自身免疫与炎症市场会继续增长

1、Credit Suisse Equity ResearchAmericas/United StatesSomething Big Is Getting Bigger Will Autoimmune/Inflammatory Markets Continue to Grow?April 3, 2019RESEARCH ANALYSTSDISCLOSURE APPENDIX AT THE BACK OF THIS REPORT CONTAINS IMPORTANT DISCLOSURES, ANALYST CERTIFICATIONS, LEGAL ENTITY DISCLOSUREAND THE

2、 STATUS OF NON-US ANALYSTS. US Disclosure: Credit Suisse does and seeks to do business with companies covered in its research reports. As a result, investorsDISCLOSURE APPENDIX AT THE BACK OF THIS REPORT CONTAINS IMPORTANT DISCLOSURES, ANALYST CERTIFICATIONS, LEGAL ENTITY DISCLOSUREAND THE STATUS OF

3、 NON-US ANALYSTS. US Disclosure: Credit Suisse does and seeks to do business with companies covered in its research reports. As a result, investorsshouldbeawarethattheFirmmayhaveaconflictofinterestthatcouldaffecttheobjectivityofthisreport.Investorsshouldconsiderthisreportasonlyasingle factor in maki

4、ng their investment decision.Research Analyst+1 212-325-6573 HYPERLINK mailto:martin.auster martin.austerTiago FauthResearch Analyst+1 212-325-7569 HYPERLINK mailto:first.last tiago.fauthcredit HYPERLINK mailto:first.last - HYPERLINK mailto:first.last Mark ConnollyResearch Associate+1 212-325-7576 H

5、YPERLINK mailto:mark.connolly mark.connollycredit HYPERLINK mailto:mark.connolly - HYPERLINK mailto:mark.connolly Our investor dialogue suggests a significant focus on smid cap companies with high growth potential through a novel technologyplatformwithbroaddrugdevelopmentcapabilitiesandoncompaniesad

6、dressingmajortotaladdressablemarket (TAM) opportunities. This piece explores smid biotechs ability to compete in “crowded” large ($10b+) TAMindications.There remains an unmet need and room for marketexpansionAutoimmune/inflammatory markets have grown substantially in the past years driven by new the

7、rapeutics options, despite generally being considered crowded.Claims data and physician feedback suggest underpenetration of biologics and novel oral agents among moderate/severe patients, even within well established disease categories.believe new mechanism biologics, novel oral agents, and even bi

8、osimilars are all pro-growth factors that support expansion of penetration of addressable target markets.Cycling through different therapeutic options is common, and allows for new entrants to capture shareA significant portion of patients do not achieve long-term responses with currently available

9、options owing to suboptimal drug coverage, development of anti-drug antibodies, or recalcitrant disease.Patients often cycle through options within the same class, while the best outcomes have been shown to be experiencedbypatientswhoswitchtoagentswithadifferentmechanismofaction. Manyopportunitiesex

10、istfornew- to-market agents to garner share.There is strong demand for oral agents, which we view as potentially expansionary for end marketsIn our market research, patient preferences around route of administration plays a meaningful role in the underpenetration ofbiologics.Orals may have higher ac

11、ceptance among patients, attracting new subjects into treatment and, as importantly, can help keep patients who have failed 1L anti-TNF therapies in the treatment loop.Formulary placement / rebates still play a big role, but less of a concern for earlier-stage biotechsRebate negotiations in exchange

12、 for preferential formulary placement, especially for drugs approved for multiple indications, could stack the deck against smaller players, and still play a big role on the launch trajectory. Rebate reform, if enacted, could help to level the playing field.Promising drug candidates are often acquir

13、ed/ in-licensed by well-established players with commercial infrastructure and access in place. continue to see demand for assets in large markets, where a few years head start could translate into multi-billion dollar potential.Biosimilars are unlikely to sate the markets appetite for novel/improve

14、d agents, and could have anexpansionary effect on the number of total treatedpatientsexpect increasing availability of anti-TNF biosimilars to further cement the class position in the treatment paradigm, potentially relegating most novel agents to 2nd line or similarly to what is seen Availability o

