Bristol Myers Squibb, bluebird bio Submit Second BLA for MM CAR T-Cell Treatment

Bristol Myers Squibb and bluebird bio submitted a second Biologics License Application (BLA) to the FDA for idecabtagene vicleucel (ide-cel), the companies’ investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell immunotherapy. The treatment is indicated for adults with relapsed and refractory multiple myeloma.

Ide-cel functions by recognizing and binding to BCMA on the surface of multiple myeloma cells. This leads to CAR T-cell proliferation, cytokine secretion, and subsequent cytolytic killing of BCMA-expressing cells. The treatment is currently not approved in any region.

An original BLA was submitted in March 2020 while the new submission includes information regarding the Chemistry, Manufacturing and Controls (CMC) modules, addressing regulatory requests the FDA issued in May 2020.

Results from the phase 2 KarMMa study showed high overall response rates (ORRs) in patients treated with ide-cel. All participants had relapsed and refractory multiple myeloma, were exposed to at least 3 prior therapies (an immunomodulatory [IMiD] agent, a proteasome inhibitor [PI] and an anti-CD38 antibody), and were refractory to their last regimen. Results were announced during an oral presentation at the American Society of Clinical Oncology 2020 (ASCO20) Virtual Scientific Program.

“Patients with relapsed and refractory multiple myeloma that have been exposed to all 3 major drug classes, including an IMiD agent, a PI and an anti-CD38 antibody, have fewer treatment options and poor outcomes, including shorter response durations and lower overall survival,” the companies’ statement reads.

KarMMA included a total of 140 patients, 128 of whom received ide-cel across target dose levels of 150-450 x 106 CAR+ T cells. Eighty four percent of patients enrolled were refractory to all 3 classes of treatments and 94% were refractory to anti-CD38 antibodies specifically.

The study yielded the following results:

• 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 a 19-month median DoR for patients who had a CR or sCR
• Median progression-free survival (PFS) was 8.8 months, with a 20.2-month median PFS for patients who had a CR or sCR
• Nearly all subgroups had an ORR of 50% or greater, including older and high-risk patients
• 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, as of May 2020

Cytopenia and cytokine release syndrome (CRS) were the most commonly reported adverse events. Researchers determined cytopenias were not dose related. In addition, CRS of any grade was reported in 84% of patients, while grade 3 or higher CRS occurred in <6% of participants. On patient died from the complication. Eighteen percent of patients exhibited investigator identified neurotoxicity events, including grade 3 events in 3% of patients; however, no grade 4 or 5 neurotoxicity events were reported.

“Patients in the KarMMa study reflect a very advanced and highly refractory population, so it is particularly gratifying that the results…demonstrating deep and durable responses, underscore the potential of ide-cel as a meaningful new treatment option for these patients,” said David Davidson, MD, chief medical officer of bluebird bio.

Ide-cel was previously granted Breakthrough Therapy Designation (BTD) by the FDA and received PRIority MEdicines (PRIME) designation and validation from the European Medicines Agency (EMA) in May 2020. The treatment was also granted accelerated assessment by the EMA in March 2020.

“We are very encouraged and excited by the depth and durability of responses seen with ide-cel in this first pivotal study of a CAR T cell therapy in multiple myeloma,” said Nikhil C. Munshi, MD, an author of the study. “Patients with relapsed and refractory multiple myeloma have decreased life expectancy, with no clear standard of care and limited responses to currently available treatment options, leaving them in critical need of new therapies.”