UL VT vizolsg 202 e Huouca3 pue (@310 103 WA = wpeuion 1= o b ~ sy suopm mpsumgpis | pmcspupoas o6 qupmpedn« waaw e speos sy |ty . Tenguceauts o iy spe s | e b ks ortwea| e Sommmrempum e ncs | | mieoeios | ovmpmmnmanin | omas e b foramauynp [ | Ypras oy M oyemes| s g e o mmrbe Y53 YD 5YS 41 g i v | 1 gt « | cxmapouge Jonan epsummagy | pRELSA | eon e 0 yuse e s s gy S0 v | i | S e b i | o quaseren o anzinszan cpny o e e o« | wmpt v | an msvenpospegpinas | wervoan | e oo o woms b a5 0y g o Ao . cyal e |y 2z ungo s Syt | vy ¥ o pymnd ey« wrmasn aupg s oy cpowz MBI | et oy g v i [ U aq S ugorsg o ot ey | oy 1e Gespers: RS ks ofpuesBnp | €4 pRmAMLPE:Y e pouu ) | 34 ) e st yn g« [ quumpeen i i vopemipuaemp | s Ao, o 1356 GRS | 1 NIBMPUE SR « Aramup ou pame 34520 3¢ e pudouap. werio o aung i mp o fans« | Tyer-“Geet- GRET- nopiau | ey an n wremins | ey oo o s | 00 v e gt e euogeios | wurd sy o wo 0 oyt s 10 ogsehj i sp paascefins s | (Hpoumd:umunma wmtuccs s i prorp snny ram gz« | o sy « sumonco | arunpprny s | “ammg B R R G ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT P 202 e Huouca3 pue (@310 103 WA o uramp xiom o oot o sTaepen . mamainve Duem e e+ xdom iy mi W~ suopm mpsung pics | pmuspeonl sanmy s supcsos ymasys |t SoLsomm AW o uenm e s | 12 s szl el [ 100 | szgveshus e uR e e | AR st = Too vy |t | avemer | cmem g e U | Y58 VD5V oo | nmpou Aoty s soucs v | g pneiion | nee m oy | o e | Tty | s i wpucorp kim0 v+ | o uwen o gy [ oo wneoba e+ | mpou mev e oo | o waumy STy Hoom i E nsay oo sppmucnogenn | s pphas ot mumommcn« nuar oy iy b g | St T—— o2 oo ot o im0 Kima umsts usew | ewn Rgpymeseapurs e nzos | mpuppie | oveysiomamrn | ommi o2 s oo apminp | e | o s m e | e mersopen e iy s | s’y et o v | 55 e« | omap i3 o udrumenn v | i G | e YL e | sty it s upucoop oy o e« | | om tmesca | ‘ueaarin r i | o qugpepein« anainsaan ot s e o« | anspou gy | an smepwps et | grvoem. seaw| " wama ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR VRS A | e | i VAl | TR P ‘i g g | ooz “manpons | sammopa ‘Supniou ov oy medemgopumstacs | v e VSR mempooon | -zpomd) o 30 D O et e wnvadl | geovomoenen | segTiem g upergapcoudcp [ paognpanse | o oo i v R e nean o ety [ opemaimnn | supo pus (yurempesn e o w s e oo | cyeampos | uny o} SRRV o Pumvaw ‘encurasou o ximymsa vopdomeid wapmse | ayjoeusnn s | seqmpmei ( uoiea | oz Tl Ky rpte s 501 | s e3A T | opeApsu ML) o Ageununy v wcan e iym weunsaiye | ‘usuia o | seovepe popue | SEapriesine avaces | pusian {aunclypus oo | pus stomsueg o | o omspouign | ooz s 310 3upnpu) o D e e euompE e | oy poplpun paspn - poums) wdapruiapon | suopmpyuom wppmdns | o anppeedn | ussdsraraty | mumnn 1o ol s vy | cupussp e | tpuo v puumina | gvvoom 25 | et e opki e o] ke mts o rptpns [t o s g g | sy vomursipoa rumma sppes o Mg |ty sy i e st ybus | e ucksom ing ) 2 e s e i st ppon 10| A e eary e B S RAARDR Suogo o | BT G PP g0 AR oo g g oot ()i weammeng o oy pnp g | pdomuman zuw | ‘wosatn s ayu PR i | o mempou e e domaen | e | oL e ] ayemes | Aopumin 8 o e o o snipuap oo [ guompw | s wovt Py g m ey av| e | oEumm—" san o | Too¢ vy o e s e mg | w3 s twy | pmremy ] wan w0 o o o sy caaneoo opaseunpnm | purgs cuey mrnpney | zmeq e | “amamg P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT azoteg TR D U 12U iy QUG i roudahap £ i, umjoum gty way avappein o o Jones o o sp o omanq “ov)aempnit e i e perder woum = o nwioes Poges ) uppau e atoup) s . Fopicy | v g o i smama | o g | <2 aumppeine - wweciens | ooz pur e o ueces 40 sk S Al sweeapail upom i S | 55 quppeRine 3 0o O am auncai et | ot B | s ol oo oot hur o1 wooc e | e oudimd | eadn e swamcuno | s ansprprine vt o o e o | ) ey ot peogs wey g ovagtootu ot et i) | peusmumooge | proasepanseacyh | o suoarse TR AT oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT P 202 e Huouca3 pue (@310 103 WA e 1 yun wEy w1 YU e AR ademg mpumaE oraca, o s ot 40 sy pun I o o pamapuoog a0 g e gy g e e s ey 1020 WM oG B0 WELAY i oy 19 ey TP opaddreoumusiy ouaga/pezyang 1o ey porsacine o uncary « ouraa itia Jpras Bunp sampesau e suoeapu ot pue oq o0 | {22 ommeys PRl e o e pradpEe 10 R« g A Mo oz wn mpen p ooy oqen aypesan o cpw y e cyatp S im0y md sy 2o o o et [ uermsnsurn | ammpo gen [ ceavowmvpm [ st | dmesadu 10 U iU LT Y ot o Bur o | - ooe Uy 1o ey oy g v« | e ey, warnice [ zrates | ouiese aypecmaygn | o s | smomRnempouninuu [ /s poc ez ey xccae y ddeswpond sostnup | enbmpeu e | gy umwepres | desmpouou o ‘oo ppcuiounuuayesnddrsounus | s ¢ vorispmusap | pussompisoag e | eungeng opmusap g [ e oaren, cpazane | grows s oo n oy [ mpmespou | g s aivem | -mpmempou | avum g rup waehmo e e« | Wepuwia | prowsemmed | paima | seoueiew | e g S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT e DD o Ty s i it s pox oo e e oo /pn s angasop pun oo | fpeencce o0 R g ez e KoY ol e | s | panaga cavommon | scppaen [ aaesem rapiso | pun sprepeaznd | o seungeng amamaiEa pumomnte [ farporos Japmocums | s drppouonu [ oo | e wasioe ity eimiauiroes | iduspou wocans s evmmpmns | perp | e[ e P popr aaue| 2o g sioppes e e | coampou | vz towsaun| swposiez| puawesomed| pmawe| o] s TR SR oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT o otea 202 e Huouca3 pue (@310 103 WA T | BORSEE 0 BumE) | prp mympn o e | e peean, »| qungha - ] wivr s 1o o3 0s) e | exveuom Tvaipemge | ipramp o | i | 005 o8 P 0105 App g wow woymumgnd | AING Wndpo Amupd ionpe | a5 quINp | o7 oo A vrvz| pemuee [ “o0sov 1 20 Ao 08 p k20 . oty | orpaarhorac cuoney | pamuopunssu wzym| g TR g oe 20 yypwam o ormmakrrum [ wminmou 4o ey pedens 1o wrte pogiy Tpooaspeq Yon g e o e ausina | geaioas e | 4y Bupmit 0 Tanpe SQumake e oy . ave peas o [ pons o s ‘v Sumese | 10 waos 5va wore | Shumaen ) aemune e fpoaun o o vy wpsae | peayes v | paue o mung bapus A eon wauma o s | - spevalan | i My ovag e oy e 7 | e | s e e e (epsnona) o o g ominets | o V19 o sxlop ‘v duumpciona | i umima ‘Serppououml VDR KRR 'kl U opacn [ supoas e ‘s g g | 10 st g w pepom s ot pasms s o) s | vopenmy | smpurours priiea |+ oqwae RS S saanbagm e wsunran | o rapsae 0% amurgene Ao 0 e g Bpnp siean ~aaepq savppiet [ o0 o it oo o | g | ez s e | o e s pun s o ke | A | niopopwuhe apem | umener o (ominonimt dioae | praimdrooge | S pre asa | w10z K AN o YA Supsocs oo i s s e | ampqumt 210 s 1] mamunp vonmpmaorse o oy s ot s jimemd ampmmiomoo | oo geurgee | arkor wanes | peomowo wa | (ovimpmum [ mgomod mogrurpeut ‘o | cvmempous | vtz P qungorg sy ey wopreppige | ysmaomone | o somemymppopar | mypmryping | sawocmsigrz| g T PR oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT oo 202 e Huouca3 pue (@310 103 WA T i mwo oy awspopr Souypenn B sy o6 wos iyl “qeunypnpueg wassaery oD | Supo up o, im0 fouan prmarin foaoreq wytempona e 5T ke toxiopr pssancu gy | 0.0 wwE-u ol tppauyses 0 7 aons (v | o it 0o copsens opun s | s apmrminbu | g wu) oy ey v wodmpio e [ yhmesu weesppenvem | ssede dpeppouounuiay | oot angina ‘unean yerassaniouniuu | gy ] Mo wymcyo | us oy usurmn | yhmbu e o [ aunsh pommme | o i ooy kowogeo [ a pejonu sl gty | el e gt onprpains spmneope | sowam ppeuommiy | pawemu | smpamaea| avweie sy o yps g cpmmyuvn | st g | sppume s owapge | oz gmmnring oaus sovup Bupenpoucuruns | 3esg e [ Suurewoo smcurerou | tyw i moom oo [ vum 1o wpmmtdnsoununuspumsts | zpeoeumise | 1osueurmmou ophosa |z imee S srazpeut A R o | g | o | sy oy ) g sy e g e e | e[ gz im0 Syt ooy | paatinp umt \orincwonpem | e sk | mmampons e v quungig cnimamavopm | mmpsbd e | wepvovm et | wsunena | e spopest | giom o gz owsanmgny T Tt oqon mas n| eygar TR R oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT anoi 202 o D03 put NI 03 SR ORI MU LA S BTAIS B 5L AN LMD [ L ORI AL O8I ' L3 RSIUOURI L3 e 30 AL A ‘e 1 NPT S O 0BT A U0 AL U 0 SRR 504 PRI O R0 T s 0 ORENE) U ORAOHTYsaH 110, VAN WS BRI .0 SH ‘PRLIOORL30 Y BRI N T AL SH U I3 U SO A "ML "2 Y D A3 AR A AL 2 L 1 SR ShLY T WSO 24100 LA A ] VLIS U L VAN ANSEEOUTLALY LB D RS 03] PSS S LI P 00 A S Y DO 10 IS 1 U 20y A 958 " e LD YA T BN A Y ] P spuzancie S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ewrodsy 20z SN HIDUDI3 PUE [ERUID 10§ MR v % v 5 i W T S| Tes | &v | 6% | & s W BN | 067 | w007 oue | ohawa v = o [ vo [m | @ o [ = v | swowomy e s ss|me|sw |ws| zm | o | w [ |ves|ow | 555 | uoor cugy | SHEINT v v | |we | v | e v | e [ @ (@ o T | | ew |t || v | o e o [t T [ ne | Srwmin % [ w v [ m | o e [ouwmlwlm o T | Sucrow| D o [ow e | oo | em [owmvwlon €| o | Sucoroumy v o v [ w | w | vn ywlolmla vis T o & |om| B | e m | T [ o [ons | e g ey | o ampn v [ oo | w | e | o | o [ow|ow| = o | mocouy s o || w [a] w | |0 |mm]vw|w @ | oo v & [ve | 5| o | o | ow o |ow] w - o o e e | | & e [ e[ = v oo || e | [t o m = [ Somon . e s | e || o | o | [w | | Sicorowv| o % [ w o em [ [ [ewla w o o= T wholwlw Vo | oy " wl e Yo e [w [mwlw v | SR | o\ e W T Tw o Twle o = e & Tew v [ w[F ] & [ [ N -y uny Lpmg. [T [ G . P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT e odsg a5z MO HUOUDS PUE VIO 104 QIR a;:. aaz n. o [ [ o [ o [ = [ = [ [ | oo [ompon | = | rwere] 22 A Twe | = i [ | | it [ @ [ & ] | % [ [ 7 | sivou] e - [ [w [ m (= o [wm =] ™| ] o - o [ [ [ m == = =[] =T s [ e e Sl n T n | el atoalal & | ra ot s W ® [ ® 3 W | ® o ® 5 A Tazowe oo a5 w e w ool a | u{ar| o svmm S e e o & e le e a e Tor = o [ [ | [ [ [ e =] o | ] ] e =15 = = e | w (= e s T w e e e | % | LA ] [ " ® o [ w | o = = Tutn| (T o = Tes e fram 7 | & Tw N ™ e o[ w w8 e | & e T = e p ot e e Tar|w vl o = & e fmralel | = Ta - o = o |ow[ =] va [ o= [ ] swwcom o - E| vt | [ | | vm | v e | swooromw | ummporn o aremy o = e m| = = [ = - T T T [ i i v | uepemp ameng “u- - el by S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT surodsy 20z SN HIDUDI3 PUE [ERUID 10§ MR o] @ [ ] on | = | o o] | | v [ C]— w [ w || | | s ||| | w | sewen o [ o || om | o | o | o | | | e || emven) et sw |so | e | e L wm w0 e | ond o [ | [ o] o [ v o w | 2= | e = v CIEAFEARE = ez o o | 2 [ o [m | w = = e [ | [ [ ] | v [ | W] amame o= w | o | o 5w [ w o] ]| on | ow [w o T ) | | | 7 || | | | | | = w | o [ o || e [ 2B one ) |y Lo oo [ oo o | [ [ | ] w | e T Tem [ v | | 2 [ 22, [ o e o | m ]| = | o ampen | ™ | rusunn ¥ W [ o [ o | o | oo | 0| | i S P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ot odey 20z SN HIDUDI3 PUE [ERUID 10§ MR D u |m|w = = L] . w || % | e on 5 B || n|m I o ® |w|w o | | tows = [m|u|m vz ) LT = = vz o | om | o sworwn - e s w | |vm|w| o | o sven| 2 s |w|m|w| va [sw |0 s "= ™ ® [ w| v | ew [ w o o [ow o | o | ew [wee | Sown| | v v | v | ew [ we | uomim =an = ver oW o) Saey | T[] sworvan e s o [ co| oo | g | 5o [ o8| Lougrem]| oo aw w ||| | ST | e v | mweom zan e [ [vis [ oo [ S0 | o [m| mworwn e oo [ [ows [ [ 05 | o [sz| sumwn [ [ w s & [ LY - gy | M| | e P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT e a5z MO HUOUDS PUE VIO 104 QIR dnothqns UL oy g mpuodEANSU eI VA2 T, U VAN KIVT U 2§ TOHOM VT, TN L5 URAPeC ] GRITUDDI VILL SO I3 1 e s fets e ... et el el e e = e el ] = n] = || o B 2 =2 TR e[l [ o[ [w]a B w o] e 2 L= e mE e e - -l v o o 2z || o |ampe| 2| | ® T g fwopen | | sauoneana - e w2 = | BT | oo amen| | | | P g [mpen | %[ caugosina| A e [ e [ P ] e e = | T W] W | g [ame| O || )6 ey [ompen | % | suooeana T et T ST R e e o[ = s = g meg venrmp ween - - —_ S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT o s o mapas st WD o g = [ w [ [va [ [ o [ o [ | & [Swww " s [ v = o W e W W | e | en | Ve | tm | u | ko] gaane B v e w | v | ve | ew | e | o | Seonromy] oawmaw Voo o e | e e | rw | ow | o |Suowow] i o gor o - 7z 9er ¥ [C3 65 | SO0t Oue | ONALGIaYT & e | e | e | v | | e e | = P S 7 O I LT S B - I S v e | es | v | | e | | e [Suowow T w e e [ ew ww |w w ous snswor [osumon [ oy [t | eream | mpon |ovosun | oo | 2 | 1= . w [ BB m [ | o | wm | w | e e = T B [ [ w | w | = [ m | w [pelm v = | @ | m | % 0w & T e e e | [ w | W = e [ e e e | = [wwen 5 W v v | e | e | de | rw | e | o[ Suchrowy] -owowsar W e e e e [ w | w w [ u oud S O O O O 7 T v oo [ vm e [ ew T ew e o [ron] omat v e ow e [ e | e | a ou o L T R B ) Passeua vea X o . » = e S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT et 202 e Huouca3 pue (@310 103 WA o n o [ m|m|m| = | m | m | 5 |suoome| wes i w« W e [ e e | w | ww e ) [T o ¥ [ e e S PR ‘oo R0UaR3 - ALIBY ATy 40 URULERAL I 10 SAPONFLIY [RUOOURY P UYL AVT oSt odey 207 O AUIDUDIS PUE [ERUID 10§ RAIY w w W T W ] I} e W[ o A = TeE | e | ous | o0& | T | % SOSLINON| ELAMPM | gy | ownn | veenen | wmoom | cremoson | wemye | BB | MOKRWLL ppn o Gl | g0 | oum | i& | & | RO | ELIMNN | oy | owan | ovenen | ompow | crozam | www | T o - T vE T =0 PR | SR | sy | g | ™ awpwn | % | pupom ras | swe | 208 T EE T = = = e sovaia | wpwn g +hazove smow | cvmen | TR S ] e o " o | g gt =0 3 . m | ow | o | | e S| oemne v w | w | o | o | e = W | e | = | @ | wieom = ve | m [ T [ on | tucww| swvamm 3 wn | we | w o | Pacewa 7 W " | v @ o | P s Ve wa | o | w | sw = I3 oai T oz v | wa | e | ew | tw | v | em | v | mews| ATV ™ w v | w [ ww | w Tn w [ w | mvaw ] w w w | ® | vw | = £ s | = Twve i w w m | & | w | w m | | R w w m | e | mwm | = o | w o8 w ™ w [ [ [ = o [ w | Wavaw w w a ® | | w m % [ e | wirww w w W w [ ew | o [ w | harw]| Y™ w w w C L 5 w | e ) . T R ‘oo R0UaR3 - ALIBY ATy 40 URULERAL I 10 SAPONFLIY [RUOOURY P UYL AVT 61 vleg 207 O AUIDUDIS PUE [ERUID 10§ RAIY W i & S W s o[ wumva] O 7] e 7 0] e v oad W W 3 Taige vin o W o W W 00% A ine. a0 - = = + 8w 06 vin S ae - »n - +Sw T vin ) Ve o | oivow = o | ocevar T a3 il sz FUEVAN | 4 suncvan i = W i e w St sV T v [ en | m 7 o s S SE T A& T | Tm - CEEAEA R R AI E e E - Siin T om | rwe | ow | rE | T FRATIUN | BN | grpormn | e | mezaen | uwpow | suzwrao | s = " - ain T m | ree | aw | oe e SRSTIUN | OB | gysa | opwn | voeatn | vmpow | ovvwpany | anpe | S| o) ewims - Tiin 1 on | mie [ am i TESTLUN | CRIMEN | yos e | o | ooeagn | wmpow | g | wmpw | S o o [tw |t [ en o e | | woww] awaw s [ sw [ o | w [ ew | ® ] 'reazs T o oo oW AP | OTEUD! | WMPSN | A\WET DN | MABW - 0 0e vl Tz e | = g | oten | mpons | oo | s R PR ‘oo R0UaR3 - ALIBY ATy 40 URULERAL I 10 SAPONFLIY [RUOOURY P UYL AVT ot odng Tz oy HUIDUDES PUE AU 104 SIAIY g1 Y8, OIS UMY 1y a8 mpUOCEAIIOU QLI TVAHO) 0V, VIS TUVAACD VTP TP T-ONON S0V1, T2 R0 7 URPRPESN ) TRLINRILY VL THRAISCFCD 3 S WORmp. PS5 4m U1 Abla 40 ‘YeR 0 44K EFGAM OW3 AL 2D 5 0 ‘PRUOORL U "Bl Y HLIRAI R VoS3 LU0 41 W oY S AT YD) UL A A A9 58 LA YA ULBPCAR Y e w [ w | |mn || m | w9 ] e w [ w [ [m [ x [ [ o [ w0 | eS| mwe i B w [ w [ [ [ v [ | = w0 ™ e e e w [ w [ [va [ ¢ [ o [ & [ = [ & [ o228 w [ v (w [(wm [ [ o & [ 7 [ * [aa oo | M « | a [ v ] & | o % | % | % | uat® = W w w1 = = Tl et oo SRUTIVO | VLN | rosoy | owan | -seatn | wmeow | sreamn | wmran | | vmuoneana I B B TR sowoen SRETIUN | LN | oy | e | svamn | omeow | o Frzaw | wewan » +BugnEdna | OvaugEn T e e e mepe B = TRUEIUN | TLUAN | gocry | gy | ciovami | ompow | & rrzwmn | s - Ao e [ | o o 7 COSEIVON| TLMEN | yucamy | wowwn | oveaen | owoom | rprzaen | awew | | mooruna - e et (o acm i Sasnnl AP | ersamn | v | osen | o | crowzwm | sesew - B 008 40 A o et (e arm SRS, NP | gusaor | wpan | overuor | wwpw | vz | wwmew i -~ e e 7 LTI | LLIMBN | pycoy | mpan | ceeuor | wwpon | oz | wmw | T | muoveina I un LOSEEUN | SLIMBN | cocnry | ampann | yieuol | wwpow | stz ol | apew b B 00% 4N sl S e i Sen e s SISTIWN | LN | oy | ampann | vl | wwpow | ovrreae | pew i o S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT estodsy 20z SN HIDUDI3 PUE [ERUID 10§ MR = e e o oo | W] v o i [ | vurwa e e wJofor £ o = ™ W Em[w o = o o[ oc | o | Seoea v w oo e | D] v o oo [ |t T ® I £ e w w W | "G o o s. || o] P w W [ | = | saseromy N ™ w = o i = W om0 o v v oa | on | Suwomv| zowm w & Voo [ e | Waaan] ~ v 5 lolu £ v w o | e | oo = = o | | o] TN T 5 va Twlu ] —— @ [ o [ o [ e [ W[ & [ we [w] ] I oo o] o v e P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT o1 o 202 e Huouca3 pue (@310 103 WA vz e T o | T w w W oo | e | W™ ona | T w w ™ ™ ™ an W [ w [ o T ; T 7 agryp | THEER[ W o W | oo | ey | W[ S8 | MWL pyum 4 ; T s agrap | TR W w W | argwor | oepen | W[ o oy d " i = | SO [ ™ w [emamw | B Tele] ,ume] o L " oor | e | S| w w [osacm | J0 el e a2 a0 oo " Tor 7 . e ogram |TEEN] W m ™ | omoovun | nean | W] %[ suvom = 9 v w w w o w (wm ], - o v e w w w w o a [ecfen] a, | smne S 3 ™ W ™ 3 S |t [en| wivom o w w w w w o s || swrww| W st o ™ ™ ™ ® G o[ wueww sav w w ™ ™ ™ z O I I LT [ oy % ™ W ™ T & |oe [ or ot Y s var w w w s vu | [ [ swraw | BT e & ™ ™ ™ v v @] wowew s w w W ™ o v o] urew| v w5 @ ™ W ™ S | e | warew| wme ] w ™ w ™ [ wm on @ e ® ] W W ] oo | o " | el B LG 00y SOUPRAT ~ RIS AONY IO URNLLESAL S0 10 SPOURY 1RUOFIOUORY P SIS XY e o mapas st D o g i - 7T w7 s [ w [ w [ w [omenm | i [m]m] s | veeomay [owmen | w | w | w | owavem | 2%, |wm|m | i [, W W & Ta w | ez i tumtan S . O w | = RO v W W oW e oo o o W ol | oo 5 N W & 3 W | T sTvan £a anden v W W o Tw e ] w W e W | 1 " W W o T | ] g = P T N I 5w 5] s [T I o T T (7 I ) = i RPN w ™ w L L] w5 | oos o agem M- T - e = woozan | TP w w w @ OET ampep | O | ST owpoevy | FYHEH T - T " i [ W | W | W | i | o || e = ; ™ w [ w [ wm | w]| = v | o] e W W W T w W = wow o] T w W W e W o T | e vir . o movam |OWRR| W w W | moman | ey |W[e] Mowes e e e W] e e W oo ] = < T B R R o1 vley ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR B0y O YUY ) DI L RIS 1 1 O 010 s 2 s 00 e 0 AL A 20 0 O P U preae 1 o s s s g 04 L1 WA 2 s s 1 ST a1 ‘A UG MBS SOV T2 oy ) i ) ety g ) i ALY YT ) OFPY AR BAGR EUFSEREL sgee oN 5 w [ M ] ow ] o | m2]0] ™ v T o [ v [ v v o o (o] et é | e W e [ w [ v [ = [ 5 5] ea® T T = w [ [ [ w [w ] o [ [w|e] T w [ [ v (o n | (%] seer™| | s [ wn [w ] w [ = T [ sa® T T e w ™ w RagAD | prmpan | 6rs | ere oL, i sowe = o e w w W | RO | mpen ||| ougpeuna| aumen W | | o e [ | s S T w m M| mpoaen | e | €] ) sucoean R o Ll w M| mooan | smen ] sugoean| 2O0F o W W [ [meeenm] 20 [m[m] o T 5 R G P s e = . T P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 280884 20z SN HIDUDI3 PUE [ERUID 10§ MR .._.._....ssq!.,.a i:a. — T 0 T 0 A e e s et e e e e B S e W e wa o i . O ettt - wmpmedn ST E WSTR[ e ey ||| vz S Ta T w e v | || v | e o o e - e e e = ws o o [ o [ | || | o e e T B T = e e oo o o] . O - o A = ToTaTs ot wtw = S R B | [ | % | [ el DRSASIRIEL) Sosg 3D AL T R R G st odeg ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR psopm el 2L o O i 09 1300 e i ) i Ak AZ A ) e O P Y “epurn i 4 U B o a8 207 ol e 43 TRLEYER 41 LNV LR Y L LGl U 0207 AP ATy 8 v P ONELTH £ VHLZYS 2 VHLZTE L VLTSS PO AP UG 1 ey STv-TITNG ZVSTIE TV SO W8P0 91 PP ‘NS SCHT THVAMAGE ST DL VT T GO XIVT 8 FEOAS S SRS SYOT 50 WD w | w [w] o [e ] v [ar ey W w [ W [ w | v [ e | % [wwobeomama| i W w [ w [ w | w [ vz | w [mosiemam]| OOV W w [ w [ w [ w [ = [w o agos | om xu W W fw ] g | e [ | soLemuonedna sonouD owm | sm mo wolow W | e [ T | esuonana [ OYAUEN THw | T w [ w [ w | o [Fa] | = SLeom Torm | w | w [ w [ w [FER]LE | e | s e | w | w [ w [ [FER] [ = [aosimcina]| 2o Tarn |7 w [ w [ w [ [FR]Z = on win | o ww [ w | o [FEe] 2= | sk Trm | W w [ w [ w [ w [EZR] 2| = [mesntama @ [ | o | wew | o | wes oty gy " wuy [ ounspeg e Py oy S P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT s ot 202 e Huouca3 pue (@310 103 WA w w w w o % w w [ o8 w W ) ™ T | [ e | [ws| Suoewr zeum w o aw w I I I A 3 o5 ™ o ) w ™ w | ve | we [e| Suoewr ™ o ] ™ 3 3 o e 2] e T w W ] w0 & aw W setuvav w W o " % oot W [oor| situgnve] covemme [} o w [} o wr W @i wieow e To | m | sm ar w ™ W @ o o | m | s = a w we || Woeana sv | wn | om m ] ™ sz [oz| Bwcorawav| swwamcoo s & e ) a w w o[ Sucorone 3¢ o ves @ a ™ e oo v | w | w 3 ) w e[ ) v ® o e ] w o] wowow] o o = = ) w = || Seomonw w = = > ) w w w ona ™ ™ = = ) w v || Seowony o e w & w ™ T[] Seommev]| vowowaaw & W w v w ™ « = ona o * 0 = v = v v comols | muenenclapente; | spracsaspes ey . | M| oty ) i AL MUOAALY ISR SRR LTS EL B R R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ooz séey oz Oy HuIDUDSS P [ENUID 10} SIAIY wowe | Gawse [ ee V& 3 ™ = L £ o ] ™5 = o o = wow [ rwame| % w o = v oo wou | ewemEs | e v o = o Buomounv| ronon el = ] w = o 3 Trw oo o ot o | % * " N sy gy Vo gy 5en s inopaxt uo o e 0N TR OV AL 0T A a0 244 SN T o e PO VI I T RLARLHOMS ST B o OV O SN S o i LY 0T L S0 i s e T T T T I R [ ) w W | w [ w W [ 6 | w [w[oiwwwn war w o T W m e [l ivou S " W e | e | w [ o a - w | wm | | o | o | w o] el tum (T T I 3 I 3 “Anodqrs | w [ w w0 | w | ew | e | w | w e meoww| s ST s T v % v % | wonmeteins | s | oain o | —— T P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR Toue £ & T L] TEags e w T St | covzaan eraw 5 w W oo TRas o 3 ] v L) Vi 3 3 iz smacs ™ = o Suitove | sazsne W L3 = 3 e TEarE] W o = " oY ~ o e W e 3 v STV | 0 T Tomg | 3 T = o | e Sorco wara| ™= w [ = s = sz omvece: werk| w oy w | s s oy swarm| 1w ™ oez ™ - o s W ] = 3 W 3 Gaa| NS e Twan T e w o S ToraTe Vor o | = L VEas 5% et = W L) ) V= @ [3 T o e o & & % ooz oev Geacs 3 @ 5 = Waoromv| wausa ) T 3 = = o8 Tmas o ] = = LT oxe x _. . p .5 st VT P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT oz odsa 20z SN HIDUDI3 PUE [ERUID 10§ MR e 3 ® = Bl ) % ® o Sirou| M= VRO0T % o o Buogevil | anasens. ] o ™ & ™ ou | Tvus: vaare = i o W o ] o w z 3 | T2 ThRwTy e o = ™ LT ] Tz 0 W = | vz o o o w v 3 v w %o m ¥ 3 v e ] - ) o v o W W 7o T £3 v W W o= o = & w ) 7 wor o 3 e w v [ = £ ™ w o o = 3 w w e o * Bt @ | wean e e i3 = v oxa * " . e Ve S P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT etz odey a5z MO HUOUDS PUE VIO 104 QIR L AN & = e OB ot eemeer| % ® ™ ST DL | oy ) o) ) w 3 % BL-08 w w w = @ & ¥t o w w w = ™ 3 mticEaa| zows w w w v w e oo w w w = o = oo - w w = = v o SacoEaw w w w o = v 1 - ] 0 W W o o = W Wroevan [ w w W o & o Tagvan ) W w 3 W T W ] ST oz W W = o = W Wioewin| -umme w w i o 3 @ Riswn| e w w e ™ ~ o Sazzvan w w - o O o oad a— GwaT] v = = o 3 SR rarz| ww o o o o eimvan| avay ) o W or = o Sivom w w = L o e Fapevan P w w o wa o S Togvan| 4 w w v o W e o w w = 3 3 3 aoEvan W W W i o i Wstvan 1n w w ® i z i3 oat| mnsan Srw e BUEE) 30 UL 0 W Loy SIUSRIAT ~ FAEULIBD ATOTY J0 LRULESL S I0) SNPORLTY [CUOIOUDYY PLt SIUINUI NV ez ot et W AU U 1ERUID 40§ SR o T & Vo B W T raw i3 o | e | Woweowv] e o FarE L} o e | e | o] = - £ o | = o e | va T e e o o[ 0| | Suomaw| wausar £ = £ F ] oud e | twerw o & | || o | Swomaw oo ywate o e | | o] o ) i £ v u v u th s Tweew i | | S - i oo | W] vowon i - 3 T a T+ ] = o — T T v T = = B oW LSV SUONG RO MRS 6T OHRL rossgne g oy, ISR PTHP “Uad URPRE Y TN VAL OISR A S A1 5 LD 1 G TR N A0 Y e 22 04 20 ) "W 00 S 100 Y AN o G 0 g oy i 1. 