15、f additionalagentsatdiscountedpricescouldmodestlyincreasethenumberoftreatedpatientsbyimprovingaccess.We highlight 2 smid-cap companies in our universe that benefit from these macro factors:Anaptys Bio (ANAB, $143): is driven by its anti-IL-33 etokimab, with Ph2b data in AD and nasal polyps (NP) H2 2

16、019.Proof of concept has been established in P2a studies for AD and Asthma.IL-33 is a promising target with high interest from large pharma/biotech. ANAB is first-mover IL-33 in AD/Asthma/NP are in early stage of biologic penetration; we see a novel best-in-class agent having $4b Arena (ARNA, $77):i

17、sdrivenbyoralS1Pmodulator,etrasimod;initiatingPh3UCtrialsoonwithinductiondatapossiblyearly end of 2020; CD just behind.There is an opportunity for etrasimod to differentiate from other oral agents (JAKi) and intra-classcompetitors.see a best-of-breed oral agent in IDB commanding peak sales $3b+; whi

18、le Ph3 data points are long-dated, etrasimods promising clinical profile and than 50% forboth UC/CD, with a 10% and 14% rate of switching for UC and CD respectively for the same period.2Lack of Efficacy Can Lead to Patients Exiting AsmallstudyonUCtreatmentpatternsshowed that 50% of ADA and IFX users

19、 discontinued therapy within 12 months, with 50% of discontinuers not restarting/ switching therapies. 3The Case for Switching MoA: A study of Commercial and Medicare Advantage claims on treatment persistenceRheumatoid Arthritis patients switching biologics showed higher persistence rates for MOA sw

20、itchers versus TNFi cyclers, and lower rates of subsequent switching. 4spoketophysiciansacrossdisciplinesthemajorityhighlightthatthereremainsanunmetneed fornewagentsthatcanproducedurableresponseswithdifferentiatedmechanismsofaction.Source: Credit Suisse Research, (1) Lin, Pei-Tzu, Shu-Hui Wang, and

21、Ching-Chi Chi. Scientific reports (2018), (2) Patel, Haridarshan, Trevor Lissoos, and David T. Rubin. PloS5one (2017), (3) Null, Kyle D., et al. Value in Health (2017), (4) Chastek, Benjamin, et al. Advances in therapy (2017).Not a One-Size-Fits-AllStrategyThere Are Different Ways to WinBeingfirst-i

22、n-classinanindicationhelps,butisnoteverything.Whilethesemarketstendto be “sticky” (Remicade in IBD), there remains potential for differentiation on duration of response and administrative convenience momentum among theIL-5s)Oralscanalwayscarveoutaniche.Dosingconveniencealone,withoutdifferentiationon

23、 seems to be sufficient to drive share gain in some markets (Otezla in Psoriasis).Differentiation on efficacy is a best-case scenario (multiple agents in MS, Xeljanz in RA), and could disrupt the market by driving the bulk of the share away from biologics.Thereareexamplesofhighlysuccessfulcommercial

24、launchesforbothfollowerswitha proven mechanism of action and new agents with novel mechanisms of action. (There are five anti-TNF agents approved, all with multi-billion dollar sales)Costs, route of administration and treatment failure remain barriers to biologic uptake. see biosimilars,oralagents,a

25、ndnovelMoAbiologicshavingthepotentialtofurtherincrease penetration of addressable target markets within inflammatory/atopicdisease.Relevant Cases forNew Agents in Established MktsNovel Orals Inevitably FindTheirFooting generalaversiontoinjectablesoffersanopportunityfornoveloralswithamenableclinical

26、profilestoentermaturemarketsandexpand/takemarketshare PsoriasisOtezlaMSto$1.4bninPsoriasis;5yrs onthemktOral agent in a market served by injectablesGenerallyseenas“goodenough”forsome patientsReasonable safety profile (despite some GI AEs in some patients) and oral dosing likely broaden prescriber ba

27、se3rdtomarketoralthatachieved$3.5bnin sales 3 yrs postlaunchDifferentiated safety profile than oral alternatives (e.g., no first-dose monitoring for cardiac complications)commercial prowess in MS$1.4$1.1$0.9$1.4$1.1$0.9$0.4$0.1$4.2$4.3$3.6$4.0$2.9$0.9FY14FY15FY16FY17FY18FY13FY14FY15FY16FY17FY18Relev

