Setback for Bristol Myers Squibb’s BCMA CAR-T Therapy Idecabtagene Vicleucel as FDA Issues Refusal to File

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On May 13, 2020, the U.S. marketing application for a key BCMA-CAR T-cell therapy asset acquired by Bristol-Myers Squibb encountered obstacles, as the FDA issued a Refusal to File, indicating that additional CMC data were required for the BCMA-CAR T-cell therapy Idecabtagene Vicleucel (ide-cel, bb2121). Bristol-Myers Squibb expects to resubmit the marketing application before July 2020.

At the beginning of 2019, Bristol-Myers Squibb made a major acquisition of Celgene, obtaining two blockbuster assets: 1. The S1P receptor modulator ozanimod. After experiencing setbacks (including receiving a Refusal to File [RTF] due to issues with its active metabolite), Zeposia (ozanimod) was finally approved for marketing in the United States on March 26, 2020, becoming the second approved next-generation S1P receptor modulator; 2. The BCMA-CAR T-cell therapy idecabtagene vicleucel. Coincidentally, on May 13, 2020, it received a Refusal to File due to deficiencies in CMC data!

Idecabtagene vicleucel is currently the leading BCMA-directed CAR T-cell therapy worldwide and is expected to be the first approved BCMA-targeted CAR T-cell therapy.

Recently, Bristol-Myers Squibb still has an Opdivo combined with Yervoy for the first-line indication of non-small cell lung cancer in the marketing review stage, and updates are expected in mid-May. Opdivo combined with Yervoy is expected to become the first approved tumor immunotherapy combination therapy for non-small cell lung cancer, which will also be the first first-line lung cancer therapy for Opdivo.

This article will focus on reviewing the key clinical data and clinical progress of Idecabtagene Vicleucel.

I. Idecabtagene Vicleucel: Pivotal Clinical Trial KarMMa, Objective Response Rate of 73.4%

http://investor.bluebirdbio.com/static-files/ed76cc34-963a-4e63-b576-9a612c4dc578

The pivotal clinical trial supporting the current marketing application for Idecabtagene Vicleucel is KarMMa (NCT03361748). According to the disclosed clinical data, in the high-dose cohort, Idecabtagene Vicleucel demonstrated a high objective response rate (ORR) in patients with multiple myeloma who had received four or more prior lines of therapy, with an ORR of 81.5% and a complete response/strict complete response (CR/sCR) rate of 35.2%. Across all patients with multiple myeloma, the ORR was 73.4%, and the CR/sCR rate was 31.3%.

Idecabtagene Vicleucel vs. Standard Therapy Provides Deep Remission for Patients with Multiple Myeloma After Fourth-Line Treatment: In Traditional Standard Therapy, ORR is 30% and CR is 3%.

II. Multiple Myeloma: An estimated 69,000 patients in the United States, with first-line therapies covering 31,000 cases

DOI: 10.1038/nrdp.2017.46

Globally, multiple myeloma is highly prevalent in Europe and the United States. Statistical data indicate that in 2019, there were an estimated 69,000 patients with multiple myeloma in the United States, among whom 31,000 received first-line therapy, 20,000 received second-line therapy, 12,000 received third-line therapy, and 6,000 received fourth-line or subsequent therapies.

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As mentioned above, idecabtagene vicleucel has currently disclosed data from a pivotal registrational clinical trial, namely KarMMa (NCT03361748). Meanwhile, several other pivotal clinical trials of idecabtagene vicleucel are still under development, including KarMMa-3 for third-line treatment of multiple myeloma, KarMMa-2 for second-line treatment, and KarMMa-4 for first-line treatment.

These Three Clinical Trial Advances Deserve Continued Attention!

III. Bristol-Myers Squibb’s Acquisition of Two Late-Stage Clinical Assets Faces a Bumpy Road to Market; Progress of Opdivo in Combination with Yervoy Also Warrants Close Attention

In early 2019, Bristol-Myers Squibb made a major acquisition of Celgene, kicking off the new year! Among the clinical pipeline assets acquired, ozanimod and idecabtagene vicleucel are the two most heavily watched blockbuster candidates.

o On March 26, 2020, after overcoming setbacks, Zeposia (ozanimod) was finally approved for marketing in the United States, becoming the second approved next-generation S1P receptor modulator, with the approved indication of relapsing-remitting multiple sclerosis (RRMS). Due to issues related to its active metabolite CC-112273, it received a Refusal to File (RTF) letter, resulting in Zeposia’s approval being delayed by nearly two years compared to the initially expected timeline.

o In a similar vein, on May 13, 2020, the BCMA-CAR T-cell therapy Idecabtagene Vicleucel (ide-cel, bb2121) also encountered obstacles in its path to market approval due to deficiencies in CMC data.

On May 7, 2020, Bristol-Myers Squibb announced its first-quarter 2020 financial results. Global sales of Opdivo declined year-over-year for the first time, reaching $1.766 billion, a 2% decrease compared to the same period last year. Due to setbacks in expanding indications for non-small cell lung cancer, Opdivo’s first-mover advantage has been completely eroded.

Based on the PDUFA date of May 15, 2020, if the expansion of Opdivo in combination with Yervoy proceeds smoothly, it will mark Opdivo’s first approved first-line therapy for lung cancer, representing a milestone advancement in the treatment of non-small cell lung cancer (NSCLC). The Opdivo and Yervoy combination will become the first chemotherapy-free regimen for NSCLC. The author will continue to monitor this regulatory progress closely.