0 A AR U Y S DU S SEESH A PRI o U LS Vom0 | voeave | o6t i ® W ® OO R Woe | reava| o W o W TR | stozpe oot ezEwsyE| o9 W w = ® RGN | S o) o] ) T ® T ® L) S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT stz odey a5z MO HUOUDS PUE VIO 104 QIR w w T [ m W o [ e ] v ot S ] e i SR w ru T Lt v w o o4 Siw w w v Sutw w ) iy S| sovamna ] l = i FeaE 3 T S remrn o vt St Fann o T S| o ] 5 o e s_ 3 S Tenen i T e & T T w ] W e o 3 " e w e W o T W [ [ e ( = 7 w o T = e e ] e e~ o srieon w mam - o [ [ m ] o [ % W | vwars o v |m | o m | omeon it = e | ewesa = w | @ || m | ooven v = ] E e e i o P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sz odey a5z MO HUOUDS PUE VIO 104 QIR o w w W 2 B aevan oo w 0 L] 2 BoeTvn | goog kmeen om0 w ) % o [ a [ Tuvrvan| wmam = w ] o w e [ w o] W T 00 w o 3 we | oe [ LT = - = Tm | we o [ me Taroeeana o W w z G | e | tee | Bi-mievin 0o W ) 5 @ [ e | wr | mowmwn| v = w W (3 we | e | v L0 ot w w « ™ | o | m Wogyan o oo w w 5 o e Bustvan| o £ w ™ o | e | wx 2] oo w ] o w | | = Sagivan o) w w0 3 w | a | w Sustvan T £ w ] W ™ e [ m oa| s o yormre T | wi | o | sivsucoev ) a o 3 o] M [ VR as @z [ | o Sucoevar | e = = B nlw | zvums ) FRevE e | %t | GRE Vel = ] e [ w | we oeg] T 0% Tom T | oo | we irooe Vil = o] W = | & e s TR mro w s ™ s |« | w | ovmupme| omme o P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT n veey a5z MO HUOUDS PUE VIO 104 QIR s Loy i, SRR PSP L2050 % RN YA TNUHORS VAL APl N 531 9208235 0 S 1 P 00 Ao D e o 12D e 250 D R O AR 1 T P i a5 s s ey 5 Geungeg 1SN 40 A R 1) PSR SV Ul s = - i > = = e e R o> = w0 o wmen] e e - - el o vore | wonce B n o [ | ™ [ : S0 e vore | emarn - o o | | o ] e = = e - - - e || W - 5 = e - o - 5 = . = - = e B - B e . W w - 0 vz o 3 £O%s, === S > w = N T o w = e e s —wwu = - = I = . P L ‘oo R2U0g3 - AeLIB ACTY 40 URULERAL 0 10 SAPONFLIY [RUOIOUORY P LU VT etz odey 207 SN HIDUDI3 PUE [ERUID 10§ MR W wm [Ew s w] @ [m e s [ w] & ] 2] T o w [ m [ m|m] m | m | w ] om ]| m | m | m | Caeeane Tz w | ow | |ew|mm| ow | ow | w || m || e | onveons oo | suancy Bawr| gy wo [ ow || w e oW | w | w ||| o | omveos ooy ovev W | w [wen|wmw| W] w [wles|wm|u|wm o84 T W W (o[ e [w[ W w (W] e w] w | oo W [ o | e o [ w [ va [ e [ u | w | Svonow| smaw W W [wte wo|w | w [wte| w|e % ) oo | T8 | vee [ cue | s || m | oworver | v | s | s | 1 | s | meowou = zonom oo | % vor | e | | e | wi | vweizie | oov | ver | s | oor | e | muoowev| s | o @ s Z ] w | w [m e a e w o w | B | = = =] ™ |oween || x| = | oo w | 2 [en| @ | & | w |room| = & | = o | Muomaw| voson o W | o [w v wlv[w] w [wm|= |[wlala ] T oy o = o oy | owes uon | w | W | u [T owe fwe| x| N | W P o ssa & ey o wma i a8 PUE 05 5V HRU0NND K3 WINL-UING OTTH HIeL S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT etz odey 20z SN HIDUDI3 PUE [ERUID 10§ MR a = o 0w w Wt w e S w | w e [ e w | w @ oo [ w6 W] s S sovamom w | w [afw e e | w [ e w ] @] o e e e e || e | oo toror | | [ooe | e | o6 [ | voncr | | v | an | 15 | x| urow w | 5 [ [ [ [ = [oweow| | oo | o | & | 0 | wwnon| sovmmm w | [w [ ]| w [ || om | @ | oea oro | 5% [ oo [owt | | || w0 o | om | m | = | m o | & (v m |w | wo| w || |m| %] = T o |3 [wi | m|t | m | w o] m @] = w [ [ m]s @] w || a|m| =™ | | | [ [ | [ ow e [ w e wo | w v [ ow e e [wow| w[ww| v [ a]m o | o | o [ [ e | w | e | e i w | A | v (o e [ot[mlm | w e or [ w e o ———~ w [ 8 [nu o o =] w [0, [ ox][w [ =] o | mowow] = e atae - oL e | e | v || ow £y vE | o | W | ® " ooy Ovey | QI wer it 5 - = IR E R way o n % gy ma e S P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT orz st 202 e Huouca3 pue (@310 103 WA v = e | 3, [ow [ [ [ [ ] [ [ o [ [ o] & | mem o o oo | S [vwe [ [om [ [ | o | v [on [ | o | | o o | 30 (o [ [ o | w W | ow [ | e | seow o ||| [ [ | | e e | e | o oo || | o [y oo | | e e o | o | W] gl S| e [ [ am [ [ a e £ Voo ||| o e o v | | e e e | e | S o || e T o || e [ [ o | S| o S || o e |l o T i v o i o Vi [ o [ | 8 [so | amsovsws | om | vee | ot | o i - e w e E Erery . . o [ ow | om [or s | rmervee | o | o | s | v | S wwlew (e w s ] sor [ v | e | 8 v v | v | ow | o | ot S o I O T N A T ) Sone T oo [ [w [ [ [on] w Jrm] w5 ] % ] e mme e e o | w [vo|ow @ [ [mn] w w8 5] 8 | sl e war - a1 et | oven [ 28| o [0 ] e |5 x| W |« oo W o % Apey wa e P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT zoiea 202 o D03 put NI 03 SR ¥ o o m avarm| w | x| o | e | oore suaa o |0 [ | ok, [omsosm | v | 0 |ow [ @ | o avisgen W (= m [ [ & o [w| w ez | w | w | w| 6 e |m| e w | w || e |ez|w|w | w |w| o |m| m| m L W w W w o] wm | w [w|w [wm| & w w | m |w| @ |m|w|m | m |w| v |m ., m W m | w x| m|m| w | m | w| e |m|m | om o W w w7 wma]w | W w] e [w =] w We | w W] & [ [w[we 5T [ o [ wwwm b | w [ [ o [w e F S I Y | w e v w ][] w s [ w ] oot o, e | W W [ [ & [ [we T e [ 5 [ W] e ore || w |t | [ e ® o [ & | awwan] e o0 | wC [ v | e [ [ v [tore ™ [ [ & | men 5 | w o] o [wolm v s [ w o5 Tar | e[ we [ 5o [ woe [ [ oo | wmmar [ [ e [ e [ | v | Bwwrwn] S | W | | soe [ v [en| am [wmaes| W | ve | we [ we | we | Mmeana = - w v | oxss | % | W T one fwes| x| | n an w X | e v e ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR = [T TEweT Fogor oy = w o] ® ) n rws [ vw [ w [ =] % oea] "R ) n e e | @ | Foow oy 7 e ] Toy [ |1 | v FUGEORY | _opom = W s w e w ) 7] W T [ or | w [ W TR oY = [ w o] = | e Fuogr oy 3 = n T [w|w| « oaa | -owom N mpa o ypa - owe | ows olig| % |wejimn| %[N . [C T T S ooty cess SR 104 42 SN NN AR ULLAI0MS TTTE BAL weuns v, R 76 PGB V) QRO VAL PRSI0 S I TR TN K 0 R O LI 2D oo 0 0 0905011590 30 IHANY 300 SN ‘R 0 Y I ) 1T ) AL 1 eS0TI N0 BRI 440 A BOURDRD ) PR TV PRV "ML 8 00 3T U BN 10 LA 0 153 PN 05 5V 10 Ep uLm s T o o] w Juw[em] s [alg.] & [w[u]ala] o | wpe T o woow | w [ [ww| (@ gp| W (W] % [ 5] P | sunmere| soee | e wow | w | [ s [w (o] w [w s v e w | e oave | w | W | e[ ¢ am | w W] * [ v e w W0 084 o6 = & ond | owss |wwn| % [ W | [T omes fwey| x| W |« ay wa wa N -l s L1 e S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sz olea 207 SN HIDUDI3 PUE [ERUID 10§ MR o W w W e [ Tz v % ™ ] 3 e Savuve] savazne ] ™ ] 3 i L T G o 3 wov | vermse | vor a0t £ 0 & ot = ] = = W Toroe o o = e w oo - wn 3 ] ] = =% | o W] wwave [ % wle] w Foszony = m wrmvi | v w = w oot oy w = = wlal = oo g arae veizo | vemer | e% W [ [ o orgog o> | reax | R i PO WY woos | ewzmse | 6o o [ @ [ o FuQr oY, W W W W% 2w ) awvany o w W w & [w [ Sioos g w w w [ | e Suozany w w w = [ | e Taooramy w ™ w w = [ wm oud | sovaser | o= v o TaaEony o wwad | PN | oy L I - s oo oo mmvsi P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT vicosag Vo e s ot 3D 5y RIS o [ e [ o [ wiw | e [ || a [ oower o | vmaes | e | vim | e v e [a [ on [ omow] e 5 omwen o | ves | tw & Tl w Sivous o | v | ve | e | rwvi | ow T [ w Totever Tore | veswon | s | s | wwena [ ow Twr [ av | ar W] el R ] Torr | Taew | tor | e | | o0 T [ [ T v | savarnts | ew | v | e | vor e [ wr | o T . || e s e T | Gar] anarevan e v T | | e o Vo o e o | e £ o = o o | W | & T L8 SWiDa, T T T T e S| T S e T [ - Tale =] T T | e | e | won = T o T A o o o 6 o2 | er i 08d. e oo | Gmr | [ oovs v o [ L - - o e & i G v ST e w . T TS w W sow | e e s w | evom | rran N Sou| e Tt o | e e | e | | e o i | rem o | ow [ | | e | oubirina] sovmme £ = vim e | e | e e Sioar ™ sy sopnd . oy s o waysap | % n 2 N -y A T R LA S 0 . S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT stzoto 202 e Huouca3 pue (@310 103 WA W W] ey [ oo [ 1] RO A = = W W [ ve ness W ] W W W s [ wvRe W ] Wooud : % mo [ vware | @ | wom | | w [ww | @ | ool : - | o o | team | & | wom | e | @ @ ® | 9 | pomnd| o = = s e | W e E reoad w | vim v | & e | e | e | sk C3 i e e | W e | wehiwar| o w e i | = w e T w W [ awwere] 3 v e | e W W ST = T o T ) o Tt T ST T oai e e W W FTE T “nne 000> W W z o Tugvan g o W W T S T e i W [ W T T =W % oo T anmad S - n; '—oy iaq - K N -y A Trames s wmumnoe B R R orzedey ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR e vy YR RN PO, “oBur 10, U 2 A ) N VL PR3 |G L AL RIS 5 U awap LA 15 SRl YR 4 19 1 14 e I A2 A 0D oRoa] A U5 990 40 PRGN ISR LN U " " 1 WIS 93 GGG 410 YRR 1 AV KXY P VB O CARTY w _... W | o= [swwe [ an [w | ] 5 [ mwuccaa ou qpow owad | PWS e P | weguemn | %W u - oo o st Ll s TR ST oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT zete 202 e Huouca3 pue (@310 103 WA o W W[ aenes = w ] o Fooomy P E = won W W | Goraveioas Tor w | w 008 oMY it = [ W | ewwasnes @ w | = o T i CRIEOaT w w w [ eseaserons w e | 2 | et " ST GV O | w w w | covmwes s w w [ = Ao P 5 w w | smanwans w m [ wm [T cRuooouy | L W W W_| omarenws W - | oal poies W W Ve W] oS dna W w s e | Tuoeowmy W W Ve w e arcor o | .z w CI) W oar W ™ TEvw w | % L W w sorwm % | % Sugoromv| wausvr W w e wm % | % oal o0 [ T = | e oo - o000 o (o] N BT OV | ooy = e w | w ] e sEve T | e ooz Ry W F | reace D% Iz on | e o0 oY * £ Care D% TEEve % | @ 06| -oMoN3avT ) o o o - owe | e = g s | W - o o QWIS HRIOOHND N3 WAL QIR TTT 8L, ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR i3 = T W = | S £ = 3 W e Dieom| M i W - W Baowvas | dnodns £ w o W w oar| Touz: i GEd o W e v =0 GEd v W T oar| TYMZH i o= T W v =0 T oo W] oar| Twum Vo e e T S%-vm % [ w ETEL T ey we w53 e e & | & QurRuzuyE| omme = = emve & | o Diros| N e T TEVE W | s w0 T® sw e & | wr | su-mizw| vz = am v ve & | e Sirou L S Ve & e Tivieve L 7 Ve o e Tizieve o s 7oz e o e v " T o ver v W W ] e s T W e Tavieve w0 s S W e Tacive 00 s e w | Tative| vavazme = T S N ona To— i - ot wmd | oxm [ = [r——— .. v S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT szete 202 e Huouca3 pue (@310 103 WA o e | o 5 T 5 | somreant®s] wwees = 30 a0 TS 5 i) N O8d e - k) - - " 531 + WU OOF 4N 0 e w | w | | )| Gn T == e " w | e | e T | wweime| oo T = ] = " = | s " i |t [ w = o = ond Fome W W = T o T T " o & Tatriar W w s 2 oai 020z o 7 T 53 % T s U0 [ - 53 % 2 i ep v i wore W W == T wErn W W s & oui T T T T TS e T T v | rerroseer | e[ sar s | | TV et i s e o T Tr e | vo | et b s T TO® | Sz 0ree | O | CorRcer DS i3 o ™= YTETvan | 3 e e e - ] aranevn = Ll ] ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR wlow | w w o | sz | sz | fucozomy wvanm wlow | w w cown |z | x| woomos| T aaw wlow [ ow w rewn | o | o ot Wl w | w ™ W % | emmoew CAL ] ™ W | e | Puooromv| st w W W ™ W = ot e 5| | o | s o | = | muoozowmy o [ w | conee | F5T o | w | mucorowe| aw Telve V[ W [veare | o @ w ] o [ w | srmes | s o | v | suoszom o | w |roner | - wr | wr | swoowy| romow an o wm | = = @ | u o T i S ] - -— om T o |0 | o | D] = s | W aury - s e et a0 PUI 10 HOOAND KRNI WIBL-UIOS FTTD WAL “haSgrs Y (O, HILp B0 “GURHPe A LIS L PS50 I 1 LD RS 5 AP PP 05 ERM 1104 AL Y0 RS 0l A 120 A 4102200542 040 SR St 4y s s S oy ST WA B GRUNRITG N B DA 10000 A0 1 ATV oY T S P Y T "X TG I AR 0 5 YOS 0 09 L S e _| SR avsy | 0% Grs T ® | ® | Aomioind oo | ety | vie TrE T ¥ | % | meosuesia BEE) 30 UL 0 W Loy SIUSRIAT ~ FAEULIBD ATOTY J0 LRULESL S I0) SNPORLTY [CUOIOUDYY PLt SIUINUI NV Tzz odng T[22 ‘Mo HUIOUDD3 PUR |EUIE) J03 MUY w [ [ [sear ] v | nw [rown | 8| o0 | omel] k0 W[ B o 90E | SN | & | eor Oiroad| oM W T s [Erar ] W |6 | & e [ wow A TN - 1 W W W w W o Tw[ar £ W Tw e s e T | e e[ | W w W | 000 ” or N (3 o | & Bz ve v T T e e w W T ar W T W | w T e Tl ae | W | o | | e W we | w v | e | m | emew]| T T £ e = o w | ow | oo | ow | e [ ow ] e ] oo etuanina T e o w| ow [ e w | ow | w 5 Loz | s | ooy oo | -m Gl dus Soor w e e wfow | [ [ e || e | ieoms % 101 ouaY = Wl w [ w w[w ] m | W | | o o W] w [ w [ w | w [ [sewn o] o | suamem o T - e T BT e ]« B[]0 ] o |2 e ] > P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT e T a2y SIS [_toks w T w T w T w 3 ] gl w W = ] W W 3 Tagevan W i e W W W = ] ansvan w| w w | wow o = | = = mumet] sz W w | w Wl | | we | W w e s T Tw e Trrmer T var ] v T T T wee T Samevar e Wl w T w Twlw T o T T+ Twlw o] "tz W T w Twlwe wan] & T ws T w Twlw wwwr, Wl w T w Twlw o T w T » Twle oar W w T w Twlmo war] = T ws T w Twlwwww Wl w T wwlm] = [ w [ ws ¢ Twle oar] vz v o Wl w [ [w[ow] w [ w | o [ o [#] %] ] m= L W w e w[w | w [ w | @ [ o (8] 8| g e w . w W | w W o e o | e ueom| " , = w | w | o w [ [ cwer | v | ovm [eron | e | | g o T o ™ om0 [ e [ @ [T | W o - - n - = o ] S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ezzotng a5z MO HUOUDS PUE VIO 104 QIR o e o i e ot s s o e o e e v i A i e i Wl om | w 5 | 5 | aal™ s W | w [w 0 | | ) o eara | "0 W w | w [w W [ w | En L T w ] w | w [w e | o o WL sowown w w w w “ 05 B 00% ¢ | QY ALEN wl w | W |w o | | sueom W w | w [w = | % | S W w [ W [w @ [ | ] W e w o= a w w | w |w = | @ | ™ wl W | v || T T - et el — . - d p " mury s s S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT vezosng o mapas st D o g o | T