28、ant Cases forNew Agents in Established MktsOld Dog, New Physician familiarity with traditional MoAs with additional features/attributes have been able demonstrate significant marketuptake RASimponiMSOcrevus$1bninRAwithin4yrsonthemkt(approved 09)Launched while 4 other TNF-alphas were on the market(am

29、ongotherviableoptionswithdifferent MoAs)Comparableefficacyandoptimalmonthlydosing regimen$2.5bninMS;2yrsonthemktLatest MS drug to be approved in the marketUptake can be attributed to markedly positive physiciansfamiliaritywithoff- labelutilization,andbettersafetythan$2.3$1.9$2.3$1.9$2.0$1.4$1.5$0.9$

30、0.9FY14FY15FY16FY17FY18FY17FY18Relevant Cases forNew Agents in Established MktsDifferentiated MoAsAre Generally Welcomed Compounds with novel MoAs benefit from building up physicians armamentarium against the high rate of relapses andnon-responders PsoriasisCosentyxUC&CDEntyvioto$2bninPsoriasis;4yrs

31、 onthe mktLaunched against three anti-TNFs, one IL12 /IL-23, and an oral PDE4iPhysicians we spoke to believe Cosentyx was the firstagentwithanoticeableefficacyimprovement vs approved therapies at launch, which led to broader utilization as a 2nd linebiologicto$2b+inIBD;5yrsonthemktLaunched against 4

32、 anti-TNFs across UC/CD with a new MoA and IV dosing (Q8W)Established efficacy in both nave and anti-TNF failures. No black box warningSimultaneous launch in UC and CD$2.3$1.8$1.3$1.8$1.3$0.7$0.3$1.5$1.5$0.9$0.3FY15FY16FY17FY18FY14FY15FY16FY17FY18Biosimilars to Limited Impact onNovelFront-lineTherap

33、y to Remain Just CheaperAnti-TNF biologics are front-line therapy in IBD/RA/PsoriasisBiosimilars have successfully launched in EU and are poised to impact the US market, even if delayedAs the CS Pharma team discussed in the “ HYPERLINK /s/V7edvi4AF-Z8Ws Keepin HYPERLINK /s/V7edvi4AF-Z8Ws g HYPERLINK

34、 /s/V7edvi4AF-Z8Ws U HYPERLINK /s/V7edvi4AF-Z8Ws p HYPERLINK /s/V7edvi4AF-Z8Ws wit HYPERLINK /s/V7edvi4AF-Z8Ws h HYPERLINK /s/V7edvi4AF-Z8Ws th HYPERLINK /s/V7edvi4AF-Z8Ws e HYPERLINK /s/V7edvi4AF-Z8Ws Biosimilars” note, the EU impact from recent biosimilar launches is being closely watched.EU Humir

35、a erosion has been greater than initially expected with discounts of 10-80% and recent entrants at the higher end of the range.Merck saw rapid erosion in Remicade EU sales upon entry of biosimilars, with a loss of 2/3 sales in threeyears,primarilyduetobiosimilarplayersaggressivepricediscounttowingov

36、ernmenttendersEnbrel is experiencing gradual erosion in the EU as reported by with a loss of 1/3 of sales in the two years since launch of first biosimilar in Jan 2016.In the US, IP litigation has forced several biosimilar makers to postpone launches for several years (Humira biosimilars expected on

37、ly in 2023); impact from other front-line biosimilars in the US has been smaller than initially expected.10Source: Credit Suisse ResearchSelect StocksHighlightsGoodThingsCome toThose Who .Orals Have Historically Demonstrated Substantial Penetration in Mature MarketsKey Debates and Drivers:Potentiall

38、ybest-in-classoraltherapeuticinlargemarketsthat have high patient-turnover.Main overhang is the entrenchment of existing agents in theIBD markets and being the 3rd-4th oral to launch.While we do encounter investor push back as major events are skewed towards 2021+, $1.3b cash position (60% of curren

