J.P. 摩根-美股-生物科技行业-摩根大通生物科技研究：BCMA深度研究-2019.4-99页.pdf

Matthew T Holt,Ph.D.212-622-J.P.Morgan Securities LLCJ.P.Morgan Biotech ResearchUpdated BCMA Landscape Deep DiveNorth America Equity ResearchApril 2019Cory W.Kasimov AC212-622-J.P.Morgan Securities LLCCarmen Augustine,CFA212-622-J.P.Morgan Securities LLCArun Kiran Pasumarthy+91-22-6157-J.P.Morgan India Private LimitedSee the end pages of this presentation for analyst certification and important disclosures,including non-US analyst disclosures.J.P.Morgan does and seeks to do business with companies covered in its research reports.As a result,investors should be awarethat the firm may have a conflict of interest that could affect the objectivity of this report.Investors should consider this report as only a single factor in making their investment decision.2With multiple BCMA-directed therapies making their way through the clinic for multiple myeloma,we are providing an update on the competitive landscape and expected catalysts over the next 12+months.By our count,there are 30 BCMA-directed therapies either in or advancing towards the clinicThese can be divided into CAR T therapies(both autologous&allogeneic)and biologic-based approaches(e.g.bispecifics&antibody-drug conjugates,or ADCs)that each comprise 50%of the landscapeThough its difficult to crown one therapy(or even modality)as best-in-class given the early-stage of development(even following a very busy ASH),CELG/BLUEs bb2121 and GSKs 916 remain neck and neck in the race for first-to-marketIn our view,durability remains the most important consideration,and well need to wait until late 2019/2020(at the earliest)to have a better understanding of how BCMA therapies stack upThat said,pivotal data for bb2121&916 in 2H19 are the key 2019 catalysts to watch;we suspect these will inform future BCMA developmentand though initial datasets from these programs have set the bar very high,we ultimately see room for multiple players.We do see room for multiple players/modalities within the MM space given the unmet need in patients that are high risk,not eligible for transplant,or who have failed several therapies We expect a combination of efficacy,safety,and dosing convenience/combinability to determine how this plays out commerciallyin the likely event that multiple therapies/modalities make it to marketFollowing a plethora of datasets at ASH,its still too early to pronounce winnersalthough there is some evidence of separationb/w candidates(as evidenced by a couple of program discontinuations)Within this deck,youll find:A brief introduction to BCMA&CAR T/biologic modalities An updated&detailed review of the more mature datasets thus far,including data presented at ASH 2018A brief overview of multiple myeloma and historical data in the relapsed and refractory multiple myeloma settingOverview of the BCMA Landscape:Executive Summary3ASH 2018 was rife with BCMA data sets,although the conference(as expected)offered limited visibility into eventual competitive positioningThere were 50 ASH abstracts relevant to BCMA-directed therapies What we saw included initial clinical data for many CAR T constructs(and a few biologic approaches)with a focus on response rates and safety given the limited follow-up for most of these programsSee our BCMA-related ASH takeaways(hereand here)however,it is becoming increasingly clear that not all BCMA CAR Ts are created equal,with two major players pressing the reset button after disappointing initial attemptsNovartis has moved away from pursuing a BCMA CAR T monotherapy and will instead look at combination approaches with CD19-directed CAR T therapiesAt our Healthcare Conference,Gilead noted that their KITE-585 BCMA CAR-T therapy“was not as good as competitors”and is planning