o Tl v - s s & sl ot o o s e S| ovaman F - _.. o el e £ Fiy o~ o w | - - oo | wm |m| o | eeiee St cnveont w | w w | smarmow | @ || m e : oo o w | - W | ormronnm | e |m| m o cwvecRd [ [ - TENET DN = | e ond | AHBEDAANT; - W W rearmnm | mw W] W S w | w w m Jo] Suoe v T ) | S o I ] oo [ w ] n our e | ey | wvavom | a S W remre | trea o | reowemus | o] w S cury] zonowan P T Srareows [ u w o rvane || ewrnom | o[ on S W roar |t | seoowoms | r | on St o - w W BTN DN e u « ona| FONOWIT o w— wed | omx | oumaua = e e fwme | s - i i N0 SRINNG KW LURLAIONS VT TD AL S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT swzoiea 202 o D03 put NI 03 SR e | W w T m o] w Sacevan e | ™ Ve m o & Sumvin| ol = ™ Vi s o] w oai| are - i ww | veass o o o] w [ swemoew| ] wo | E) e | FEae & | Tumeva - wo = w| w | T e | Tean = v | w e = o wo v |m m o T ——— W [ W 0] e [w] w ST o = | W ™ v [al o Sotizav| umes = w 0] o] w Svom| v T | zemer ] W[ wr Sty oy | romow @ = e e otz | savammn = o w v o] o Srvou e | erac w Vi Tl o Sz w | vreer n v T | an Tavio] sovzne W i T o ] e [ i o | e Ty e [ i » | w Tz - i e ] Taywe] E] i = W oar ot | ow = uayanrg | W | bem > g EUIE0E) 30 URPL OT W Loy SIUSRIAT ~ FAEULIBD ATOTY J0 LRULESL S I0) SNPORLTY [CUOIOUDYY PLt SIUINUI NV s otea 120 Moy i put D 0 I Py Ty PN 1 A 25 oy e s s 5 e 1 e A 902 s O U S At UM e 4 i 2 e oy A1 4T Y Sy ] AR L) G SRR U Vo U8 Y UV UV e 51 74 SOV 1 G ) e 1 0 A A T ] 7 N - ] s rean Tal w | amtmi] o | ] s over || o [ aiee - " e el w oo ] v TN o ] w o [anmibiir| D I v £ e ] w R w & & wmmma] oo w w0 = ] w : & e w : Vo[ - [} [ o8 ows o vt | oan | oamim o ummt v s a ] e oot - W W = | o o w w@ | w P o ana [ w oo an x T | v | mmlweana| o w v | v 71 o W W T |t [ wlowoew] w w o | e wema| M o W W W | we e | w ww | o5 w w ™| W oo Vel w ww AN oRa | Tvuma vomee o ™ m oL Suym Teare v w | e Stz | v = - | Sivoe| T sourr o w | ow Suoce cury rous o . e | e | w Suoct oy | Tosow -agr i - W voure| vowe | u | w ond T Y s pxn [ ommnm | @ | mn [ W], - o s [ ——— B R R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT szt Vosc o i3 pu R oy s W[ o i3 T LT W o i3 | e Soroiey] T W ) oo e S| T T vareo FeRe L o] rowe o Tratr o e S| cowm T W vearim e e aow T —— Wi | o | owusswa | « T v ions oomss | W — o ra = e o ST SVH PTG R WL ONS TFTD AL e e [ w | w [ msoioeam e | | % | momoem| o 2 o e | 5| B | mmbiozaa) 0l on | v W08 = " o | O | suemiooednd | somowo ) av ial o | | suemuocana| jumen = | e Sueom [ CAR WP 008 e | s | mmbimcan | L] wayhmsy " £ s S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ez oteg TR D U 12U iy QUG W W W W] W 00E 4 W W W W] PRwedT| 20005 ™ W w | C2) a ] ] I o ar ™ w ) | w PR R ] w w | aw | O W] ey [y e LT o] amer T AN ETLT] v ) = ] o Tivou| mne W W W AN oot eV W W W T & WoTowev] o W W W T % eg | ueumroon W W w IR oo a0 a w ] e | o it oV ] w w Trore | oot cuav ] w w voren | wr R awvanca o ] rraeT v Ve B ana | rear T v | it v | veare v T | S o w an ] Voo | on n w ] vewe v ot ovav ] W W] v moT bW T | % RooToveV | N s ) W W] Srm DS Ve | % oRd s | bwn | owueame ® D | W - — LT o S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT vezolna Vot ot Huiouct Put 1B 10} G W[ w | W [ mawow] e ] i Siwo w VoRT T TrnsTORE | e W W] s ™ Trwer L T T T w vousr ™ Foasromm | srem | v | Sumowy = = = e | _srwm | wm o ™ ™ Tarcow | rrem 03 e [ Sumo ™ ™ vemsTonm | vowm = = [ umow| s ™ ™ TN | v - £l e ™ TomET w [wrnreme v CANLT T 3 o T romerom | o [ e | Swowow| o0 Ty = = STaTv o ™ w ) e FomEr S [rrneow | v | | wowowr =0 vomer T [eonrrmes | vewe [ m | wmmowr]| cown Ty = = viavowE | v | w 1 e T L e | owe | cuwea | o 2 [vweweees] W] — v e SaVH donm: ot UOPPSIINC SIYH AN Y UL NS £TTE MR £ 100 AP T AP NPT S S e 0 Ko ) B ) A 2 s 0 el A g i ey s v i sy AP ) Yo B s P 2o VIS o THTVIN g o i s 0 e oy ™ ™ vom o = PR o ar oy ™ ™ vom o » WD o0Eana | srepeiL 000 W ] VorE T | m WM zaNG| e o) W ] vorE Vo | L) wad | D | omusau ® D w5 | N - o~ T o o TR AT oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT ez s 202 e Huouca3 pue (@310 103 WA o o S0 IS 35 U0 Aap RS 105 WA HENAI10} URAD T e R A A0 AR 3000 D e 004 e 20 "IN RO N R B U S 1 4] SRR 10 ‘ZURIP UK RS URPHRS ) TRRARS VG RPN UV *SONOKHO QO LI PR 7 G1OS PR T 10S QY LA 207 ek URISINg 2084 1) $PE2H QY N JUMSYEI i TSVAN e VL2 LTS VALY 8507 ARV 126 S TR 7 233 U 4 SPEAA o 3m 0ORAA0 STH O R WA : : o o w ™ vom 8] wety ; ; i v w w om T 9| s sveena i " L v w w o 5] ) W W % voR Woond i) —— o owE T © = o | B ou Toas i3 & = o | o] S = = & = o | vond w T} T} [ e w 7} 7} & [ mwon| ow ) 73 73 = | o w T} T} e | o w T} T} S [ wwrow w T} T} oSO T~ i3 ST L e T P P R ‘oo R2U0g3 - AeLIB ACTY 40 URULERAL 0 10 SAPONFLIY [RUOIOUORY P LU VT zez odog 20 Moy HUIDUCD3 PUE [RUID 10§ SINATUIH o W W W Jam] & [m it savamne o W W LA L) — W W W Ew [ w " Tarw — savmng W W e lw]wlw T T o W W [@m[E] & [ & o a T T Soney] s = W w w_[ea[m] o [ LT W w W eulw] & [ w T T W W m[m] & W T w W W [vejw| ® [ w SicoT v npEodmmmON] K w W [vs[w] v | =w S| ot N w ™ D & ] Suootovay | NG Ty oo W W em[or] = | = S v W w W elm| w = oo W L LI T N — i e st PR SELIOGARY YDA 90BN AU L O BT M08 S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sezota otz oy uvucsa ut e 0y iy W W W Ts = T W w W 3 OuehiErvn| LA W w W T v Cacma| wam W W W T [w] o [ o [ Gomsramumem W W W [rv[m] e [ m [wemeammw] awms w- s w [vaare | w [valw] w [ @ | oo R T w [wnra | w [vw|w| w | % | msmees| o s w [vwmca | w [refw] w | B | o AT B o | T = , M [emam] W | W oL mroMiosev | w0 w W w vl w | @ - ot var | TV wor [ ewerr | tw [mie[ = [ & T oo [evemve | e fem|w| & | w Lror = m W (wlm| W = w0 [owara | s e[ w| W [ % oSG wo rwarm| s lnlw| w | ® W | = = = [vala] s v T o SRR Co W W W e[ w [ m i -~ W W W [ew[m] = [ Tt vea| D [osrmima| % [H] b v ™ ity P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ez odey 20z SN HIDUDI3 PUE [ERUID 10§ MR W | Twern = ) W] &= [ & L B AT wi| & | v Suvon = = = sonown avauamn &% w W ) ™ o w [ w w w ) w W w W W o T TV eSuoEvan o van e usrvan Tagzvnedusran e wineotd oSBTV CedeRusTvan GuiePagIvan R o LEEEIRE W W w w w W w W n w ) ™ " w [ w Tasevneuorvan T 53 van e st van Turzvanedusrvn aoE vane v caiESuOEvan CedeRuzTvan oRaeRuEzvan CRaeDid W W W w W w W w w w wed | bwes | oeiueuu | % ] o vaneRuorvan T sTvaneausvan TurzvaneRusrvn RoE van¢ 0w GeieSuotwn oy gy S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sezodey 20z SN HIDUDI3 PUE [ERUID 10§ MR BEIE) 30 UL 0 W Loy SIUSRIAT ~ FAEULIBD ATOTY J0 LRULESL S I0) SNPORLTY [CUOIOUDYY PLt SIUINUI NV o€z oy et W AU U 1ERUID 40§ SR W W W w ] W [ HT — savamnn W W W mw % [ " wrwn L W W W wmw]w [w LT = savamnn W W W [wmw o [w] LTI o o W W w (e @ [w]e SO W w w ra| = |ww Tuorony| zdmakys oo T W W W ] = [ w oY W w W e = [w [w aoonY Tmpodmmcnd iy yoom. W W W %] wm [w]m TG W W ew]| e [ w Tumromy e T N N ™ o 3 o | w i o0z oy spanasans aiaLa T W w e & o = TamonY umpmden) oy mom W W W m] W = [= TRy w | w W ow| e [wes Fiorwony B " - o it | O% |umuua | ¥ | ¥ " y g wen et S IR KUE WL T 6T HOEL P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ecoing o5 ape st D oy g o e w— T I T T T ooy o - o T T TR e e R w [ . re L] oo | T 0400 55 Y] D Bl 00% VAL anNuma o W [rsmsT w % [ W e {sswpuodsed v 1) .1+ MO B 005 YL N T e T w [romrn| w [es| w [w][= e s T W W W W [wlw = T | o we | ] o [vware] w [we| w [ale Ty oo v | oo || W i oz = | s | v o e £ oo (e | i e | & T w R oo [vwmie | ow| s | w W P = - E 5 3 o &= o8d B [Prpod wmnaorn) Y oM S [ w [ w T [ w [wlwm e e W W [ w v [ = [ ] Sz W o ] o e | *] [t w . iy o ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR 3 S psvanehu o6 ¥ W cvanePusivan WiszvneRusIvn ook vancoud 7% Guehiosvan DRacFuTTvan CweRITzva als|8|a|-|a|a|a] OB com B pevane e van WwnerTva BuszvneSussvan Tucevancou GRaehus Y achuTIvan afaafalala[o[=| [a]g alaz|al«|=| s wfanfal«|d|n| SmieSuTLvan OBicou RV £ oG VA€ GV o v 5 v BvrvaneBwscvan Bu0EWINC08d Gachucvan omerIsTva o[ 5| [ | =] 1| | RacSuTLvan ) = [o[g5(2]e|2 - =-.=s=--~i = |ofa|n|af|d]|n oy iy EUIE00) 30 URPL OT W Loy SIUSRIAT ~ FAEULIBD ATOTY J0 LRULESL S I0) SNPORLTY [CUOIOUDYY PLt SIUINUI NV secotog 120 Moy i put D 0 I (RN R P, s MU L 5 AP YA RO YL SIS w 3 w " 3 I w SR o0E o NN 005 0¥ w v w o ] v [ w ] = e WL B0 oo [crasE] w [ 5| ® | | @ WS Ri0E I = | W e | v [ & w Sivom S0P v Hagen A o — [ o[ oxm [ e %] ¥ " wom S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ovzedsy 20z SN HIDUDI3 PUE [ERUID 10§ MR W] w [ [ew[we[w] w [ _w T o o [ [ ove | Fueanc dansmy w wo | ow || | o wo | [ o] e | mtdem T | avuz w wo | ow || me e ow wo | v | ms || w | semestam e | w | o | winieso § § ] s s s g B § Augoev | FEI ¥ s 2 £ g § WOGT OE#Y | 2 dodbans WiooTover] | awia v 55| |55 55 |5s 55| |5s 48 (&= 2 8 g w n s Suorouey| ovaa s u oy [ ot i e e PUE DS V290000 AU WO GTT ML P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT g ot 120 Moy i put D 0 I W] w [ w Jee] w [m] = ] SOTOWY | ol o vt oy i | oW | o [ w [ ® [ © = " £ gy oy FmuRAC KR 1iged 12] Pl L Adprag. R JAOHR SN TR KO L] TTTD SN g e 2 v ' U7 ‘- ez e w | w | w ow|m w | m | w ew|w = w| = w | m | w|m|e|w | W w w wE e Wl oo [ szaser | se | % | o || oow | ermete | or | o |wz] e | oz o= e ans 00w | esmaver | 56 | % | @ | o |woow wmowe | o | | @ 0| @ | pmel| ZNms ane | cvn W W [ e ww] W] W || elwl el oo . G W w [ w [ew [ [ [ [ (e[ w [ ew | Suman s = ‘ —— . | o | x| wa | o | x| W " o W v R PR oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT Tty 202 e Huouca3 pue (@310 103 WA ™ W W T T T T G vane Gt van ™ ] W w [ w || ®w S stvane SasTvan W ™ W ] w [ e w SrzvaneParIvan w ™ w o 5 u v Buvaneced| OO W ] W = w [ s w CoeeRaGENn | ot W ] w ™ w |« & ueeSisivan | e w w n = @ [e] = P trvn w w n v . v * Cadetnd - W ] W T | ok [ wr | we wioevin W w W e s [ we | we ioeana| dnmmi e L) w w w ] = [a] @ S| T W m w v | w | a ] o Suoroney | ‘g e s W w W e e [ e L) W w W e [ | % | W iogr ovey oA W w W W] wm [ & w o ovev W w W cw | wm | @ | W oot ovey Tl T W " W ® [ W [ ] w Fiioos oo ™ ™ W o] wm | w | W o cuv w1 - ] w0 W T w [w | W SRR G | anaschy i | owe | ot | % W v u o — [ soms S P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT evzotsy 20z SN HIDUDI3 PUE [ERUID 10§ MR w w ™ E W w [ ot W e o8 Ny “osar 2| e = & woe | reave & T = e £l @ LT S Wit | SN0 S8 pun (3|5 %88 |s|s] siga;!:n Scevinducevan SarTvencSueTvan SuwzvancParivan o vaneta CicRucEvan OmeRITIYan ousePusIvan Sueon BucEVineRIOEYan B sTvineRIET¥IN SuszvneRuEIv W oEvine0sd GicSuTEvan ORicSuSTVIN oaschussvan ousco 5|5|ss|s|s|s|s| |s|s|s|s|s|s|s[s | ns|a|=[a|a|m|§|«|5|2|a|<|a|a]- 2 ' o|a|s{a|[a]s|~| |o|x|s|a]-|alal= [ T v A 0 VIS i | owe | otewemn [ x | W [ v Ao s e 1 1 bk 8 B R R G yzeteg ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR B =pucds o AN TYYAMO) X0V, S ers VAT VTP -ONOI OV, o TR S KL 474 B A )R ) v 0P s o oy 004 ‘o0 1 G “BepN P SHRI 1 B R ALY 10 SELARP ] 8RS B 115 ) PR} .15 S 15 R S U0 I iy B 2 0N pus vz T T v T ‘e W W W o [ w 7D R 0k ana = w0 e ana Dwe | Crawesm Ao s e 1 1 bk 8 - pms. TR R R G svzeteg ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR 01 o YO, WU By VPRI M5 519 EPUILE S35 UMD RNPUS 0 WARBYAI 5 VoS 1 AIo 1050 TN A 110 R 0 A 420 oo 200040 00N 10 a1 100 YN RSUUT i U "L S S35 HST LD ] SUBRUP A AL S ) VIS w54 e U 510G A X K i 4L 2L AP UIEFS | e e e LT VAL 2 AIZ33 T VL3 S-S5 SV-STETI GNAIESCVI 3 W0 LSRR W25 R 20 VWO O Py W Fia W & O BT w v [ " v ok ana w £ [ W R 0 T | STNUNG 105 Qv ALk w T - o T o firra] e LTI o o = D B mana ) e e Tirom| OWWRMANmED T o o - woy e " e omnisors T 1TYHO08 UG AN Limy-DT TET ML P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ovzeeey a5z MO HUOUDS PUE VIO 104 QIR S g, e L 1550 A 5 e e s e 1) ) s ) i s e i e A TR 1Yyt i 1 LEYERD 41 I 0 001, P U R TS X 4 YR U (3.4 A 8 ISR L R AT 8 R 50 DL L7 AL Y T S5 L S AL oA S A KT = ] TR ok we = W A w [ wo = W Mot uosanG | TN = T W] e 1) oo | ] cown o] w T e | | cawn w0 « e mLrmn | o = [ seme || we Sleone| Amn T L L e B % | PR e e v W[ T © | o | (mema oL NoRo0R VL TopmdainT | £vuzH 2 e el . o1y .