BMS, bluebird bio’s Investigational BCMA CAR-T Therapy Faces Regulatory Setback

By Rajaneesh K. Gopinath, Ph.D. &

T. Chakraborty, Ph.D.

Bristol Myers Squibb (BMS) and bluebird bio had just amended their collaboration agreement for ide-cel, but their approval hopes suffered a hitch after the FDA declined its BLA. A resubmission is on the cards, and more importantly, both companies announced that updated positive trial results of the immunotherapy candidate would be presented in the upcoming ASCO 2020 meeting.

Multiple Myeloma

Multiple myeloma (MM) is the second most common blood cancer after Non-Hodgkin Lymphoma. Studies reveal that in 2020, an estimated 32,270 adults (17,530 men and 14,740 women) in the US will be diagnosed with the disease with approximately 12,830 deaths (7,190 men and 5,640 women) [1]. The overall 5-year survival rate of patients is 52%, but it could rise to 74% if the cancer is detected at an early stage. Unfortunately, in 95% of the cases, it is already spread to distant parts of the body at the time of diagnosis.

CAR-T Therapies for MM

Chimeric Antigen Receptor T (CAR-T) cell therapy is an immunotherapeutic approach where the receptor of the patient-derived T-cell is genetically manipulated to enhance its immune response against tumors. CAR-T cell therapies have gained widespread prominence in recent years to treat various types of cancer [2]. The B-cell maturation antigen (BCMA) expressed by mature B lymphocytes is an attractive therapeutic target since it is constitutively activated in MM patients. Therefore, CAR-T cell therapies commonly use receptors to target this cell surface protein [3].

BMS, bluebird bio’s Investigational BCMA CAR-T Therapy

Idecabtagene Vicleucel (ide-cel; bb2121) is one such CAR-T cell therapy where the BCMA receptor is genetically expressed in the patient’s T-cell. Ide-cel identifies the BCMA expressed on the surface of myeloma cells and activates the T-cells. This leads to the secretion of proinflammatory cytokines that target and destroy BCMA expressing cancer cells.

Ide-cel was originally developed by Celgene in collaboration with bluebird bio, but BMS got hold of it, all thanks to the US$ 74 billion worth acquisition of Celgene. Earlier in the week, BMS and bluebird amended their existing co-promotion/co-development agreement. As per the new terms, bluebird will get a one-time upfront payment of $200 million in place of the previous milestone and royalty payments. This will be an upgrade for the company from being a passive supplier outside of the US to an equal partner that shares the profits and losses within the country.

“With bluebird exiting the passive participation as supplier outside the U.S., we and BMS are taking steps to ensure an efficient and robust supply chain for this program. This, together with the monetization of our ex-U.S. royalties and milestones will allow bluebird to continue to participate in co-developing and co-commercializing ide-cel within the U.S. and to refocus resources on our internal programs and pipeline,” said Joanne Smith-Farrell, Ph.D., Chief Business Officer and Oncology Franchise Leader of bluebird bio.

FDA’s Refusal to File

Both companies filed the Biologics Licence Application (BLA) for ide-cel in March. However, on May 13th, they announced receiving a Refusal to File (RTF) letter from the FDA. After conducting a preliminary review, the regulatory agency deemed that the Chemistry, Manufacturing, and Control (CMC) module of the BLA needs additional details. However, requests were not made for any clinical or non-clinical data.

One of the remaining steps of the Contingent Value Rights (CVR) issued upon the close of the Celgene acquisition is the FDA approval of ide-cel before March 31st, 2021. The other one is the approval of liso-cel before December 31st, 2020. BMS remains steadfast in progressing both the applications to achieve its milestones and honor the CVR.

Phase 2 KarMMa Study

Multiple clinical studies (KarMMa-2, KarMMa-3, KarMMa-4) are currently evaluating ide-cel in earlier lines of treatment for patients with MM, including newly diagnosed ones. However, ide-cel built its reputation with the strong showing in the pivotal Phase 2, KarMMa trial that evaluated its efficacy and safety in patients with relapsed and refractory MM. The study showed that ide-cell improved both the overall response rate and complete response rate, the primary and second endpoints respectively. The updated results from the study will be presented at the ASCO20 virtual scientific program in two weeks.

Ide-cel has been granted multiple designations for multiple myeloma by the FDA including Breakthrough Therapy Designation (BTD) and PRIority Medicines (PRIME) along with Accelerated Assessment by the European Medicines Agency (EMA). If approved, it will become the first BCMA directed CAR-T cell therapy for MM. BMS is planning for a BLA resubmission no later than July 2020.

Related Article: Beigene’s Tislelizumab-Chemo Combo Nails Primary Endpoint in Phase 3 Trial

References

1. https://www.cancer.net/cancer-types/multiple-myeloma/statistics
2. https://www.geneonline.com/2020/04/26/car-t-therapy-a-boon-for-cancer-treatment/
3. https://www.nature.com/articles/s41375-020-0734-z
4. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-provide-regulatory-updat
5. https://news.bms.com/press-release/celltherapy/bristol-myers-squibb-and-bluebird-bio-announce-submission-biologics-licens
6. http://investor.bluebirdbio.com/news-releases/news-release-details/bluebird-bio-announces-amended-bcma-car-t-collaboration
7. https://news.bms.com/press-release/corporatefinancial-news/bristol-myers-squibb-and-bluebird-bio-announce-positive-top-li

Author

Rajaneesh K. Gopinath