a dual targeted approach to improve outcomes(specific details TBD)and there were a few other updates and smaller deals that occurred post-ASH as wellGSK completed enrollment for the GSK 916 pivotal in 4L patients earlier than expected and now is guiding to a 2H19 readout with a BLAsubmission by YE19(this was accompanied by a publicationfor the initial Phase 1/2 study with an updated mPFS of 12 months vs.the previous 7.9 months at the interim)A CT.gov update for CELGs CC-93269 bispecific indicates that development plans may have changed.The Phase 1 study is now listed as“active,not recruiting”with only 19 patients enrolled(vs.an original target of 125 pts)BLUE continues to expect trial initiations for bb2121 in the 2ndand 3rdline in r/r MM in 1H19ABBV partnered with little known Teneobioto develop their BCMA-targeted bispecific TNB-383B(the initiation of clinical studies is expected in 1H19)So Whats New Since the Last Update?4Intro to BCMA and CAR T/biologic modalities.5The BCMA-directed treatment landscape in multiple myeloma An Overview.9CAR T BCMA Approaches.16BLUE:bb2121 data in relapsed/refractory multiple myeloma.17BLUE:bb21217 data in relapsed/refractory multiple myeloma.27CELG:JCARH125 data in relapsed/refractory multiple myeloma.34JNJ/Legend Nanjing:LCAR-B38M data in relapsed/refractory multiple myeloma.42Advanced Biologic BCMA Approaches.50GSK:GSK 916 data in relapsed/refractory multiple myeloma.51AMGN:AMG420 data in relapsed/refractory multiple myeloma.59Multiple myeloma overview.66Appendix 1:Whats the current bar in relapsed/refractory multiple myeloma?.69Appendix 2:Clinical trials with BCMA-directed therapies.80Table of Contents5Intro to BCMA and CAR T/biologic modalities6B cell maturation antigen(BCMA)is a member of the Tumor Necrosis Factor(TNF)superfamilyIn healthy cells.BCMA is expressed on terminally differentiated B cells that include some B cells and some normal plasma cells(see graphic below).Its restricted expression in healthy tissues makes it a good target,as on-target toxicity is limited.BCMA resides on the cell surface and is a receptor for the two ligands BAFF and APRIL.One function of these ligands is to stimulate antibody production in plasma cells.Other roles for BCMA in healthy cells include:1)playing a role in the regulation of the immune system;2)controlling proliferation;3)differentiation;and 4)apoptosis of B cells.In multiple myeloma.BCMA is expressed on multiple myeloma cells(=an abnormal plasma cell),and in most cases the presentation is uniform.Interestingly,soluble BCMA has been identified in the serum of multiple myeloma patients and is higher in patients with progressive disease;aconsideration for targeting the BCMA antigen.In MM,BCMA is thought to play a role in protecting myeloma cells from apoptosis.One interesting(and unanswered)question is whether eliminating highly expressing BCMA cells would dampen multiple myelomas proliferation potential.Source:Maus et al.CCR Translations 2013What Is BCMA?BCMA is a great candidate in MM given(1)its expression is limited to plasma cells and(2)its prevalence amongst MM cellsCAR T 101:OverviewSource:CELG Company presentation;June et al.Cancer Immunotherapy 2018;Company Reports;JP Morgan Research CARs are artificial fusion proteins that can be delineated into targeting,costimulatory and T cell activation components2ndgeneration CARs consist of three main components:Antigen-recognition domain Typically,this is a binder derived from a highly specific antibody.Proper target selection remains critical in CAR T therapy to prevent on-and off-target toxicities.Co-stimulatory domain The inclusion of a“co-stim”domain leads to more robust T cell activity.Two commonly used co-stim domains are CD28 and 4-1BB.Although there is