+ oo oo v TR o = ] ] @ | wysemp " - —— o = rensU OUIRING AN LB ST ML TR SR oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT avgolea 202 e Huouca3 pue (@310 103 WA = w [ o ™ W Tl = W B AN | NNLNG-IO8 O ALER 3 w | @ ) o P W [ w R A B T ® | @ LA B ) o Sivom| CoMMoavAumn e i i | o | vawusan [ W = “ sy b A0 SRUONO AN sk VT BIEL B R R evzodny ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR oo | W [ee [ ar ooEvan oo [ w Tewe o [oe] e astvan | zan ansvan | W w s [afm oo e | w W [w & Bonevan e | w W [we | ot [ v | cumosmopy [ Swsran W w e & [or o8 oo | w [T CICA G igevan | 1 snsve 00 | —we oo [enee| orev Sagvan T [ ve = [we o o i w [smera] sz Jox| s m ooz oy W | soewes | cor [zor] o [om| swwimcx [ Buomony w [ = o[z o o8 w [wars | w o9 |w Bunovay | T W _[rwvern| so [sn| e[| owims [ Sucoromw w [ = [o]ol¢ e w [ w oo | w [on B oot vy W W | & [ [ wokere [ wonroer w [ w w5 v[w one W W w [ea] s [« Bunmonm | vonowsavr w [ w an [ew] 6 [ v | seoke [ wonomm W W W rml e [ 0d e ‘reumy wma] ons [osamessa| 5 [ = [ | e - keSO A0 POURELS Y SN Ay NG ST TS MIEL B R R G rzetng U305 2054215 oG 064 LS00 YN I B N B 200 500003 - LIS A0y 0 YRS o 1) PO BUCRXUDYY PR S NYT 20z SN HIDUDI3 PUE [ERUID 10§ MR 1 R S0 WSO 24 UL 1 SABEUP ] TR ™ BrvsutEvan csmccrory SvRusTvan v B o LI o v Susrvan ¥ R oy ] Wiogvan Vo oy Wstvan W = ||%|=|=[8]8] (=[] = [8]|n|#|%|5|8|[8]5) Osamayma crmy -y oy spg S P LT ‘oo R2U0g3 - AeLIB ACTY 40 URULERAL 0 10 SAPONFLIY [RUOIOUORY P LU VT oezodea V202 it iU P 1ERUID 10 eUIE T 0 VT o | ] Ty | erwa T e 3 S oum EC] Eil i [or | (e 06d L £k 6 s [ F £ m o o o ey il - T oo EEC] 0 ] s6 1 Rt 08d o I W T W g o 13 w i W]y [TV ™ W @l W [ Famrouv o I o W osi o m Bl m Wi v | avamoraan o 13 STy 13 T o | aw (1] Ed | o oway- T w Wi W oo S wr W G Ty T w i hewes [ Farorouny o m €l oo N W w16 VirgozoRY| | oMM 0] > Wl wenpon [~ Fipor o] o w o ot o W vilw oy 1] 13 oo yees [~ Fiter | w w e oar o Ty wor Faoery| zonowann ] m Sor rmeron [ Faors oo 0] 3 i o Gy L S| R (oW | % [UT W] g | by | s | ot kNSNS #5291 A3 POyAIS VDY OB 4 SRINUNG TS WIEL P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 152 st 202 e Huouca3 pue (@310 103 WA ™ w_w] m] o w| w] wem o w w w| ekl @] & & Womonv| vonom n w| | | a| w| o eeus[ mmow| o w P Y B u oua T = o ~t u e | PWE || * M ow | e |y | e 2w womwew®BY K3 POURAIS 52 153 8n0LSqU8 40 BLLOTN "LZTD AL und X TR VAL YPUSISRIS3 B 5oL FUR.a 00NN PRLIOOLI o "I 53N U R B QaITrD 10 R KRB0 RPN THVE UAPYUCO | UTPRSE-fy ‘LRSI Y 70 F AP ZEYT-Y 7 O pUR TIO-T OV AT 0V ALYZET % 0105 T 0105 0EIZ AvEy-Ueuing £ w2738 209 3308 TV s i g " rrx O 53 w o = = WTwE| sovamme w W | (wnpon [ Bt ] o w ™ o T3 o | Ea ot [T [ e ] gy [T o ar e+l w w S| o [ swEet R en B 91| ooy RO VL Ei) ar STen] ] % 5 Soar T sy o [t [ v 3 e var =] oww lomevin % [0 T gt | toteey [ | oot i) P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sz odey 20z SN HIDUDI3 PUE [ERUID 10§ MR w o Wl | amy| emgvn| aar ] | v Srvos % | = Woewin oo z] = x| ey | Posvan ] = 3 o T 00 3 I Wooevan | s S wil me| oe| eev [ Busmwan ] w| o] oo ) = = o v won =] & 2| swwomopy [ Suarvan ] e o o ] . ww m | o Pawvan| v ) o m| w| sy suawn ] o] w| e ) CT [T o worw] o] w] w] m] @ oz ony | rwacz| _rw| _sw| o] &x| | e Socomy n | wm| wvw| | o w oea| cowon wwwore| w| _® o] = = Boomonv| ww w|owass| ew| ve| ¢ = | i [ Worony ) | o o o ¢ 3 ) ) w w| e w| m| Bz oy " W w| e sl m| wm o1 oy oat w=d] O Jwman| * [ M w | e | o | e S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT eszotng a5z MO HUOUDS PUE VIO 104 QIR ] ] W[ & B6] W Soc oy, ] ] W[ T o] w W] aew Sogmiomy]| oMMV w W W[ TH] [ e W oot w W W[ TE =] e W SO oWV w W W ] o] e W amas oot WY w W W[ ZZ] 2 =] W o] w w W[ T @ e w SuokowY| TONONIYT w " W EA] [ W W] (e oot oy w _._. W[ En| s ®] w ot T mpa o ] o | woyaaa | %] T M| - uny i o raung oA 040 A4 POURIARS S 15V HnocBa 4q ;w00 SETD L o pupapesn s 5 oot O A3 N S U Um0 Ao B D0 P T MU 0 U CUTY L PL i 5P e SN G0 OV AL SONDHHD O ALKSG S PN T 010K ALK 2 T 0 sy Y1 e RIS VAL T VALZ33 T VALTS TR B B LTS S1-STESES SV TSR SENTAR “ET30 07300 IO 00 e L U ST YL VT 11 RER 518 o pOADY 153 0 wo| w| w| w6 o a P oo w| w| ] ] W | el ) Y 1 B oo we| w| w| o we| m| o e = — . b O%F | wogaa| * x n Aademy. v A i P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT vz odsq a5z MO HUOUDS PUE VIO 104 QIR ] ) va] e s W] W wre s s Ruccw ] | | W ] & ) VEE | @ | Ve[ w| | 9m e s v Terwmpon T T m| e & B % Sivom S| W T TR @] W[ W mars i Pucoevas P T | €] s W W oo W00 |5et TR VE| W R R e L a9 o ] o = T oo ot | W G sy - RugosviL P T =] o] w W o o[ Wz | e %] | " o Tz ag e el = = W W w % ] T e W w w] W[ w Baaam W w0 S & w Sucez oy W W o W[ W s oot cwew. e = € w W ot w w W | W EogEana| T3 W W W | W ooz owy. w w W e | @ oo owv. 0 = @ w[ W Oaa SR W W W[ TE] E[ B[ W UG WY w W W[ re| w] B W amas 001 VY. w W W[ en] ¢ E[ W o1 S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sszodey 20z SN HIDUDI3 PUE [ERUID 10§ MR L 4 YO VL IO SIS 1L AN Y A, A A 0GSeR O PRGSO R U By AT 41 AR SRS GEAS VG YCURDLID) L8PS 1 NEEOE AR 0T OV AV Pt 0 SHBADR 71T 7 5 51 O ALYSE ST PAUL FZOT-0Y 7 S5 IO O ALK SOMOMD TV AU G105 0115 Y1GZ bpey-veururg 2 1Py 2OV N IR V-4 I ATV URLTING 7 5 ) S 1 A 1 v e e 4 PO ¢ 153 O e Vv won| % wel su| = m| w rasas otz ana ] ] wm| W] = e w | v od zoos To0s woow | | woe| ww| o] we| w0 wsumeana | O @ = w|val o] @ W o o ) W vEw] ] =] w[ B ® Tz W W ]| oW W s T = m| v €[ B[ ® ] W ewen| re| TR ®| B & ToTwe| soemne W W W W W W[ W] o T ] =] mSwl ] W] & ] o R TG 200500003 - LIS A0y 0 YRS o 1) PO BUCRXUDYY PR SIS NYT P 120 Mo i put R 0y I e [sa] o | o [ | va [ we [ m Fucevan ow | o | m | or | oo | ew | | e | mwev Tanvin| g m (o] & [oc | ow [ ew [ 0 [ ] e [ru| ® | o [we | o2 | x| o Tucevan wow [ewr| o | o | ooe | tw | & | o | weew| suavn P I T I T I T o wow |7w| e | me | e | e | we | we Tagevin | ookt wow [ | o | e [woo | v | o | e | ww [ umwn m (vl o [wl o [ ow [ w [ o o Twow S W [rw] = T [ w [ e [on [ o o w e w [ s [ w | v | s | en | wiee [ uwiomy w (o] ¢ | w [ w [ ve [ o oni| zowm W [ee| ¢ s | w | rw | w a G 0¥ b w [em| ¢ | o [ w | ew [ 6 | o | et [ ucoromr w o] » [ 2 [ w [ o [ o] . oar EC I T I B i B GO W[ w | o [ [ w | vw [0 | w | o [ oo W &t [ w[w ][ = [alw ] P I T S N I oo N W el . T w [ w [ ww [ v | w | o [Sacronw W ez ¢ |« [ W | en [ ¢ | n 2] T - i [ [ & [ W [emd] % [ o ] W - i e wen A ik A PO 06 PR 05 5 BB A SN 6E°TD SHIEL ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR o W] W[ eW] W] oo o ||| Wi [ ] Ve[ 3] cgmewon | Wiwrou] comomaa T w] w] wlTe[ ] ® o e S s | B Sk | [ | w foma [ B k| w | w | - [ T L - ™ SrwenfOHaARS a4y POy D6 PUs S 5V oM A RGOS T SHSRL mand 35PN i) o0 PALIOSA S0 YN LU N R 2 LSO 4 LT ALY e ) AP Y 310 L2 2044 PR NNILNOD-O108 OV ALSHTI SONDHH) OY ALIEGT Z 0105 PR T G105 OY ALK 1202 AS84-UmEg al 344101 SPH NG ' VALZ93 2 YLZTA F VALZ33 S0 S RSN 1| 64 Ay 52U ‘-SI5308 S T340 COV-23H0 20N ST T ST 50 WHAAP008 Q12 VAU UV VAN VT DL 3V 5 A 10 30 o AQ PRI 061G 8 05 193 00 Ay 5 w || o | o e | ow | 2 | e Atuoevin oy 5 w (w| o | e o | ew || e smugvin w Jw| ¢ | o | = | o | w | w v w || o | o e | o | e | oo oy w |olm | w|oe| m | 0| w w |em| & | we | s | ow | o | v we || & | @ |wo| o | & | e Tucevin W [sw| @ | w | e | vw | s | m | owwew [ Susmwn = [o| o [ & | & | ew | & | o ] wmi [ w| o | W [ema]| x [ u N wa £ | e [ S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sz odey 20z SN HIDUDI3 PUE [ERUID 10§ MR ] m] ] O] 5[] m| mi| o] %] %[0 @wmen oo T oy | san[ 4y || | | o e | [ | P— wo 2%, o | m] ] ] [ W] | m| m|FA] w[wE CT] Woo | r| T | TH| W[ W | e | & T a @ Sucosvu oy = {e)mmmpon | | | | | 8] m| m| oex| w| = % 2.0 L W[ e | v wlee] B[ Waroang W] w6 & w(re| w & ooz OB | e w] W wlrz[ e8] @] "™ uorow W w| W[ =B T | e W] e w [T | e | Bamang] NG | e W] 2 i e o6z Owey [ Tw| W] e wire|m w9 oy W | B B wlee| & ® oo W[ e[ %] B w[TH] ¥ B ooz Gy Wi o] w Wil o| w| | (e[ Suooousy W e T ' £ Oia| ToNoM3VT W[ e W wew| @ w ooz oWy ™ W] O] W[ %] {0 wempon [ Seoroumy w wrE T ® ] ™ £ L oo Gy W WEm| w| @] s | Suootousy ] wlEn| €[ = ] S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT eszodey 20z SN HIDUDI3 PUE [ERUID 10§ MR ] ] m] o] wlw] w] wm] ] el e 7] ww w | TR wore | @ || o ooe | woe| more | | wwee | o f oo | o e e (o | Muoigng | TS | | m| vl wlwl ml| ml wilelwlw ] ol [ g E[ W[ R] W[ E] [[T] B FPp W W W W[ W e s s T 6 B | w| w| o] 5[ 7] N R Siiwm| Sovmne W W W W W] w9 TV ® | m| wmlTEF[® 7] [ T~ T W[ TR TR] W] W | &R E|va] W] = @ @ o 22 Wiames | +SucoswL m| | | T B m| wm| ww[a]® S| s | G | TR | S| B 9| Ve[ wWer| o3| T %[ B - = o o2 .:. tomapon | +muooeva m| | | R W B @ m| wmlwww St TR | S | | V| W[ | WO W[ %[ || = o uoev ws aw L ] | ] E] W | m] men] W[ ) oo | Iz | | | W[ m| | W e v || = @ o sucoevar e e S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ooz edey 20z SN HIDUDI3 PUE [ERUID 10§ MR [ ————— AR A Y OV g O T e Pt Y Y SO i Pt o o O e oD ) S n o R e 752 v v AY-UPITING G wIR *dN PR 2 i THNSVIN T N THNSVE IV J0) TRRAS 10U RIS A1ANS SSTOEP q POURRIN OG ISV PUR DS ISVS U0 w0 s Y [ e e 5| o] o e’ P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 298 202 e Huouca3 pue (@310 103 WA oo [ ar [or [ w W | vo | w e [ ™ o o we [ = [ o [ - = Bt w [ w | o [ w o | evsaeneny [ Barvan va [ s [ w [m ™ 2 o e | s oz [ w W tEvan | 10 v ves s [ ve [ ™ | azvan o w e ™ = e e e TE [ B = [ W oy v | & [ % [ L W | ke [ Sromomy I ® i3 W o s | ver W wozasev | “O = [ F V= W | e [ Sromomy T " " o0s vee | & il w o0z oy v | % aid | iz [ ooy Yo | ¢ T w ] o | W o o orou | vowowaon = ® T | o> [ S ooora Y v v [ v W ] - ] % [ v ], [@] e [« oot itny [ | e e | ey s o e st S 3 POLEPEIIS IS PO 30 5% PUE SugeonE i) SR N4 SN A S0UIRIING TS TS ML P L ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT Z9z 0800 20 Moy HUIDUCD3 PUE [RUID 10§ SINATUIH T T T ] e o W W W[ = S [ FIFT 3] oo [ o] *O%% W W W[ W e o e S s | o [owmnun | wee | @ = v Amioiay .y — wepecan oy s ird o cemeAGHOADS BT 6 PO DRG0y D) SN nLBTe A OIS 2T BRIBL Umomd 6 OpEap RIS oqEaK O PRLIIAL1oU AN I 102 i W WesBop 2y YR 41 UREOITN:ONGY PRI 6204 9T 0 GESAN-4d I EAPON ST DL WL TV Tz U2 D 180 SO¥ S5 "SIV TS ‘E0V-EZ3340 DO ST 1OV-ST33VE R UMS900) 212044 QNI 30T TN VT DL A 10 A 20 A PRI R 42 USR] Wl TR 44 VO ERY o | n w = S esutcvan Tw | s w & | wimesmopy [ 5L isTvan T | = | w [w w o e ou: avay T | wr | o [ w 3 Sivsumvan ze | v | e [aw w wr| orer [SlrResiven T | e | e [aw w 3 o ® [ o | w @ w = Nooevan T= | o | o [an w o | mmcseropy [ urvan W [t e [ w = oo W | o | o a0 w ™ Woevan % [ v |, o] ewmiweeen | S vy | ey | i e v | I M i 0 S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT P V252 it iU P 1D 10 eUIH W W W W] W W W o -~ -~ - W] - | e o8 W W W] W W | i W W W W W T[] o | T o ) vl W o T . W W W] L ) e W W w| we [ w o | W w W W] @ T TS| W W W w| we [ w Sivon W W W T ] ] e W W W w| we [ w o, W w W W @ ] o o Wl T T [ w on W w W[ e T S W W w| e T w ] W[ W w| we [ w oL vz N aw N ™ T T ] Otd - T W W W W] W [ T o GiEY W W W w T W] e | Swmiow W W w W vE W osd | vowom W W] T w Fowme| W W W w W Wor || teiwseon | Susrone W w W[ T w o W W W W W oG GIEY W w W Wl W ™ w T owee P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ozoe TR D U 12U iy QUG = =] & & % ey T oo £ I Taa e vz = @[ E[ @] ® S T W R W ® = s e = = w[ w[ w o . e va| e m| W = e waespon e = | w| ®[ % o = & = -.. tnms haadi = = W[ = o5 e o I I = Tz wanspn o = @ %] ®[ & o TR e W e | v | wey N | o e Lomay a o i i a0t 3 ok oreHARS 96906101 AQ POURARS DBUSE) WACH-CR SRV NOLBTS 4] ELOTNG BT BHILL oD VAL YT K 50U ap U5 1 2 e 0 PR 1o N M 3 WY L A EXAU T ARG TV VLR U T QRPN Ol 0 APR IV FT Wt P 0 Y AL 334 O AL 910 PAAL T2 G