BMS’ Breyanzi Beats COVID-19 Constraints, Emerges As First RMAT Approval
Executive Summary
After missing user fee date due to inspection delay, US FDA clears the CAR-T therapy for treatment of adults with relapsed or refractory large B-cell lymphoma.
The Center for Biologics Evaluation and Research’s 5 February 2021 approval of Bristol Myers Squibb Company’s chimeric antigen receptor T-cell (CAR-T) therapy Breyanzi is notable not only for its designations – in addition to the RMAT, Breyanzi holds a breakthrough therapy designation – but as the first major product to have been approved after a COVID-19-induced missed user fee goal.
When Breyanzi’s 16 November 2020 user fee goal passed without a letter from the US FDA, Mallinckrodt plc’s bioengineered skin tissue StrataGraft looked like it could become the first RMAT-designated agent approved by the FDA. But StrataGraft’s 2 February 2021 goal date for treatment of serious burns also passed without news, and Breyanzi nabbed an approval on 5 February – more than 13 months after the CAR-T therapy was submitted.
Back in November, Bristol explained the FDA could not inspect a third-party manufacturing facility in Texas. (Also see "US FDA Reaffirms Commitment To Resuming Domestic Inspections As Industry Frustration Grows" - Pink Sheet, 27 Nov, 2020.)
Throughout the COVID-19 crisis, the agency has been fine-tuning its approach to reconciling a quality review system that relies on in-person facility inspections with the reality of travel restrictions. (Also see "US FDA Resumes China, India Inspections In Bid To Keep Drug Approvals On Schedule" - Pink Sheet, 26 Jan, 2021.)
The agency has been conducting remote reviews of records; when review suggests an issue, the FDA will issue a complete response letter, but in the absence of a signal the review will continue past the user fee goal date without a decision.
If an application is headed toward a complete response letter, the FDA will now provide the sponsor more information and allow for more consideration of feedback under revised guidance issued on 1 February. (Also see "US FDA To Share Remote Assessment Findings And Mull Replies Before Issuing Complete Responses" - Pink Sheet, 1 Feb, 2021.)
While Breyanzi (lisocabtagene maraleucel) is the first RMAT agent to be approved, it is also the sixth gene therapy to reach the US market. The FDA noted that Breyanzi is also the third gene therapy indicated for a form of non-Hodgkin lymphoma.
“Gene and cell therapies have evolved from promising concepts to practical cancer treatment regimens,” CBER director Peter Marks remarked in the agency’s approval announcement.
Breyanzi, a CD19-directed genetically modified autologous CAR-T cell therapy, is indicated for the treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) after two or more lines of systemic therapy.
The indication includes diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B. Labeling specifies that Breyanzi is not indicated to treat primary central nervous system lymphoma.
BMS “plans to manufacture Breyanzi for each individual patient at its state-of-the-art cellular immunotherapy manufacturing facility in Bothell, Washington,” the company said. The process has a 24-day target turnaround time.
In light of COVID-19, BMS highlighted the administration options for Breyanzi, which can be administered on an outpatient or inpatient basis. Additionally, “BMS will offer patients disposable wearable technology during the initial post-infusion monitoring period, which will help them track their temperature in real time through a smartphone when away from the treatment center.”
The risk of cytokine release syndrome and neurologic toxicities prompted the FDA to impose a Risk Evaluation and Mitigation Strategy (REMS) with elements to assure safe use (ETASU), including requiring certification of facilities that dispense the therapy.
The Breyanzi REMS is akin to those for other CAR-T therapies like Gilead Sciences, Inc.’s Tecartus and Yescarta. (Also see "Keeping Track: Kite’s Tecartus Is Third CAR-T With US FDA Approval; Submissions Round-Up" - Pink Sheet, 26 Jul, 2020.)
The Breyanzi approval rests on the 268-patient TRANSCEND NHL 001 trial, which found a response in 73% of the 192 patients treated with a therapeutic dose, including a complete remission rate of 54%. “Of 104 patients treated with Breyanzi who achieved a best overall response of CR, 65% had remission lasting at least six months and 62% had remission lasting at least nine months,” BMS said.