39、t mkt cap) and etrasimods potential make it worth investing in our Estimated Peak End Markets:UlcerativeColitis Crohns Disease$8-12b$15b$8-12b$15bWe currently model $3b+ in peak sales across Ulcerative Colitis and Crohns Disease.AssetEnd-MarketsEtrasimodS1P receptor agonist selective for S1Pr1,S1Pr4

40、, and S1Pr5EtrasimodModulates lymphocyte trafficking by preventing their egression from the lymph nodes into theplasmaHigh selectivity avoids the 2 receptorsassociated with bradycardia and AV block (S1Pr 2&3)P2 data in UC was potential best in classOzanimod (CELG) data in CD de-risksMoAModerate/high

41、 growth (UC/CD), entrenched competitorsCompetitive clinical pipeline SOTP Valuation($/sh) oHigh optionalityEtrasimod-UCPhase3InductionDataReadoutend-2020 - early-2021111625 2 1 42077246CatalystTimingEtrasimod-111625 2 1 42077246CatalystTimingPotential DifferentiationPotential best-in-class, selectiv

42、e S1P modulatorOral agentFavorable safety/efficacy in UCEtrasimod-UCPhase3(Treat-through)DataReadoutend-2021 - early-2022Etrasimod-CDPhase2/3Induction-1DataReadoutend-2021 - early-2022Etrasimod-CDPh2/3Induction-2DataReadoutend-2021 - early-2022Etrasimod-CDPhase3MaintenanceDataReadout2H 2022 - 1H 202

43、3GoodThingsCome toThose Who .Orals Have Historically Demonstrated Substantial Penetration in Mature MarketsTheonlyindicationwithdataonetrasimodandJAKissuggestetrasimod maybemoreefficaciousthanitscompetitors = 10.3% = 20.0% = 14.0% = 10.3% = 10.3% = 20.0% = 14.0% = 10.3% = 18.7%Clinical Remission Rat

44、es based on 4-domiain Mayo Score except for Upadacitnib (adapted-Mayo Score no physicians global assessment)Etrasimod2mg(QD)producednoSAEsintheirPh2UCtrial,furtheringourbest-in-class and oral drug of choice thesisUlcerative ColitisFDA Approval TimelineRemicadeTNF-alphaSimponi (SQ)TNF-alphaXeljanz/Xe

45、ljanz XRJAK/STATSep-05Sep-06Sep-07Sep-08Sep-09Sep-10Sep-11Sep-12Sep-13Sep-14Sep-15Sep-16Sep-17Sep-18Estimated Global Sales ($b)$3.1$3.8$3.1$3.8$4.3$1.7$0.7$1.0$1.4HumiraTNF-alphaEntyvioIntegrin2018ETxMix2024E TxMix1%23%76%10% 23%76%10% 7%14%50%20%HumiraEntyvioSimponiXeljanzRemicadeWith relative bett

46、er efficacy to front-line agents and a potentially less aggressive disease course compared to Crohns, the marketforbiologics/advanced oral agents for UC is at an earlier stage, but catching up.Thereremainsanunmetneedforsustainablelong-termremission.Failuresoccuroften,andpatientsmayswitchproduct/clas

47、sesmultipletimes during the course of the disease.Current clinical pipeline is exploring multiple targets, and is heavily focused on JAKs.Crohns DiseaseFDA Approval TimelineRemicadeTNF-alphaTysabriIntegrinEntyvioIntegrinAug-98 Aug-99 Aug-00 Aug-01 Aug-02 Aug-03 Aug-04 Aug-05 Aug-06 Aug-07 Aug-08 Aug

48、-09 Aug-10 Aug-11 Aug-12 Aug-13 Aug-14 Aug-15 Aug-16 Aug-17 Aug-18HumiraTNF-alphaCimziaStelaraIL-12 / IL-23TNF-alpha$7.6$8.6$7.6$8.6$5.7$6.8$4.1$4.7$10.4$11.42018ETxMix2024E TxMix4% 2% 4% 2% 1%10%9%16%17%74%67%HumiraRemicadeStelaraEntyvioCimziaOthers2018 estimated market for biologics in Crohns dise

