BMS/Bluebird's BCMA-Targeted CAR-T Therapy ide-cel Receives Accelerated Assessment in EU Amid FDA Filing Setback

Bristol-Myers Squibb (BMS) and its partner bluebird bio recently announced jointly that the European Medicines Agency (EMA) has accepted the Marketing Authorization Application (MAA) for idecabtagene vicleucel (ide-cel, bb2121). The EMA has confirmed the completeness of the MAA and initiated the centralized review procedure. In March this year, ide-cel was granted accelerated assessment status by the EMA, shortening the MAA review cycle to 150 days.

ide-cel is an investigational anti-B-cell maturation antigen (anti-BCMA) chimeric antigen receptor (CAR) T-cell therapy developed for the treatment of patients with relapsed/refractory multiple myeloma (R/R MM), specifically indicated for adult patients with MM who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

In March this year, Bristol-Myers Squibb (BMS) and bluebird bio Inc. submitted a Biologics License Application (BLA) to the U.S. FDA for ide-cel for the same indication. Notably, in mid-May this year, the FDA issued a refusal-to-file letter, declining to accept the BLA. Following an initial review, the FDA determined that further details were required in the Chemistry, Manufacturing, and Controls (CMC) module of the BLA to complete the review. However, the agency did not request additional clinical or non-clinical data. BMS plans to resubmit the BLA by the end of July 2020.

The regulatory application for ide-cel is based on the results of the pivotal Phase II KarMMa study. In this study, 128 heavily pre-treated patients with relapsed and refractory multiple myeloma, who had previously received at least three therapies and were refractory to the last therapy (defined by the International Myeloma Working Group [IMWG] as no response to treatment or disease progression within 60 days of treatment), received ide-cel at dose levels of 150–450 × 10⁶ CAR+ T cells. These patients had a median of six prior lines of therapy; 84% were triple-class refractory, meaning they were refractory to all three commonly used classes of agents, including immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 antibodies; 94% were refractory to anti-CD38 antibodies. The median follow-up duration was 13.3 months.

The study met its primary endpoint of overall response rate (ORR) and the key secondary endpoint of complete response rate (CR). Safety results were consistent with previously reported ide-cel data. The data showed an ORR of 73% across all dose levels, with 33% of patients achieving a complete response (CR) or stringent complete response (sCR). The median duration of response (DoR) was 10.7 months, and the median DoR for patients with CR or sCR was 19.0 months. The median progression-free survival (PFS) was 8.8 months, while the median PFS for patients with CR or sCR was 20.2 months. All patients who achieved CR or sCR and were evaluable for minimal residual disease (MRD) were MRD-negative.

Consistent clinically meaningful benefits were observed across all subgroups, with objective response rates (ORR) of 50% or higher in nearly all subgroups, including elderly 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 a 12-month survival rate of 78%. The results support a favorable risk–benefit profile for ide-cel at the target dose level of 150–450 × 10⁶ CAR+ T cells. Detailed data will be presented at the American Society of Clinical Oncology (ASCO) 2020 Virtual Scientific Program on May 29.

Stanley Franke, M.D., Senior Vice President of Cell Therapy Development at Bristol-Myers Squibb, stated, “Europe is one of the regions with the highest incidence of multiple myeloma. Patients who experience relapse and are refractory to standard treatment regimens require new therapeutic options to improve their prognosis. We will continue to collaborate with the EMA to bring ide-cel to patients in the European Union who are battling this aggressive blood cancer.”

ide-cel is the first CAR-T cell therapy targeting BCMA and for the treatment of MM to be submitted for regulatory approval. BCMA is a protein widely expressed on multiple myeloma (MM) cancer cells, making it an important potential target for treating this aggressive blood cancer.