Bt 100V ¥ ALZGT SONCAH QY ALIEGT 70105 T 0105 AT A LRLSHD 6 434K 22N “P-TBU DUT Sy iy 2380 1 55834 o WV T 41 SV - TIWINCO SOVIUINH 1 A e A OYADS SR LIl IR S U0 K W =T W] W TE[ W T S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT cagotey 207 ‘M AUDUDI3 PUE [EAUID 10} SRS e TE = ot W W W W W W ) s Sutnve W= =W £ N | BR S ® B 2] Suznve v W[ W W W W W] mesen Tt W= =W o e o '] ity & e [ovm | o | 2L 0| e y oty o e T ASpaAPS 0620611 g PoyIR.IS VAU WAGHE2 SN~ oIS 4G FWIOTING YT WGRL wromd B VL SRR A 1L A oo 06T 1 e R O BB T TR VG AR LISPURGEPE 1Y 10 43N FIST- EZ 0 pUE 0054 0¥ AIVIEN K OV AN §TI AL T~ G 94 0T 1 ALV SOOI 0¥ ALISE 7 C106°F 105 BFIZ AP URLIEING 796 '-S0 T “V-3Z3308 0% AL UPLEATD 7 WAL ) O T o) TSV T 0 TUTSVEI 41O NYHO0 YT <-ONO VT T-ONOW KIVTA TR 0 . ks 2508 A PP Sl U D 140K 220 U0 0y W[ 5 V| sk| | W = uznve w asen St || | s o = | sovaze w wmapan St = | | o v o W ERT ] W] W] W T S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT o0z edey 20z SN HIDUDI3 PUE [ERUID 10§ MR Tooeva i 3 3 58] R 2§ a—w = & | G| v fi s W w A S s 1 O — W w = o v S| W[ R[H] e [ i T S o e S W w[B] e e T s — — o [ Srony| N O — =5 =3 L —— D¥sa O o 41 v ~ - o o - - vt o maverkSHAANE 963060 4q POURRES SBURE) WG4 SN~ nOLIUS 44 FOLLONG TS WAV ey wasd 2o 2004 S P S R s R U > RPN Y A A A LS Y10 P ZEAEY 2 v e TI0CE C ALHTEN 5034 Y AICRIN VST PR 201-C 52 i 0T Ty ALK 'SONGHED ¥ ALHTE 2 G105 S 0105 0z Meras e 2 4L STV 2-SZ3300 Y-S0 I LY TE ST 1 5P 7 o TWTSVII ) TSI v € VALZ T ‘VHLZ T LTS3 V400 HIVT2-ONCIA SIVE -OHON S0VT 0 1 SR R0e 10U 0.0 00 #5083 PRUTES ERd UL MOURS LG8 G245 U0 B0 P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sz eeny 20z SN HIDUDI3 PUE [ERUID 10§ MR e o e . om0 ot 4 A IO 40 4 U R OO U B R W FUNFID 1 ‘UK DU 0 WM TYT-Y VT o P TI-5 OV ALHTEN ‘54 OV AL TG PR TOT-CY VIR 00V OV ALEEIN YONGHI O ALH3BI"2 TS 0706 T Ak UPLENS T PR " S2530G ‘2AV-CT3348 L T2 D PP o7 950 40 ST 4 VI 1SSV TV KIVTA U BTERAR 18 5 TP G PRUTEES Sl U, P KR 40 U0 T T e R e W WM W W] e T £ e o TS s e W W o] w W W W W] e i = =W = o £ T~ - ] a] w s ) s LN oL = == % o v o = ] ® = pppr-ap—y e oo = = e = o | | e w| Foeva =, W = @ o L3 ) ] o wn e = vz ST {s) mampow e = = —r o I S = anes- ofasanag B ool = = e ) S P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT e mewseseseenonsweg IR gy W W] W ww] W] [ W[ ®] o w] o ®wam| om0 ] W] W] wlw[ W] w[ W] w6 e[| wd[ Gwraa]| wear Tomow| A W W] W ow[w] w] ] W[ew] e e o] SAuvaa | w W wlw] w| w] w[re] welw| w9 Emeaw] © W W W] | ] e[ W vm| e @] o[ S| W w] W wlw w e w[ee]| ool w| o0 Reeza] gme (I ] [ ] e oz s ] [T — o [ Sromomy LI Wl e oud | vonon e m | S| A s ] | o ooy v | w ] I | e e [ TR [ e[ Pl | o [ v ] o o] T s wi W ww] W P S0 wi| W[ wiw[ W ] = o —— v ][, L M o | ww | W — ] - . = —— ||| | o & [ v AR PR 1 o A perus asmm 1 o ent ) Sy 4 PomAEAS ) Pt D30 CY00S s A SOIRANG ‘95T HAEL SRR ooy R2U0R3 - ALIBY ATy 40 URULERAL I 10 SAPONFLIY [RUOOURY PR LU AVT eszosg V207 e ucuca3 pue (231D 103 WA = = ) W[ we] Fw ] R | ovmn T o I o agm- o M00SWL = = = W ow = & ] e | weaer| we W[ ww| e ™ S| W = = - W eww| T | e ] - [ w W [T} W W W i ] ) w w TR | e [ Saonrony ™ W ) " e w 53] | s ™ W w o TE w oo o W I} W W | i | o mempon [ Suoor iy ] W W W 7T w 2] w W [} W T w oz ot [} w e o T | iveees [ Boowovey w W w W Vo w 080 ™ W ) " T w aouw | zawowaa w W W W W e T w W w Wl W e w o T e ot | o | o | i | [ @ - | s =) arwrioNog OPEORK] A POURARS QYOS inoiBane A SIS “LTTD SHISL W] W] W] W] W[W[ W] W] W[ 6] 5] %] ook euvaw : W] e [ w ] ] i [ m | a| 9| Syhuzan] aasam SRR ooy R0UaR3 - ALIBY ATy 40 URULERAL I 10 SAPORFLIY [RUOOUDRY PR LU VT oz e o s 0y g = T S —— - - + e ] ot [ . T | | ][ e | T | | x| o | o ] wr0A2E 0500010 A4 POURS 7103 P X1 | W9 | ZEE LG GAE3 1 wi| | || A W ] ] e o Wl wl wiwtwl o el W e s w = = oy ww] [ w[w] T ww i W w| [ wlw | s | Wl e Wl w oue| sonon w| | [ ® wlw| © ™ o | v i 18 2 = T o w| - w[w | | e | o il | e o w W o w w| 7| wlw] o] wjw] | w|w s w W [ " Wl W] ww] T w| w| e w| w| so| @ W e | e v w o Oad | TONOM w| ow| T[T w | o | ow | o w( o ] = " e Ea 53 s | - ] W[ ] w[w | | e | o | o i w—wl wwwlw £ TR R oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT azoin 202 o D03 put NI 03 SR i1 P Y RGOV Y08 1Y A R 04 VAL O34 AT ST e I o e 0 O I SONGAID OV ALBA 7 T ot e 0w 2005 v e e 0 e 2 ) VAN T A Y VA S 1 R 50 ki o A R 7 10 W W T o W) W W - | - w1 - zove ] W i3 w[ W w| e = | s [ W[ w| e =] S| N o W i vl v [ W w| o= == v - | w [ aw ] 8 | )] e om) | o | tuw [ W] w| e ] = E[ T - o T ol T ala == T o & frhnam | DTEVL T e w S T = | T o T ol w| w|w]w "a w = | Sorms o o e e S S W W o o[ W e W = o w| | o] Tl w & s | ovena e W e e = S TR T ‘oo ROUORAZ - 100 ATy 40 URULERAL I 10 SAPORFLIY [EUOOUDRY PR LU AVT fzzodng 257 3y AUIDUDIS PUE [ERUID 10§ MR AR WOOT G et mmsapopy romon | w oad ot T— mpay - v - Ceaweia e e a5 | W -~ 7 ey iU 5 U 3 ISPUREE 1 RGN U 10 SN 719T- B2 4 pUE 0034 0V AN ST 0 AV ‘SO eyl AT e O ¥ kg o580 1 ARG Y04 SO 6 BN ' TD BEL AT SONOIAR) Y ALY T 0105 T 15 108 O UPLCanD 7 etmd £ T8 ‘S0y-23540 OS24 VY23 212 PRI 44 91 1 2 ) NSV T INSYN ) Ty 5 VLT YAIZ3 T YUIZDA "RAINO SIVY I I 04 s i 4 POUEEDS 130 0 e W ] W oo oY W oo Gy ] W 0] i ] o7 | vowowsan W w ) 01 oY | e = 7] w 7] St oY ™ [ ” Suioor o o ] ™ [0 ] SuGROMY| oMWV oo oeRv ™ w e ] o T ey v T ary i Aoty Py A1 PAURIES U204 SN A4y SOIING “BE°TS MHIEL S P R ‘oo R2UagA3 - LIRS 40 URULERAL I 10 SAPONFLIY [RUOIOLRY PR UL VT izote 202 e Huouca3 pue (@310 103 WA o [ ovmm —— e wE W] v = e w| s | eouoomo = o = W[ 5w Sirom =y wE[ W[ % T or| e —myer | eimmnpons | emuoorvar = = W[ W T w Suvom e e W[ W a wres W] ey | SOV = | w| @y [ W] w o ™o BT SF[ W[ T Vo iz nes W (o meapopy | BIOEVEL = = W[ T E w = e W we| W[ m LR s W] ey | PO = = W[ W ] ® w i T WE T W[ T T Tz e W imuapon | MOV == W[ WL T w o [Z.0) T w W] w ™ W[ w w W[ wm vowon ™ W w o w W[ w ™ W w w W[ w ™ W w ™ W[ w ™ W w S P L ‘oo R2UagA3 - LIRS 40 URULERAL I 10 SAPONFLIY [RUOIOLRY PR UL VT sz 08eg TR D U 12U iy QUG HTE W mrwe ] e L I L) w w w = W = | At ) w & W ] e W W T W E o e w E] o W E] Gaawey W w W w W W nd| oy sam o W[ wow " W = o T ) O w FERET| wapqua w w w W W ) W e W Ty iz | Wtew | o | Sewve | womwe | o 2 T s ] —— RiRADE 962961 49 PoURRIS 53 PUP UOrSea.dec STVH KIAPELY SV NGBS Aq ALOTING T TD BBL “qeLnuporen VAL YIRS 1E5H 5L oA e LIS 5 ORI DqROR 0 PO 10U A5 N U gl ALY SN ) RIS 4G CUBpYLOD 1 pLmpace:Xy TERRCKN U 70 TP -0V 7 P PR TI0-G34 OV ALIA 'ST30 0¥ ALKIAT S10Z POUL 0T o w B o[ w | warwa s r— W St w W ] o W w W = [Woowouv o [ | | e | 30 | Mooy | s o ... | T = w | o = %[00 [ | apenes [P MOV v w0 T |wo| 2z “¥EZ | Bt DT ONEY S n 1o 0 W v Wl ¢ W v [ s [ Rironv] wouson v W[ s o o e o v WO || speurs [ M| O 5 T o 7 G W w o [ T s T | s [ [y O T 7 IRECE G % | w % [ v [ %] =] % | w[u]w [ w e voamgn | v | oo | womms (o | w | oy [ it s | s | eomaen | TN | ST | TR b e vt IS W LIS DT UL P L ‘oo R2UagA3 - LIRS 40 URULERAL I 10 SAPONFLIY [RUOIOLRY PR UL VT ezodea Vot ot Huiduct Put 1D 10} UG T R e [m]w]o ] 2 0 I P Y P T v [mw] o o e ol ] T3 [w [ w W w W w o0z | oot | pyanas o T [ e [ [ [ o o m e [ owna | tvucn T [ [ w ] e [ o | B T & [w w0 ] T | T T o [w w0 s T = oon | B - T T [ w[ola T e w £ o o o (@ [ [w]w]w s[5 [w]w w sy | gn o s g o [@ [ w | w|w o [0 [w|w & | T [ [ [w [ v o [ww o suow ‘ =0 w | w |w w0 |mw w [ | w0 | omrt [ o savmna w|o | m w | | | w | e w o[ W W i oiou w0 v v [us [ v [ o [z w0 [0 s [0 | owewsr [cvr| B | savmnn w0 v = Jwe om0 ™ o w0 s [wiw o [ S w o[ u e e o R w00 w s [wiw [ s [ [xlv =T+ S Tv 1w s . ||| (| it = st TR ST oy 20000 - HApE1LIS0 AHODY 10 WAL o 10 SYPOIY ROOUOR P S YT stz ot 202 e Huouca3 pue (@310 103 WA we | 6 [an | w || wm w]w| s | @ |o]s B @ - ucpe aa omeusy Wh| zows we | 6 || w | wm | ww|m|r | @ |o|a = | par e o | v [ W [ w5 | v [ = = [ ] "o e |« [ [ o [ [ [wn| v [t |5 |, ™ EI- sy sl vows w - w o o] ¢ [wm]s[m = | s T w w o [ v [k [w & [ = oo o e oo w LT v [welv[o[afo]e C] ERNLTAT] imend ot — unare w [wv ][0 a v e EA ool ol e fofo w o i wlv e [ e [m]m e o ([ Wt ] & [w[w W] ™™ [ [ uoan o oo v [w|m ] | e sy Sl war T © [ [ || 0 | g 3 [ [ | W suvom T e | Beavan o0 T T [0 | a || oweass [3 ] S| 0 5 T [ [ [ [ = ] T T [ [ | [ | 1 T T [ | o || oeoust [T | Wt | o o[ o [ ® [wim | m e e s x v =[]~ vemepn | vemopt | vomeus | v [wossmi | 0 | sww | sumisemg momg | madmi | ws | e S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ez odey 20z SN HIDUDI3 PUE [ERUID 10§ MR e U s VOB LS R A TG 58 I i N TN i g i SRS A O 0B A I RN, LR o ORAL R S0y L R A 054 5 £ U .4 L4 0 U AL £ A 11 TP OGO LA £ e A TRy 5 IS 25 Sy Bl {1 I P S A T L P s i o SRR LR TR Wt SN/ MOS0 TV 10 JE) P PR A 1.3 4 AP 380D U 1 U XA DL 6 R, VR LB, 08 AT P 3 G 0 AR AL, IR, US4k L GOl TR UOREIICPUA 1238 PP CpmBply g, et et e o ey o e, o U A Y R, LI S oo i 0 Lo G e S 2 IR UAAGRE L PRSI Rk 5L VR 300 O 14 Ao 0> e G Ao 0> A U0 RO 00 PRI 0 4 e U N R 53 U R L1 RS 20 UL 41095650V SRR OUITY SONOHHO O AL S 34 EALCCIAD 448 UL 543 0 N o 3 [ [ [w w v [ ] o [wr [w[w]e]s O [ [ [ [ w 153 ) N R o [P wo| w | e [ [ w [ [ [ | s [ [ | 5 | s w [ [ w [ [ e S moo v % v v s e[x]v el R .. o e e e e e A P o | momg | madei | ws | el P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT e 207 3Py HIDUDI3 PUE [ERUID 10§ MR TSP e % | oo e Sucocvu woww vz e | e | e || Topdiar e w @ |muemn o Toapms wajnles | svazs uooe L Tpoodini o5 woww o || ||| ow ww (e | s | o |o|m ™= 5 3 3 5 5 e 2 2 S+ WD 08 il ouaL T SugoE v o SugE v B ez SugoE v ] o oo am| s Sugos v 7] o8 ) ) & m Ve vie Sucoe ouv | zanans. Sacor guay | ulauG v RuooeouRV | s anadens. e e 333 |e| ||| N |2 !!l:il! sgs|s|s |5 |8 |55 gls|s|s (1|5 |m|s|a|n| 8 BlEA| a2 e|e|s|0|r I «|aslg|a3/2]e| % % (5|5 5| & % 1w aumeme | wmom | vowpam 11 il i metee || W | e axtrecnerotsnd NS LIBLNT Sy TS aRL P LG ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT eszodey 20z SN HIDUDI3 PUE [ERUID 10§ MR wlwlwlw]ee[e]on]afu]n]mw a wlow[w[w] o [ofse[ o a]m]w]|m=ly L O O A 3 O I R % w5 | & | 5 |5 |m|w|w|w|@| = EY w | v | v |z ||| w|w | w|m]|s ]S W | & [ w [ v [w o] w | w [w]w e 3 T w V[ e [w [w]a] « w o [wmr| o6 | e [ome [ame| 2 « w o [eor| s | [ wi[wz| s n w o [msr| s | [m[eme| s - pamzz o wwfon| o | oo |o|ws| | w w|ew| s o | sewnesu| W= stvan Saiedu| w o [o [of[o|aw|m|[a]r a sivn w T [ow | 1 oo o5 | w | [ooe] ¢ 9| eiricon w @ [ o [ o [wor| o [ [wlaot|t o | osieond o ] W e [ Tew [wr [ w [ [ e | e v | ™ T o[ v [saler [ wwewloe e | oean e oo D w o[ [w| o [a]o]|w]w]w[oec]m[owmswm] 5, "B o ® % % ® "o [% e | s | FiLewms | wymams | vasedia | e | aviy B R R mzoeny ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR 7L 4 2 sy B SR QU VNGO VT 4By ) Y S 2 T ONOM 0Ty 7S HSBEALS i, T o) s Kegeod 2v, s pufeapod Y g L ' e L A0 s e A L, e R O W A D o oty oo o AT i il o 0 Ul 4 RN T 1. 21 LRt i e Ry 301 e R Yo /e g 30 SR 0 Y I S e AR L v w o [ | w] o o] |u|m|m|m ] T T R R R - = weos| 0 |y | wiLewms | wymoms | vaserda | o | M vy S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR Saokwin €SucEven O €SucEven 7w o w o [w Sasrvan exasiven o w o oz s o elimvin| IO Soivanedasivn| aramy Gmc a5 zvan RaGE Vane08a OaHcon Suoevin| RV S+ a0 u s v Tarpooa WAL+ M0 Fumsvar Twwdmvl) | ez S+ w0 oo v Towpuode: ol L+ manSucosom Ri2(a| 8 & [F%a|2((=]asala TP o] 2+ 0 oo v LI ey E(E g |r Sucon cury | LI . apony | winan | u nary s kg - e NS RISy TS H08L P R 6z v8ey ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 20z SN HIDUDI3 PUE [ERUID 10§ MR 4 oy o 121 oo 3013 o004 ‘PIOONL 4 RN s N 34 B B WP S ST AN WS LL VD DBV L. AL PR L2 VLT3 SV ‘T 1 9o e WA A B o 0 WK w ] w o[ o ot | weommsmedna w [ w s = WmRIwEan | 3WuND w [ wm ] T [w DR EG | ORSV W[ w = ot W[ w e | OSIraaEdn - W[ w epamss [T | mrosiemoosana o W[ w % Birow R ooy R2UaR3 - ALIBY ATy 40 URULERAL I 10 SAPORFLIY [RUOOUDRY PR LU VT 207 3Py AUIDU0I3 PUE [ERUID 10§ RAIY o | Buscvancom oanze |- . i e Sucevin oo dansom, ¥ [ Buomana| M T [ven | autuceva | oz o F e 0P goe v e oL ST 7 » + 5 & R 3! 