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Key BCMA players and what to look for at ASH Clipped from Goldman Sachs report.... 23 September 2018 Americas Healthcare: Biotechnology BCMA myeloma primer ahead of ASH Key BCMA players and what to look for at ASH A physician consultant we previously spoke with was extremely positive on the outlook for the future role of CAR-T therapy in the MM paradigm. He characterized the most recent BLUE/CELG bb2121 Ph1 efficacy data presented at ASCO 2018 as a “grand slam” in late-stage (R/R) MM and longer term expects the drug to move upstream and seemed most confident in CAR-T replacing auto-transplant (currently 7k/year in US, which could expand to 10k/year with CAR-T) in the transplant eligible setting. CAR-T treatment would follow Revlimid/Velcade/dex+/-Darzalex induction and the longer-term question would be the role of maintenance therapy following CAR-T. In the transplant ineligible setting he stated that in his view, five years from now patients will most likely get CELG’s Revlimid and JNJ’s Velcade and generic dex (RVd), or Rd plus JNJ/Genmab’s Darzalex (Dara) induction followed by (1) maintenance therapy, or (2) CAR-T treatment potentially followed by maintenance, where the question would be duration. In his view, the advantage of CAR-T is it offers patients the ability to be off of drug for some period of time. The physician was more optimistic on the outlook for bispecific antibody approaches targeting BCMA than ADCs, but noted that both of these “off-the-shelf” options could find use among the community oncologists who treat MM, while academic centers would likely focus on CAR-T. BLUE/CELG bb2121 Ph1 data set the bar against which others will be evaluated. Earlier this year at ASCO BLUE/CELG presented updated bb2121 CRB-401 Ph1 data (March 29 data cut-off, n=43) in r/r MM (median of 7-8 prior lines of therapy) across both the dose escalation (n=21) and dose expansion (n=22) cohorts with a median follow-up of 87 days for the latter. Median progression free survival (PFS) was 11.8 months (≥150e6 dose) in 18 patients from the dose escalation cohort, while the median PFS for patients from both cohorts who achieved MRD negative status (n=16) was 17.7 months. The Kaplan-Meier graphs indicate ongoing responses in several patients beyond one year including two patients over 20 months. Across the active doses (150-800e6 CAR T cells), the overall response rate (ORR) was 81% (vs. 94% at ASH 2017), complete response (CR) rate was 47% (vs. 56% prior), very good partial response (VGPR) rate of 25% (vs. 89% prior), PR of 8.3% (vs. 6% prior) and minimal residual disease (MRD) negative status in 100% of MRD evaluable patients (16/16, vs. 90%, 9/10 prior), indicating further deepening and durable responses with bb2121. The efficacy of bb2121 (450e6 dose) appeared comparable regardless of BCMA expression, with impressive ORR rates of 100% and 91% in the low (n=8) and high (n=11) BCMA expressor populations, respectively — indicating that regardless of immuno-histochemistry, BCMA is expressed at sufficiently high levels in myeloma cells to activate bb2121 CAR T cells. This is important as the Ph1 expansion cohort did not use a BCMA expression cut-off (vs. ≥50% BCMA expression in the dose escalation cohort of the Ph1 trial) which is similar to the ongoing pivotal KarMMA study. The updated bb2121 data continues to show compelling efficacy vs. standard of care JNJ’s Darzalex (29% ORR, 3% CR, and 3.7 months median PFS) particularly given 67% of patients in the bb2121 trial were refractory to Darzalex (30% penta-refractory). The safety/tolerability profile of bb2121 remains manageable and intact (vs. ASH 2017) with 63% (vs. 71% prior) of patients experiencing cytokine release syndrome (CRS) and 33% (vs. 24% prior) experiencing neurotoxicity events. Since the data was last presented at ASH 2017, there have been no additional cases of Grade 3 or Grade 4 CRS or neurotoxicity — thus the overall rates remain low (5% grade 3+ CRS and 2% neurotoxicity), which is encouraging and bode well for use in earlier line settings Based on bb2121’s observed dose-response and acceptable safety profile to-date, BLUE/CELG have amended the pivotal Ph2 KarMMA (4L MM) bb2121 study by raising the high end of the dose range to 450e6 CAR T cells (vs. 300e6 CAR T cells prior) and increasing enrollment up to 140 patients. The trial is ongoing (first patient infused in February 2018), and BLUE/CELG intend to submit a regulatory filing in the relapsed/refractory setting in 2019 — and we believe compelling results and the BTD/PRIME designations could provide an expedited pathway (GSe launch in 2020). We assume an 80% probability of success for bb2121 and model solely for the last-line setting translating to ~$3.5bn in global peak sales. Earlier-line bb2121 studies up next. BLUE/CELG recently initiated a Ph3 bb2121 (KarMMA-3) trial in 3L MM (n=381) comparing treatment arm A (n=254) patients receiving doses ranging from 150-450 e6 CAR T cells post lymphodepleting chemotherapy to arm B (n=127) patients receiving either (1) Darzalex/Pomalyst/dex; (2) Darzalex/ Velcade/dex; or (3) Ninlaro/Revlimid/dex. From here, we look to bb2121 label expansion opportunities in 2L and in 1L including high risk, transplant non-eligible (TNE) and transplant-eligible (TE). We currently do not include earlier line bb2121 in our model, which serves as an upside to our estimates. BLUE/CELG second-generation bb21217 to enhance durability and persistence. At CELG has a three pronged approach to targeting BCMA. At CELG’s multipleASH we expect a first look at next-generation bb21217 Ph1 CRB-402 data in r/r MM (n=50) to provide early signals as to whether the incorporation of the PI3K inhibitor-engineered program will enhance cell persistence and durability, as seen in preclinical studies. While data will be limited, we expect one year follow up on the longest duration patient (first patient dosed Sept. 2017) where we look to see whether the initial bb21217 profile is comparable in terms of activity and safety to bb2121 (data above). The CRB-402 trial design is similar to bb2121 CRB-401 in which patients will follow an initial dose-escalation phase (initial dose of 150e6 CAR-T cells vs. 50e6 CAR-T cells in CRB-401) to establish a recommended Ph2 dose after which patients will progress to the dose expansion phase to evaluate efficacy and safety at the recommended Ph2 dose. We currently do not include bb21217 in our model and view success on the program as upside to our estimates. myeloma deep dive event, management provided an overview of their entire BCMA portfolio (LINK). The company reviewed three approaches which include (1) CAR T (bb2121 and bb21217, which are partnered with BLUE and JCARH125 acquired via Juno), (2) T-cell engager antibody (CC-93269, Ph1 underway), and (3) an antibody drug conjugate (ADC), where an IND is planned for 2019. Management noted they believe their BCMA assets are complementary and anticipate potential use across nearly all MM patient segments as well as in combination with IMiDs. Specifically, CELG sees opportunities for BCMA ADCs in maintenance therapy and patients that are not fit for CAR-T and T-cell engagers as induction therapy and for tumor debulking. At ASH we expect the first data for bb21217 (as mentioned above) and potentially the first data for JCAR125. |
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Msg # | Subject | Author | Recs | Date Posted |
220466 | Re: Key BCMA players and what to look for at ASH | Cordari30 | 2 | 9/24/2018 1:27:32 PM |