much debate over which co-stim is best(and plenty of research ongoing),clinical data does not support one over the other and is confounded by a number of variables.T-cell activation domain This domain is required for T cell activation upon antigen binding and is the CD3 zeta domain derived directly from the TCR in the majority of CARs.Beyond choosing the right target(and target-recognition region)and a co-stim,other design factors can affect the function of CAR Ts(this also includes cell type selection).Further,few standards for CAR T design have been established and design remains largely empiric.CAR T therapy uses engineered immune cells to directly target antigens on the outside of tumor cellsChimeric Antigen Receptor(CAR)-based therapies directly target the antigen of interest(for example CD19 or BCMA)with elements from the T-cell receptor(TCR)signaling pathway(hence why they are chimeric)Upon binding the antigen,CAR T cells destroy the targeted cell and then may:1)proliferate to create more CAR T cells;and/or 2)target additional cells that contain the target antigenSee our CAR T deck(here)for a more comprehensive overview7Building on the success of antibodies that target a single antigen,two main types of“advanced”biologic approaches are used in oncology to further enhance anti-tumor activity:Source:J.P.Morgan Research;CELG Company PresentationAn antibody drug conjugate(ADC)approach relies on the chemical modification of a highly specific antibody(i.e.directed to BCMA)with a chemical that will be toxic to the cell(known as a cytotoxin)once bound to the antigen.This approach effectively localizes cell toxins to a target(in the case of BCMA,on multiple myeloma cells).There are multiple approaches being taken to modify antibodies with cytotoxic drugs(which is by no means a trivial task).There are two currently approved ADCs on the market that are used to treat specific cancers.Bispecific-based therapies include targeting domains for both the antigen(e.g.,BCMA)and T cells(e.g.CD3)or other immune cells and can be thought of as providing a bridge to facilitate immune system recognition.This approach aims to localize immune cells to the target(in the case of BCMA,on multiple myeloma cells).Here,many different approaches are being pursued(including different targets and biologic design)to engage immune cells in the correct way that leads to a robust immune response.Currently,one product has been approved to treat blood cancer.Antibody drug conjugates:Bispecifics(antibodies,engagers&molecules):Advanced Biologics 201:ADCs and Bispecifics89The BCMA-directed treatment landscape in multiple myeloma An Overview10The BCMA Landscape in r/r MM at a GlanceSource:J.P.Morgan;Company PresentationsMultiple BMCA-targeted CAR T and biologic therapies are making progress in the clinic,with the next 12 months expected to(once again)be a data rich periodGiven the early stage of development for many of these programs,it is difficult to predict which will ultimately be best-in-class;however GSKs 916&BLUEs bb2121 are neck and neck in terms of development(pivotal data in 2H19)BCMA-directed autologous CAR TBCMA-directed autologous CAR T w/additional specificity BCMA-directed allogeneic CAR T BCMA-directed antibody drug conjugateBCMA-directed bispecificSelect BCMA CAR T Programsbb2121(CELG/BLUE)bb21217(CELG/BLUE)LCAR-B38M(JNJ/Nanjing)CAR T-BCMA(NVS)xKITE-585(GILD/KITE)xJCARH125(CELG/JUNO)MCARH171(CELG/JUNO)AUTO 2(Autolus)P-BCMA-101(PSTX)Descartes-08(Cartersian Therapeutics)ALLO-715(ALLO)P-BCMA-101-Allo1(PSTX)CTX120(CRSP)Anti BCMA CAR(Casebia)Anti BCMA CAR(CBMG)P/C=Preclinical;mAb=monoclonal antibodyP/CPhase 1/2PivotalSelect BCMA Biologic ProgramsGSK2857916(GSK)AMG 420(AMGN)AMG 701(AMGN)PF-0683135(PFE)JNJ-64007957(JNJ/Genmab)CC-93269(CELG)x?MEDI2228(AZN)AMG 