5 8 w|v|s|o 3 5 wiz|x|o b @ At Picva| T o cpanse ATTIeVaL| T % |3(8)a (3|3 o fufefefrls| = n[afefefzla| = 2 i B mosn | - g el i I i i i i extcuaors ol KOS WAL BT £ TD MRRL SRR ooy R0U0R3 - LIS ATy 40 URULERAL I 10 SAPONFLIY [RUOOURY PR LU AVT eszodey 207 3PN AUIDUDIS PUE [ERUID 10§ RAI U0 P YDA Yl S0 34 13 BRSSO SN S AN o 10 2 L Ut 0 Ly 3 A P ST AT, SR 2 s 1, L (R T2 11905 T A, LR 340 R P a0, repan s, s TP Uty e TR Yl SRR VAL RS AT 1 o 0 i s s a1 s e o 42t o 54 0 0 YN A L N 5 s s i 2y 0 SBT3 A ey o B A a = s | @ (2R3 R |2 Mg Dirom ga:-:.-:: ) o wan euoevin £ 28 5% |ean s | = o cRucEvin £} sTvan eusrvin » omscSusTvan Ture van ¢Busvin a = 2 (al s« faf 2| 1219 |8|N[%| & B Oud €Sugzvan| 5| EfE|E | MR RO s | u sy i iis | Al | S P LG ‘oo R2U0g3 - AeLIB ACTY 40 URULERAL 0 10 SAPONFLIY [RUOIOUORY P LU VT ez odeq 207 SN HIDUDI3 PUE [ERUID 10§ MR e oty b 1k e A TR e T i L 0 R W) el Fpp U8 o e TR 1. AL g STATARD S AU A T AT S AT 2 S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT sszodey 20z SN HIDUDI3 PUE [ERUID 10§ MR ; ton mlw [ W] & [ a o[ = | w =] w s S w e e - > e W e | w [ w [ e [ a wea on m | m [ w [(m [ ™ [ ™ [ = [ e 9 iy a0 - e i o | wen | 50| || e | s | St | e | e | usen S | oo | T | vmena |95 | S, | rwmd. AU ApmE 2T MqEL TR ST oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT a5z MO HUOUDS PUE VIO 104 QIR Bl stump ao cuss w o amumaian wodpeen | g roanz om0 e S foomsipoa i | v o mpopon o | o deg o s port uete | npospen) s sk waumsaran | 1R s S SR« | YA oA oy || b oo rupenn | var s 381 1 i | wgros syt | s pas | o QYRS OR o | paen) v um o p s oo o pamany 10 ua miaein| e g appene | TSR | oy sy 2 ey s | %y wms e | e wmmmbts | T ums duomns 2090 vl T e vl st mp | w7 o 77 e gy | om0 g o gy wn — g ey otump e s £ wvoamiamumaian wotomannd | smemmee soangc g e N dam pacy e | e s poppoy o | o barg ovmaoupen sade | ungpospeup) e e weumaorin | 18 ey on oo SRt « | e iR P T R T ey ous | Aaesan 581 e st | msgzors v | s pa o | o v X R v apm ot npuons wamnan 210 e | e omand vorms | W saren | gz i 28 v SR | %7 whed R | £TTT P SO mORY v | amizeyar, o e | T wma i) u| et e o o weng e v oonse i g | e 1oy 7z pele sy | soen g ep s et f = o Dwemoin | Wy wopsne I ] [ opmsdegummd | L P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT 152988 20z SN HIDUDI3 PUE [ERUID 10§ MR e A S P P R A VoD W 2 D Aatp mun e G s Sy papn e Wi G 3Y YR s sz e e, o1y s | penriagn a1 10 9 wowge w Buminden g (X s PR i Y D06 s o, poegdcs aymesspou g | w5 0y fyns | anm v ey oy 21 ey ooyt | e 3o v ey o o ST g pou gy gz — nnsmpapes PR Oy SRR 3 TSRS Se——— avpuse iy i e i e Hamans s wios | seveLs o IO P oY oren e Vo8 o w wup i 3 o oA e S SR Thap 57w wepscoume (©upou.0 @M Hpom pmirnnl o a5 e (o) vamseny e 2 o4 o oo | RISESTINA WAPTED € pUE imCA! Lo o ke cpme o aporces e s ipoq s uous | oo oo hdemp | ilamidpan o 045 WD yEEATY LN I3 IO PYG [ -SFIA S0 oz s vty | g e o e p a8 2oy wear vy Al | s opro o umit g pela g oy spepey | _usessinn marvoqmny s sy o S - e gt s sy P i e U2 U P Pt vap s g o upocp ez toramsam | o ey NOT-K o NGV from) sy s o] s0zRY. ] Supu o axaso0 gy Py A ze Qv Al s Mousroumy [ e peupuopuns [ wes Deozumy way ahunp eneaod mpouopowon | {rong cam ko aunoupum s Jurdpom Aminkd | SATw g s o pobe e o tromu) s wormn wenu| e mwsng iy g e ) cpaang gy - R PR oy 20000 - HApe1LIS0 HHODY 40 WRLLRGAL O 10 SYPOIY FUOPOUORY PE S YT P 202 e Huouca3 pue (@310 103 WA A A LB oA YL KT SR 03 L FIGUSIORI 0 SOLS CIAD EOLRE YS QURIBE X 480 AT 0 T8 pofan PPt 7y “HRP 21 () HENACIeLLIRK ) P oGom D ARHOMR 70 Al RO N A o UKD UL 017 PG IR 90 B OATE 49O A P W 0 U SESHPR Ty RRRLLID A Y o 15yauimmp umod qvamapou i ap v sop sure < - vm m.mep v e | o S (vsax) ewm e 0 £ ol sl o ot Anpues | dpoq wameen o sbeeand € pue o s T Y0584 0y (g aLmpa.a 3 e 100 9 Ervaumsopen |0 W o put a2 gy ] a1 o i | oy = gy pucni e > e oo L ey e IOE/OE ave = erioe oysa s /e ovmsmos | ameie ovsosues | samavoon woa mung s g e ) Scpaang gy - S P LG ‘oo R2U0g3 - AeLIB ACTY 40 URULERAL 0 10 SAPONFLIY [RUOIOUORY P LU VT sz odsy a5z MO HUOUDS PUE VIO 104 QWA ] T W Tvs [ [ [ W T N - zos | e | o | tez - T s = e w T T T i e[ | e [} N I R = e £3 e v | % | | 6 | o6 | wen e [veen] o0 o nn | o | & |70 | @ |@enme owomn| w | wom| o T | " | & M| e | cvrampan | os ST AT o= cormon | o | 7 v | o | wewman | rwweon | w5 | woowwen v | zoe || i | w [ [ | o vron | v | & o | o o swmen | n | wm] momo Trrvn |5 | iz v | rr [t e | wv | mromm ]| " o orvoow | 7ve | [ Te | 0 | ez [owien| & | meswe vt | v | e | o | | et | e | v e e | | | o o et e |y | ] g, T Sveanpon | e | wet e | T marer o ousrmpan et | werunm] " Y x| zes | o | v | s | meriane | svevmpen | ver | e s | v | 91 | % | % | wereer [ rvpn| e | serm BeTaNpW | FoC | W1 | o | 88 | Garrebon | oo | BT WELO ¥ zavamL o |~ces || | e | siveen ey | et o e N R R R N o 2 Tveen | o5 | a5 o | % | merm [ovempn| | womn| savw srvnn | 55 | @ | ve | o | meree [ sevewn | s | s s = — [ [*]*] = - W | o | ot} g o - furd e L) S P LT ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT ooe odsy 20z SN HIDUDI3 PUE [ERUID 10§ MR S A T o 0 P VS L DS D YOO WL LI WD SFRTATE WU VL WA PARPUES G UKD XU TMEYEELLE PRLIERLSI YN ST LN G 0 WOIOqERD SO e 2B a0 PRLSI L I “NSHPLE paocc UG W U BEEYLAE WIS SRRTRIED WEPEE] S 10 WON € L ow | ar mar T [ew | w [ v = W [ew | [ew]| w 7 [ w 3| vamasomn ¥ Vo | ow [ u 08| w v w | o Sy w I I I e Vo e [ as L a I I R ver " ® =3 oy a W e [ w [ w o w T a W[ v | e [ sz | e ¥ i o | e a W s [wx [ow [ = o Tor [ s | umowws il a W[ ros [ a9 [ew | o ™ | oo 5| oveowmed = ww [ x [ [ x ™ - " sy ——— ] a - i v P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT o€ odeq 20z SN HIDUDI3 PUE [ERUID 10§ MR ] T [ [ w [ [ [ew ][] w [m] w o | T | W | W [ [ [ | [ow | & [ e o | T W W [ [ [ m =« w [m] 03 v W & [ [ w W [ve [z [ & & ST e o W w w ] e[l w % con 20 0 0 0 0 0 T c T % [ o [wiwlral x| a|n e en [ v e [ w [wlewlwlee] s @ T w e [eafwiwlom[u] o] o fu a5 | e e e muvw| covrw ] T v o s s 0T | vivEee e £ = [Ei] W05t | rermvar i 3 = Trow| o = = = 3 = wa el | e | owwema | i " = e SR O IR BN O3 5T AL S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT soe odey 20z SN HIDUDI3 PUE [ERUID 10§ MR D00 WA U 1Y A N oS 004 P! i 1 SOUARE 410250 28 o P 1210l N ) P By 0 220 22t W W 0 Far w = = et | amsmsmon ™ ™ ™ ™ % | = [ = o |y - w w ™ w e W e 5 = O ] corres ,._ " - o R = & o o | mmeums—. ,__ ,__ ... o - o & n = i 5 e N N [ R L] s | T = = = i e e | bww | osdvenma | % T . - i SR DO VL R Iy R DT ST B s wen SPIUTIER SUOUPIEI L, 0UR AR 2 AER R I WOURIJAL 473 RO 94 A8 1 S PRI YN 1T L M U 3 NP ] WEAOIED ST TEALA NPT AP o “BOE/IOE 15 ORI 08 0 3 U R 0 200 5 U0 Rl w ™ ™ o ® | m [ wepied pve | T s = w ™ e | = e o ™ W o e 0 s £ e = ™ ™ o | = (LT p— T W w i 2 = w5 R e | B | e % W I [ e T I I .. - = S P R ooy R2U0R3 - AeLIB NG 40 URULERAL 0 1 SAPONFLIY [RUOOLRY P UL AVT s0¢ odey 20z SN HIDUDI3 PUE [ERUID 10§ MR Ny o "1 1573 U O 5304 BRAR S 10 AL BP0 456 OOpnyd A KAULAAG O L 80 T VD S0VTHOPUL Z06/30F 0V 20l 404 0 OV TO€ 0 SIS 3IIONRRE U SS9 (707 LU B 361U FONEAR 00 3530 06 5V5 U 05 53 U0 e T3 | o (] w ™ Tee | o | v | ewus | amwstanw w | w an w W u w W W aaxTOML w | w 7] w w i w W W | umo o oeozum | o | woo w o o | Tm | oo | oewsvane e o | we 7] w W e | o9 | e | omwomn | wr ] w W =k " WAy | e o s | e i ™ e e | tm | weAr HTH | mresnT T | e i ™ ET) S| wwe | wm | e WEIDWTH | -cavere stapk dermatiis $AD Up):resuits rom m ranommiser,double b, placebecontrolled, phase 3. The tonzet. (B0 xion). 2021,307/1025012160-2181. ‘Simpson . Long-term Eficacy ot Barictl 2 mg o the Trestment of Atopk Dermattts North Amerlca. Papar prasemted 2. evohtonizing AtopiDarmatits (RAD) Virtus! Conference2q21, Blauvale A, Tabatn HD, Smpeon EL, e . Efcacy i Sty of Upedactint vs Duplumab In ‘Aduits With Moderate-o-Severe Adopic Dermatt: A Randombed Clinkcal TraL MMA Dermutology. 2021. iicaftrtal.gov. A Inhkor With Mackcated Toplca Therapy it Adolsscents With Atoplc Demutis (IADE TEEN). Publhed 7021, Accesed 2071 ‘Simpan E Laa M, Brar , L Dissase Characaristcsand Burn InPatiants With Atopkc Demtits: mghts From Two Phase 3 Sl of uxobtints ream sournal of ablergy omd. Ol Imuaiogy. 021,147 2]-ABIE A5, KIS, S K, Popp K, Vertiraraa M, Nesk &, Kuigowsk! M. Effects of ot cream on prurtus and gualty of I atnplc rmatic: Resut rom a phase 2, randamibed, dosa- ranging, vehicke- and ative-corkoled stuy. ournalof the Amerioan Acadenny of Dermiiogy. 2020863051313, K BS, Hownil MD, S , Papp K, Nasir, Kulgouwskd ME. Trastmant of atoplccermatitk with Mint cruam AKYIARZ nhiitor o trfamcinolons cream. Jourmalof akergy o ivcal mmnology. 2020, AS[2)572-582. Pupp K Sczpdetovak K. Eficacy und Sty of Rusinlb Crean for the Treatmens of Aloplc Darmati: Raaus From Two Phaes 3, Randomized Dobis-Bind Sexfes, 2 Annal Revolutonlzig Acapic Dermatis Conferenoe; 2020 Chicagd, L. Poale Rasuks fram Incyta’s TRUE-AD! ard TRAE-ADZ Asople Darmacits Stulesof Rusfink Cream Stow Cliclly Meaninghu Kmproverments n Patier: Reparted Quakty of e Assemments [press relemse]. Incytm.com: Incyta2020. Elchonfied L, Cll R, Forsha D, ek al. Long-tarm satety of cfsaborole ontrent nchkdren, colmsces, and ackts with ik o moderate atopk dermat k. Pedlatrcdermatobgy Confersnce: 15th wori congressof peditrc dermatology Unlted states. 2017,M4:32.51. Eicherfeld LF, Yoslpowch G, Sein Gokl L, et al. mprovement I diesse severty and prstius uteomas with crsaborole sintmart, 2K by bacelta tapic darmadie savariy Inchicran and ‘adolescents whh il to-moderste toplk dermatis. Pedtri dermaiology. 2020. Schlesaiugar | Shepar 5, Gowar , . Sefety, Efactivaness, and Pharmarokinetics af ‘Graborole I Infars Ased 3 1< 24 Months wkh MI-to-Moderate Atopk Dermatits: A Phase 14 Ope bl tocy(CrRADR CARE 2 Ameta ol ol dercklogy 0102131275- ‘Smpmon EL Pllr A5, Bogniewics M, et al. Ciaborole Oirtment Improves Cumbiy of e of Pationts whih Miki o Motdarata Atop Deratis and Thelr Familes. Darmaiagy and therupy. RS 615, Yotlpowtch G, o L, Lebwali M, Sibarbar.1, Taliran AM, Zana LT. arly Rale of Prurtus. In Aopie Devmatia with Crssborole Oitmert, ANen sterokll, Fhosghodieserase 4 nhibior. Acta Derm Vanerol. 018905438485, Paller ASWSMD, Tom WLMD, Lebwob! MG, et . Eflcacy and sfety of criaborle alrtment, vl norsseroial phosphodlestarasa 4+ (PDEA) i btor forthe opical traxtmant of topic ‘Binsituta for Cincal and Economic Review, 2021 Papa 334 IAKihibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatiis - Evidance Rsport ‘Return to Table of Conanty m 1 m . 15 06 . . 1w, daratitl AD) In chkdran s ks Sl of the Amevin Acodermy of Dermatalogy: 201675(31494-505.0496. Puller A5, Ciaborolaclnt et nproves global siopkc dermatis sevrtly: pooled ress from s pacn 3 cliricalrats. ournat of investigatoe daroatology. 2014 Confarence: 472h Annual Mestingofthe European Socley for Dermatologkal Research, ESDR 2017 Ausira. 13710 Supplamane 245103, Papp K, Szeletowsi X, Kk L et . EMflacy and Sefety of Ruxoltin Cream for the Traatmant of Aoplk Dermati: asuls From Two Phasa 3, Rantomized, Doutle-lk Stules. utnatof the Amerioan Acxdemy of Demotology. 