Idecabtagene Vicleucel Ide-cel for the Treatment of Multiple Myeloma Regulatory Update

Highlights 
- Ide-cel (Idecabtagene vicleucel) is being c0-developed by Bristol Myers Squibb and bluebird bio.
- Investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy, 
- For the treatment of adult patients with multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody. 
- Under FDA & EMA review with decision pending (expect by H1 2021)

Ide-cel is a B-cell maturation antigen (BCMA)-directed genetically modified autologous chimeric antigen receptor (CAR) T cell immunotherapy. The ide-cel CAR is comprised of a murine extracellular single-chain variable fragment (scFv) specific for recognizing BCMA, attached to a human CD8 α hinge and transmembrane domain fused to the T cell cytoplasmic signaling domains of CD137 4-1BB and CD3-ζ chain, in tandem. Ide-cel recognizes and binds to BCMA on the surface of multiple myeloma cells leading to CAR T cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells.

Regulatory Status

FDA/BLA
In September 2020, Bristol Myers Squibb &  and bluebird bio, Inc announced that the U.S. FDA has accepted for Priority Review the Biologics License Application (BLA) for idecabtagene vicleucel (ide-cel; bb2121), the companies’ iThe U.S. FDA has set a PDUFA goal date of March 27, 2021

EMA/MAA
In March 2020, European Medicines Agency (EMA) has validated its Marketing Authorization Applications (MAA) for both idecabtagene vicleucel (ide-cel, bb2121) and CC-486.


Clinical Study Update

Pivotal KarMMa Study of Ide-cel in Relapsed and Refractory Multiple Myeloma Patients
In the study, 128 patients with heavily pretreated relapsed and refractory multiple myeloma who were exposed to at least three prior therapies and were refractory to their last regimen per the International Myeloma Working Group (IMWG) definition (no response to therapy or disease progressed within 60 days) were treated with ide-cel across target dose levels of 150-450 x 106 CAR+ T cells. Patients had a median of six prior regimens; 84% were refractory to all three classes of commonly used treatments including an immunomodulatory (IMiD) agent, a proteasome inhibitor (PI) and an anti-CD38 antibody, and 94% were refractory to anti-CD38 antibodies. Median duration of follow-up was 13.3 months.

Efficacy
The overall response rate (ORR) was 73% across all dose levels, including 33% of patients who had a complete response (CR) or stringent CR (sCR). Median duration of response (DoR) was 10.7 months, with 19.0 month median DoR for patients who had a CR or sCR. Median progression-free survival (PFS) was 8.8 months, with 20.2 month median PFS for patients who had a CR or sCR. All patients who had CR or sCR and were evaluable for minimal residual disease (MRD), were MRD-negative. Clinically meaningful benefit was consistently observed across subgroups, and nearly all subgroups had an ORR of 50% or greater, including older and high-risk patients. The overall survival (OS) data continue to mature, with an estimated median OS of 19.4 months across all dose levels and 78% of patients alive at 12 months.1 Results support a favorable benefit-risk profile for ide-cel across the target dose levels of 150 to 450 × 106 CAR+ T cells.

Safety

The most frequently reported adverse events (AEs) were cytopenia and cytokine release syndrome (CRS). Cytopenias were common and not dose related. Overall, CRS of any grade was reported in 84% (107/128) of patients. Grade 3 or higher CRS occurred in <6% (7/128) of patients, with one fatal CRS event. Investigator identified neurotoxicity events (iiNT) were reported in 18% (23/128) of patients, including Grade 3 iiNT reported in 3% (4/128) of patients. There were no Grade 4 or Grade 5 iiNT events reported.

Reference 
https://www.bms.com/
https://www.bluebirdbio.com/



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