49、ase is $11bn, with three main therapeutic classes currently available. Biologics uptake in CD exceeds penetration in UC owing to disease severity.New entrants, with differentiation on efficacy have proven the ability to expand the market opportunity and garnershare.Similarlytootherlargeautoimmune/in

50、flammationmarkets,weexpectmultipleclassestocoexist.Thereishighmarketoptimismontheavailability of new oral agents, which could differentiate on efficacy and dosing regimen.GoodThingsCome toThose Who .Orals Have Historically Demonstrated Substantial Penetration in Mature MarketsKey Assumptions:Price:

51、$50,000/year (WAC) on the Xeljanzs WAC priceKey Assumptions:Price: $50,000/year (WAC) on the Xeljanzs WAC pricePeak Addressable Population (TNF-alpha antagonist non- responders): 45% (UC); 60% (CD)weestimatetheproportionof patients continuing to receive aTNF- alphaantagonistinthe2Lsettingwillprogres

52、sively decrease y-o-y (70% to54% UC), (50% to 40% CD)based on novel biologics with MoAs and the entrance or oral therapeuticsPeak Market Share: 15% we estimate oral agents will capture of the TNF-alpha antagonist non- respondersmarketandetrasimodwill reach 30% of the oral agents marketPoS:75%(UC)45%

53、(CD)- ARNAhas not presented any data of etrasimod in CD, but we believe ozanimods data from its open-label trial de-risks the opportunityM&A Prospects(ARNA)We see Arena as a potential acquisition target considering the multi-billion dollar potential for etrasimod, optionality across other indication

54、s, and late-stage status in Ulcerative Colitis. Here is a list with players in the IBD space that could be potential consolidators.CompanyProductTargetCrohns DiseaseUlcerative ColitisCommercial PlayersHumira Skyrizi UpadacitinibTNF-alpha IL-23JAK/STATApproved IIIIIIApproved IIIIIIRemicadeTNF-alphaAp

55、provedApprovedSimponi (SQ)TNF-alphaApprovedStelaraIL-12 / IL-23ApprovedBLATD-1473JAK/STATIIII/IIIJNJ-64304500UnknownIIbTremfyaIL-23IIXeljanz/Xeljanz XRJAK/STATApprovedPF-06480605TNF-SF15IIPF-06651600 /JAK/STATIIIIbPF-06700841 EntyvioIntegrin -4 -7ApprovedApproved CimziaTNF-alphaApprovedLate Clinical

56、 Stage Players BI IL-36/IL-36RIIIOzanimodS1P-RIIIIII IL-23IIIII FilgotinibJAK/STATII/III EtrolizumabIntegrin -4 -7IIIIIIAn Emerging Leaderin a Competitive SpaceEtokimab Is an Early Mover Among IL-33 Drug CandidatesKey Debates and Drivers:ANAB is developing an asset with potential best-in-class mecha

57、nism of action for atopic diseases.markets are incipient, with multi-billion dollarpotential, but competitive clinical pipeline.Main overhang is potential competition from oral agentsand other IL-33 programs.EstimatedPeakEndMarkets:Atopic Dermatitis$8-12b$8-12bSevere Asthma$10-15b+$10-15b+expect int

58、erest in the stock to pick up substantially towards mid-2019 given multiple catalysts ahead.We currently model $3-3.5b in peak sales across moderate- severe atopic dermatitis and severe asthma.SOTP Valuation ($/sh) 59 33 16 510211718143CatalystCatalystEtokimab Asthma - Phase Detailed DataEtokimabAss

59、etAntibody targeting the IL-33 cytokineIL-33 is a central mediator of atopic diseasesActs upstream from other targets in AD (IL4-r) and asthma (IgE and IL-5)Potential for Q4W SC delivery or less frequentlyOnly IL-33 targeting asset with clinical data in AD and pbo-controlled data in severe eosinophi

60、lic asthmaEnd-MarketsHigh growth, few commercial competitorsCompetitive clinical EtokimabAssetAntibody targeting the IL-33 cytokineIL-33 is a central mediator of atopic diseasesActs upstream from other targets in AD (IL4-r) and asthma (IgE and IL-5)Potential for Q4W SC delivery or less frequentlyOnl