2021. Blauvait A, Echwnfekd L Effacy of sl Cruam Among Patieres With At Darmcis el on Previous Medlcaton Hisory: Poole el From Tw) Phase 3 Stucles. Faper presantad at: Amarican Arscemy o Darmatalopy Virul Mesting Expariencilz, EL.5, Augustin M, Thac D. Palant.Reparted Outcomes of il Cream for the Tragtment of Alople Dermutits: Fooled Reaults From Two Phase 3 Stuces. Paper presentz o: American ‘Acagery of Darmtalogy Virtusl Masting Experiancado21. L, KirckL Blauvet A Efficacyof uesltinib Creem I Pefents WRh Atoplc Demmati's Who Damortratad Parta Rasporser: Pockd AralyaltFrom Two Randomizad Phase 3 Seuche. Papar resented at; American Academny of Dermatology Vsl Experienceatd. Pupp , Sraphsrwesk . EFficacy of Rl i Craam for the Trastment of Acop Darmaits by Basaline Patient Bamographics: Pooled Subgroup Anayss From Two Raniomired Phsse 3 ‘Sudes. American Acadarmy of Darmatology Virhusl Meetng Experience; 2021. ‘Smpean BL Kl , Blausait A, Effect of R Craam I Pafants Wih Aropic Dermatit ‘Wit Baselne Boly Surfoce Ares 21056 and Eczema Ares and Severly I Score 216: Pooled ReatsFrom Two Phase 3 Stcles. Paper prasatec at: Amarcan Acadamy of Dermatology. Virtul Meeting Experience2a1. Pupp , Srapharei €, el L Efcary of ol Craam for the Trstmant of Aophc Dermetti by Baseline Cical Chracteritc: Pooted Subgroup Ansiysi From Twa Randorized Phase 3 Studhes. Papar prasented st Amarcan Acscammy of Dermatoiogy Vitual Msating Experianca 021, Basrn MIA, Salek MS, Camillrt L, Stekey R iy AY. Detrmiring the Minkml Cinkally Impartant Differance and Raaporehvness of the Dermatsiogy Life Qualty nde (DLC: Further Duta. Dermatobgy. 2015:230(1):27:3. (Crarman CR, Vann AL Willame HC. Tha ptfortccented scoema meaure: davelopmant and Ikl valdation of new 0 for measrtig siopkc caema severty from th patients' arspactivm. Arch Dermatol 2004;40{12}1513-1519. Siherbeng 4, Tryscen , Smpson EL, et Inpact o Oral Abrockin> Monatherapy on Patiers- Reportad Symatoms and iy o LI In Adoleszants and Aduks whth Moderate-to-Sevire Atopkc Bermatkis: A Poole Analylsof Patient-keportsd Outcomes. American oumolof ctical dermatology. 2021:724) SA1554.. ShiNL Asrocitin n the Trastmant of Moderata-to Sevars Aoplc Darmits Rafractory to Duphumab Trestmert: An Ansists of ADE EXTEND, u Phase 3 Lo Term Exteralon Siudy. Papar presented at REvakitoniing Atnple Darmati [VAD) Wrul Corferancedia1. Cliicairil.gov. A Shudy of arcink {LYS005104) s Patienks Wit Medert to Severe Atople Dt [BREEZE-AD, 1S Nationl Lbxary of Madicine. Pkt 2018. Arcassed. Clicaltrial.gov. Study of arktini {LY003104) I Fatents With Maceratsto Severe Atoplc Derarti (BREEZE-AD3). Published 2018, Accursed. ‘Binsituta for Cincal and Economic Review, 2021 Papa 335 IAKihibitors and Monocional Antibotlie for the Trestmernt of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conterey EEE EEEE . EEEE > 1 15 Ee 1. 13 1, Ll E. Barictink Package nset. 2038, ‘Abide. Upsdackiih Packaga Insart. 2018, BeckLA, Thag! D, Deleuran M, &l Dupfumab Provides Favorsble Safety and Sustained Effacy for upn 2 YearsInan Open-Label Sty of Acuks whh MadartertSevars Atoplc: Dermatits. Americon foumotof ciniol derictuiogy. Z0202AYSST 577, FuT KE, Linas E, e . Eczema and sarmiizacion to common allrgens b the Unkad Seate: uliethnic, populton-based sy, Pediauic Dematelogy. 204, ‘Asheroft DM, Chan L, Garakla R, Stain X, Willams HC Topical pimacratmua for scouma. Cochrane Dutstiase Siet . 2067(4)C3005500. Buyma ), Yul, Moul B, et . Developmant and valkston of patiert-raported putcama naasre fo eep dintursincs and seeprelsted Impakmens. S 20103(61781792. Zmmermarn M, A D, Chapeman B KuarV, Keb 5, Carbon.. Eceromic Bakaion of Duplumah for Maseratsto-Savere Atopk: Dermatit: A Ca-ilty Anabta. dournal f dnigs i1 dermatuiogy: J00. IATRISOTSE. ‘Schm|, Largan 5, Wilkams HC What arethe bast outcame mesraments fo atopl acaema? ‘Asystematic revew. ournal of ARergy and Clica trncology, 2007 L20(6):L385-1396. A E, .. Ui Seotes e tales, 2018, Hyateba, MD: Natiaral Comter for Hesfth Statiston2024, Natonal Economic Accourts. 2018, I/ /syt oo ianal ek, Accsead Augare 1, 2018, Hanfin I, M. Omto, M. Charl . Tofta, S. Graeber, M. Tha acsem ares sl severty Index. {EASD: aasassment o elbtyn atopic dermatits. EASI Evluator Group. 2001 Futamura ML, YA.Thomas, K5, Hankervis, H. Willims, HC. Simpaon, EL . A systematicreview of Invatgator Glabal Azsasumart (1GA] I stopc cermatiti AD) rak: many optons, o Standards. Journe of the Americon Azudemy of Dematokogy. Youlpoutch G, Reariey M, Mastey ¥, atal Peak Prurfus Hismarica Reting Scae: paychomatric valdation and respander defintion forassessng fxh inmoderate-to-severe atoplc dermatis. Bt ol f dermatology (195, 15 LBLIA) 761763, Kunz B0, AP. Labrdze, L Stader,F. Ring J Tateb, A. . lrcal lidaton and gulcelnes or the. SCORAD Index: Eomanauareport of the Eurspaan Tesk Forca on AtopDermaiti. 1957. Barrett 43, I Krgh, N. Bvan, E. Granasaity, A...Ptior:-Raported Outcome Measures In ‘Alopkc Dermatits are Chronic Hand Exzema In Adulte. 2019. Salek M, 5. Beicat-fufin, LA at .. Canica evperianca and peychometricpropertis ofthe hiiren' Dematology Lfe oty Index (COLOL. 1985 2012. The Srkich fournd of dermaiogy. 2013. Foley CT, . kmpson, . Tebera, HD. Lher-xelly, L Bodhar, A . evelopmert, and contert ‘sabty f new patant ruportad ouAcom guestioneaire t mceLsthe TS A syrptorna mnd Impact o atopks dermatis: the Atopkc Dermiatkis ymptom Scale (ADerm-SS) an the Atopkc Darmatii Impact Scala {ADerms} 2015, Dodington S8, MK. Finay, AY. Saiek, M. . The Dermattis FamlyImpact platianeaire: a roview of s mEasuramar properties and cinical applkcation. The St jourmadof deatniogy. 2013, Relly M2, AS. Dukes, EM. . Tha Ry and reprockchilty of 2 work prodiucthty and actvy Impakment indtrument . furmaoeconomics. 1993. Schneldor LT, . i, P. Boguniewicz, M. Beck, L LaBowidgn, . Nova, N. Atoplc dermatit: A Practice parmeter update 2012. Ameriodn Acodemy of Alergy, Asthina & immuiogy. 2013, ‘Binsituta for Cincal and Economi Review, 2021 Pape 336 IAKihibitors and Monocional Antibotle for the Trestmernt of Atopk: Dermatiis - Evidence Rsport ‘Raturn to Table of Conarey B OB EEEE B & 1 Tig . Eimca A Heyr. Pownll L Qupfumasfo reatig moderte to severe aicpic dermatits Tachlogy appralec gukionce (TATSA). National Incsture fr Health and Care Excalenca INICE) L Aupist 2018 2008, ‘Cook D, Mulross £, Heynes RB, Systamatic ravisws: syreha of st vidanca forclrical decslors. Ann itern Med. 1957; L26(5)376.350. Higain P. Cachrana Colaboratinn Hanbook for Systamatic Reviews of Itervantions. Vrsian 510 (udated March 2011]. 2000, Mhar D, iberat] A, TatiaFt Aran DE, Group P. rafured reporting lams for systematic Peviews and mets-anayses: the FRISMA tatement. ot/ Sg. ZD10A(5}-136-M41. ‘Aguncy for Huakhcare Ressarch and Cabty. US. Pravankive Servce Task Forca Procedurs Manual. Publshe 2008, Acceszac. Ollerdor D, earsan, 0. ICER Evidence Rating Matr: A Usees Gue. io/kzr- reviowoes/mathooiosyfcers methos/kcr-evidance.rtingmatre/. . Publlhed 2020, Updatad Innuary 31, 2020. Ascesee. Diae, Wtz N, Sutcan A, s AE, NICE Dacsion Suppor Ut Tachnlcl Support Documents. In: NCE DS Techiat SUppovE DOcuMent 2: A Generalise Livear Modelfng Framework or Piwis o fetwork Wit Anclyseof Randorised Contraked Tk, Lonor Nationl Instte or Heakh and Care Excellerce (MICE] Copyright © 2014 National inathute for Health and Clncal Encalnca, urbem tharwse statad. Al rgha reservad, 2014, Cork M, EckertL Simpsn EL, 31 Duplkimab Improves patiertreported symptoms of atoplc darmtis symptoma of adaty and deprassion,and hestyreleted qualty of e In moderata- ‘5-savere atopk: dematiis: araivls of poaled dta from the ranciombre gl SOLD 1 and 50110 2. Jouro of dermatidogice treatment. 2020;31{61606-614. ‘Shvertierg 1, Trystan P, Faheach K, ata. Cormparative fficacy nd afaty of systemc tharaplas. sedIn moderace o-severe atoplc dermtti:a systemaie IRrature revew and networkrmeta- ‘makpb. Joumaf o the Ewpear ey of Devmatoiagy ond Venereoiogy. 2024;n/a{a). Sanders 6D, Neumann P, B A, eta. Recommendation fo Conduct, Methodologcal Practices, and Ruporting of Cort-effactivaness Anaiyss: Scoid Panel on Cast Efectvanmse 11 Healthand Medicine, Jom. 2016,316(10]:1083-1105, ‘Smpman EL, Sinciai , Forman S, et al Effacy an safety of abroctin n achits ‘adolascants whth modrate-to-cevers atopk cermatiis (A MONG-1) 2 mutcartrs, double- bl rondomised, plocelrcontrolled. a3 . Lot London, England). 2020,306/100481255-256. Sierberg 1, Smaon EL Thysmen.F, et ol. Efficacy and Sty of Abeoctinl s Patents with Moderstao-Sevare Asopk: Dermatk: » Ranviamizei Chrkal THl. AMA dermeology. 2020, ‘Thag! D, Bleber T, Simpeon EL et aL. A Phase 3 Study to Investgate the eMicacy and Sty of ‘Abrocttis and Dpikumab In Camparison With Placsbo n Aduts Wit Modentato-Severe Atopkc Dormatkis. ‘Thae! D, L Skmpsan D, MK, et a. Bficacy and swfety of dupthumab moratheragy In dulty with odarate-o-savern tapic dsrmatis: 2 pooled anafyssof en phase rancombed trias {UBERTY ADS0L0 2 and IBERTY AD SOLG 7). Jourml of ermtologlce Science SA[Z) 266-215. Wollaniang A, Bogunieulcz M, Tavers ot al EMcary of Barichinl In Pacents whth Atcpie Dermutits nd Atopic Comorbidies: Renits of Pooied Data from 2 Phase 3 Mortherapy Randomisad, Douis-BInd, lacsbo-Controld 16 4weak Tils (BREEZE-ADY and BREEZE-AD]. Jounalof Alergy ond Ol mmuriology. 202D:1AS(ZLARIS0, ‘Binsituta for Cincal and Economi Review, 2021 Pape 337 IAKihibitors and Monocional Antibotle for the Trestmert of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conarey 5. SmpsanEL Forman s, ShvrbargJ, et ul Barickilb in ptiants with modersta-iosavermatosic carmatis: Rasuls ram rancombsac moriotherapy Phase il the Unfad Seates nd ‘Caruck (BREEZE-ADS). Jouno of the Amerioan Actemy of Dermatalogy. 2021, 6. PidardAS, Low B, llang R, e l. Unicad tatae Valuaton of EQ-5-51 Health Sxtes Using an Intemational Protoca. ellie b hedl :thefounal of the tematunal Sockety for ‘Pharmozsecanomice ond Outzomes Research, 0152208531841, 47, Megstre of CentralTendency for Wage D3k In United Sates Socal Securty Adminbtrtion201s, 148 Heahth M. Mometacone furoate: Average wholesale price. . M Acramsl DRIAGTEX 2021 45, Kumik, Bigo-Ls-Begovnsa , Eckart , e, Economic walumtion of dupliumahfor the treatmantaf mdarate - savers atopic drmati n aduits. Dermotoiogy and theregs. 2007:7{8)483-505. 150 Costanzo A, Fumar G, Bikanel R, Paconia M, Fane F, i Turl . Costeffectivenes anabyat of duplumab for the trestment of evere atopkdemmati natts n kafy. Globol & Reglone Hasith Technodogy Amsesoment. 2020;7{1}57-65. 5L Capkal Markets Doy: Epidemiology 2015, 152 Dupbant® {dupdumas Phase 3 cata show sigicant Improvermant In sevars mopic darmatis orchkran aged 610 11.years [ress efoase, 2020. 153, nseut fur Clnkal and Economic Raviaw, 2020-2023 Valua Assemmant Framework. e/t i 2000 2123 VAF 131704, Publshed 2020, Accro. 154, Pearson SD. The CER Value Framework: Itegrating Cot Efectivenass and Afordabimty In the ‘Assemment of Health Care Value. Vo in heolt thefournalof the ntemational Socet far ‘Pharmacoecanomice ond Outzamas Resecrch, 201821[31256- 5. 255, Clnkakrials.gov. Sudy to Evahate EMcacy and Sefety of F-02565852 I Subjects Aged 12 Years ‘And Okder With Motaruta to Sevarn Atap Darmati {ADE Mano-1). Publcha 2018, Accessad, 156, Clnkcaitriaagov. Sturty Evakaring Efcary an Safutyof PR.OS65842 In Subjacts Aged 12 Years: ‘And Okder With Moderate to Severe Atoplc Dermttls1ADE Mono-2). Cinical Tiss. Publlhed 2020, Acrmsnd. 157, Clcatriols.gov. Sidy To Evaluate PLOISGS8A2 I Sublects With Moderste To Severe Atookc = Dermatit. Fubllbed 2015, Accessed271. Relch . Traatment Withdrawal and Retreatmat wih Uadactinl b atieres with Moderste- 10 Severe AtopicDermets from u Phase 2b, Randomized, Controlled T, Paper preserted st Revakitioning Acnglc Darmeits (RAD) Wrtual Confarence202L 259, simpson . Tralokinumab provides progressive Improvements beyond week 16In patents with topic derartts whth an el partal reaponse. Papar prezantad u: Revoutinnling Atopic Dematils (RAD) Virtual Conference2021. ‘Binsituta for Cincal and Economi Review, 2021 Pape 33 IAKihibitors and Monocional Antibotie for the Trestmert of Atopk: Dermatiis - Evidance Rsport ‘Raturn to Table of Conarey