The mechanism of action of ide-cel involves engineering patients’ T cells to express a chimeric BCMA receptor. The manufacturing process entails isolating T cells from each patient’s blood and modifying them using a lentiviral vector encoding the BCMA antigen receptor, thereby enabling surface expression of the BCMA receptor on the T cells. Prior to treatment, patients with multiple myeloma (MM) undergo preconditioning chemotherapy with two agents—cyclophosphamide and fludarabine—to deplete existing T cells in the body. Subsequently, bb2121 is infused. Once administered, ide-cel seeks out and destroys cells expressing BCMA.

Previously, ide-cel was granted Breakthrough Therapy Designation (BTD) by the U.S. FDA for the treatment of R/R MM in November 2017, and was also granted Priority Medicines (PRIME) designation by the European Medicines Agency (EMA) for the treatment of R/R MM.

ide-cel is part of a joint development, co-promotion, and profit-sharing agreement between Bristol-Myers Squibb and bluebird bio. The parties’ integrated clinical development program for ide-cel includes multiple clinical studies in earlier-line treatment of multiple myeloma (MM) (KarMMa-2, KarMMa-3, KarMMa-4), including newly diagnosed MM.

In addition to ide-cel, Bristol-Myers Squibb and bluebird bio are also developing the second-generation anti-BCMA CAR-T therapy bb2127. This product is further developed on the basis of the first-generation CAR-T therapy ide-cel, incorporating a PI3K inhibitory signal to produce a CAR-T product enriched with “memory T cells.” This represents a longer-lived and more potent T-cell subset with improved antitumor activity.

BCMA-Targeted Investigational Immunotherapies for MM (Source: PMID: 31277554)

Multiple Myeloma (MM) is the second most common hematologic malignancy after non-Hodgkin lymphoma. In recent years, despite significant advances in chemotherapy, proteasome inhibitors, immunomodulatory thalidomide derivatives, and CD38-targeted antibodies, nearly all patients eventually experience relapse. Therefore, there is an urgent need for new therapeutic regimens. The MM market is projected to reach $29 billion by 2027.

BCMA is an extremely important B-cell biomarker, widely expressed on the surface of multiple myeloma (MM) cells, and has become a highly prominent immunotherapeutic target for MM and other hematologic malignancies in recent years. Currently, there are more than 20 immunotherapies developed targeting BCMA, primarily categorized into three classes: chimeric antigen receptor T-cell therapy (CAR-T, represented by Bristol-Myers Squibb/bluebird bio and Novartis), bispecific antibodies (BsAb, represented by Amgen), and antibody-drug conjugates (ADC, represented by GlaxoSmithKline).

In January and February of this year, GlaxoSmithKline’s (GSK) B-cell maturation antigen (BCMA)-targeted antibody-drug conjugate (ADC), belantamab mafodotin (GSK2857916, at a dose of 2.5 mg/kg), received Priority Review from the U.S. FDA and Accelerated Assessment from the European Medicines Agency (EMA), respectively, for the treatment of patients with relapsed or refractory multiple myeloma (R/R MM) who have previously received multiple therapies, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

Belantamab mafodotin has the potential to become the first BCMA-targeted therapy to reach the market. In 2017, belantamab mafodotin was granted Breakthrough Therapy Designation (BTD) by the U.S. FDA and Priority Medicines (PRIME) designation by the European EMA, becoming the first BCMA-targeted agent to receive both BTD and PRIME designations.

Data from the pivotal Phase II DREAMM-2 study showed that in patients with relapsed/refractory multiple myeloma (R/R MM) who had received extensive prior therapy (median number of prior regimens: 7), the overall response rate (ORR) was 31% (n=30/97) in the belantamab mafodotin 2.5 mg/kg dose group and 34% (n=34/99) in the 3.4 mg/kg dose group, which is clinically meaningful. Data from the DREAMM-1 study demonstrated that the ORR reached 60% in BCMA-positive R/R MM patients treated with belantamab mafodotin. (Bioon.com)

Original Source: European Medicines Agency Validates Bristol Myers Squibb’s Applications for Idecabtagene Vicleucel (Ide-cel, bb2121)

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