224(AMGN)xREGN5458(REGN)SEA BCMA(SGEN)TNB-383B(ABBV/Teneobio)BCMA ADC(CELG/Sutro Biopharma)AFM26(AFMD)HPN217(Harpoon Therapeutics)HDP101(Heidelberg Pharma)P/C=PreclinicalP/CPhase 1/2Pivotal11Source:ASH 2017;ASCO 2018;ASH 2018;Company presentationswhile acknowledging the limited/early data,bb2121 efficacy looks highly competitive with other BCMA CAR Ts and BCMA-directed biologics:Below we highlight select data from the more advanced BCMA CAR T/biologic programs:We detail many of these programs later on in this deck.Although there were plenty of initial data sets&updates at ASH,theearly-stage nature of many of these programs(and the focus on durability)make comparisons difficult at this juncture.The BCMA Landscape in r/r MM at a GlanceNote that these trials use different BCMA cut-offs(e.g.,no selection,BCMA+,50%),enrolled different patient populations,and are data cuts from different time points(and in some cases geographic regions)making cross-trial comparisons difficult.CompanyDrugLCAR-B38MTrialPhase 1BCMA expression:No selectionDosing:per kg(3x)PreconditioningCySourceASH 2018ASH 2018ASH 20182019 BCL pubASH 2018Prior lines,median(range)7(4-17)7(3-23)7(3-14)3(1-9)6(3-11)54(2-13)Median f/u(months)6.55.92.62.1123.76.6Efficacy150 x 106150 x 106Overall150 x 106Overall2x106/kg dose3.4mg/kg q3w4x102 ug/d/cycleORR95.5%(N=21/22)83%(N=10/12)82%(N=36/44)86%(N=24/28)88%(N=57)65%(N=11/17)60%(N=21/35)70%(N=7/10)VGPR86.4%(N=19/22)50%(N=6/12)48%(N=21/44)43%(N=12/28)77%(N=44/57)29%(N=5/17)54%(N=19/35)50%(N=5/10)CR rate50.0%(N=11/22)25%(N=3/12)27%(N=12/44)18%(N=5/28)74%(N=42/57)-14%(N=5/35)40%(N=4/10)DoR,median(days)329-480-429-mPFS(months)-15(N=57)-12 mos-SafetyCRS,Gr3-49%(N=2/22)8%(N=1/12)9%(N=4)7%(N=2)7%(N=4/57)0%0%0%NT,Gr3-45%(N=1/22)8%(N=1/12)7%(N=3)7%(N=2)0%(N=57)5%(N=1/21)0%0%Infections,Gr321%(N=9/43)8%(N=1/12)14%(N=6/44)14%(N=4)NR10%(N=2/21)17%(N=6/35)21%(N=9/42)includes patients treated at other doses;dose escalation cohortBiologicsGSKGSK2857916Phase 1 No selectionper kgNAFlat dosing(1x)Flu/Cy(3x)ASCO 20188(3-23)11.8(N=18)Flat dosing(1x)Flu/Cy(3x)CAR TJNJ/NanjingAny(N=10 50%)bb21217Phase 150%bb2121Phase 1CELG/BLUECELG/JUNOJCARH125Phase 1No selectionPosediaP-BCMA-101Phase 1No selectionper kgFlu/Cy(3x)ASH 2018flat(1x)Flu/Cyper kgNAAMGNAMG 420Phase 1No selection12Source:J.P.Morgan;Company reportsAutologous approaches have made the most progress in the clinic with BLUEsbb2121 pivotal study in the 4L reading out in 2H19Allogeneic approaches are much earlier;however we could see these CARs enter the clinic sometime in 2019(with data as early as 2020)Though were likely to get updates on many of these programs starting in mid-2019,well have to wait until late 2019/2020(at the earliest)to get a sense of durability.However,what is clear(especially following the pivoting of NVS&GILD away from initial BCMA programs)is that not all CAR Ts/strategies are created equal.Within the BCMA-targeted CAR T space,multiple different strategies are being exploredThe BCMA CAR T Landscape in r/r MMBCMA-directed autologous CAR TBCMA-directed autologous CAR T w/additional specificity BCMA-directed allogeneic CAR T Select BCMA CAR T ProgramsMkt Commentsbb2121(CELG/BLUE)Pivotal studies in r/r MM(4L data is expected in 2H19)and earlier lines ongoingbb21217(CELG/BLUE)Manufacutred in combo with PI3K;Next update expected at ASH 2019LCAR-B38M(JNJ/Nanjing)Targets 2 BCMA epitopes;US-based Ph 1b/2 study initiated in 2H18CAR T-BCMA(NVS)xIn combo with CD19 CAR T therapies(Ph1 started in 2018);monotherapy not being pursuedKITE-585(GILD/KITE)xDevl discontinued;GILD planning dual targeted approach that is BCMA-basedJCARH125(CELG/JUNO)Also in combo with a GSI(LY3039478);Phase 1 updates expected in 2019/2020MCARH17