1、North America Equity Research10 April 2019US BiotechnologyUpdated Deep Dive:The BCMA Drum Beats On;What to Expect Over the Next 12+Months-ALERTBiotechnology Large CapCory Kasimov AC(1-212)622-Bloomberg JPMA KASIMOV Matthew T Holt,Ph.D.(1-212)622-Carmen Augustine,CFA(1-212)622-J.P.Morgan Securities L
2、LCSee page 96 for analyst certification and important disclosures.J.P.Morgan does and seeks to do business with companies covered in its research reports.As a result,investors should be aware that the firm may have a conflict of interest that could affect the objectivity of this report.Investors sho
3、uld consider this report as only a single factor in making their investment decision.Following ASH and ahead of a busy period for the BCMA space(including two pivotal data sets and a continuing deluge of earlier-stage data),we wanted to update our BCMA deep dive(deck attached&linked here).There has
4、been some separation(as evidenced by a couple program discontinuations),but its still way too early to crown any clear winners.Nevertheless,we believe BLUE remains well positioned.In our attached SLIDE DECK we include:(1)a comprehensive overview of the BCMA landscape;(2)detailed data sets updated po
5、st-ASH;and(3)comparisons to current treatments in r/r MM.Bottom line,the BCMA space continues to be competitive with further data updates starting in mid-2019.However,with a high bar already set,longer-term durability data(not expected until late 2019/2020 at the earliest)will be key to any therapeu
6、tic/modality differentiation.BLUE remains well positioned despite the growing wave of competition.BLUEs bb2121 CAR T remains in the lead in terms of timing and overall strengthof clinical profile,with pivotal data expected in 2H19 and a BLA filing shortlythereafter.It is neck and neck with GSKs 916
7、antibody-drug conjugate(ADC),with pivotal data also expected in 2H19.At this point,were aware of 30 CART/ADC/bispecific programs targeting BCMA,and many will have data over the next12+months.CAR Ts have produced the most compelling data sets to date.Notwithstandingthe normal caveats of cross-trial c
8、omparisons,when looking at the data presented atASH and more mature data sets,CAR T therapies(e.g.,bb2121,LCAR-B38M)haveproduced the best results to date,in our view.We see this as a high bar for futuredevelopment.though it is becoming clearer that not all BCMA CAR Ts are created equal.Though it is
9、too early to pronounce winners,there is some evidence of separation between BCMA CAR T candidates(and potentially other modalities)given recent events.Indeed,both GILD and NVS have discontinued their initial programs and instead will focus on dual/multi-target approaches.In the likely event that mor
10、e than one BCMA therapy makes it to market,wecontinue to see room for multiple players.Given the unmet need in patients whoare high risk,not eligible for transplant,or who have failed several therapies,we dosee room for multiple players/modalities within the MM space,though there is theongoing comme
11、rcial question that CARs still need to answer.That said,we believethat a combination of efficacy,safety,and dosing convenience/combinability willplay a role in the how this plays out in the likely event that multiple therapies makeit to market.We also note that theres an ongoing push in the clinic t
12、o move BCMAtargeted therapies earlier in the treatment paradigm.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-direct
13、ed 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)a
14、s 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
15、 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 pla
16、yers.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
17、 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
18、 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 Landsc
19、ape: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 f
20、ew 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
21、 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
22、 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 BLAsubmissi
23、on 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 re
24、cruiting”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 expe
25、cted 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 my
26、eloma.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.59M
27、ultiple 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)s
28、uperfamilyIn 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 r
29、eceptor 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.
30、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 targe
31、ting 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
32、?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 delineate
33、d 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 toxi
34、cities.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 c
35、onfounded 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 fa
36、ctors 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 Recepto
37、r(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
38、 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
39、.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 c
40、ell 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
41、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).He
42、re,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&molec
43、ules):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
44、 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 autologo
45、us 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)MCARH1
46、71(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
47、-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;Comp
48、any 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 t
49、here 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%),enrolle
50、d 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 2018P
