FDA Activity Recap: December 2023 Features 2 Major Approvals, Meetings, and Clinical Holds

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Catch up on any of the key FDA news stories you may have missed last month, with coverage highlights from the CGTLive™ team.

Last month, December 2023, the CGTLive team was diligently tracking the FDA's activities related to the development of cell and gene therapies for the treatment of rare, complex, and otherwise challenging diseases and disorders.

The agency has continued to ramp up its activities around these therapies as more of them progress through the pipeline in tandem. Last month proved no different, with a pair of landmark approvals for sickle cell disease coming early in December on the heels of a major announcement about an FDA-led investigation into T-cell malignancies in CAR T treatment. This was followed by a few other announcements, which our team has highlighted below.

Click the read more buttons for more details and information about each update.

FDA to Investigate Risk of T-Cell Malignancy After CAR T-Cell Therapy

November 28, 2023 — Technically occurring late in November, this announcement set the stage for a busy final month of 2023. The FDA initiated an investigation into the risk of T-cell malignancies in patients that have received B cell maturation antigen (BCMA)-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies.1

The agency has determined that the apparent risk applies to all currently approved therapies, including Abecma (idecabtagene vicleucel), Breyanzi (lisocabtagene maraleucel), Carvykti (ciltacabtagene autoleucel), Kymriah (tisagenlecleucel), Tecartus (brexucabtagene autoleucel), and Yescarta (axicabtagene ciloleucel).

In its statement, the FDA stated that the overall benefits of these products continue to outweigh their potential risks for their approved uses. According to the FDA Adverse Event Reporting System (FAERS) database, there have been 12 instances of T-cell lymphoma in patients treated with approved CAR T-cell therapies. These cases have been seen in patients treated with Kymriah (n = 7), Yescarta(n = 3), Carvykti (n = 1), and Breyanzi (n = 1).

FDA to Investigate Risk of T-Cell Malignancy After CAR T-Cell Therapy

BrainStorm Cell Therapeutics Seeks Special Protocol Assessment for New NurOwn Trial After Meeting With FDA

December 7, 2023 — BrainStorm Cell Therapeutics announced it had met with the FDA to discuss a possible regulatory path forward for debamestrocel (NurOwn), its investigational autologous mesenchymal stem cell (MSC) neurotrophic factor–secreting cell therapy product intended to treat amyotrophic lateral sclerosis (ALS).2

The company characterized the meeting as “productive” and noted that it is now seeking a Special Protocol Assessment (SPA) from the agency for a planned registrational phase 3b clinical trial. As part of the process, which the company intends to use to come into alignment with the FDA on critical elements of the study design, such as patient eligibility, end points, and planned analyses, BrainStorm plans to provide the agency with documentation supporting the SPA.

The planned phase 3b clinical trial would be BrainStorm’s second attempt at a registrational clinical trial for NurOwn. The cell therapy was previously evaluated in a pivotal phase 3 clinical trial (NCT03280056) that tested the treatment against a placebo in patients with ALS, but did not meet any of its primary or key secondary end points.

BrainStorm Cell Therapeutics Seeks Special Protocol Assessment for New NurOwn Trial After Meeting With FDA

FDA Approves bluebird bio's Lovo-Cel and Vertex and CRISPR's Exa-Cel for Sickle Cell Disease

December 8, 2023 — Announced simultaneously, a week into December, the FDA approved bluebird bio’s lovotibeglogene autotemcel (lovo-cel), marketed as Lyfgenia, as a treatment for sickle cell disease (SCD) in patients aged 12 years and older,3 and Vertex Pharmaceuticals' and CRISPR Therapeutics’ autologous gene-edited cell therapy exagamglogene autotemcel (exa-cel), marketed under the name Casgevy, for the treatment of severe sickle cell disease (SCD) in patients aged 12 years and older with recurrent vaso-occlusive crises.3

The Vertex and CRISPR product is the first CRISPR-based gene therapy to be approved in the United States and has a review date set for March 30, 2024, for a possible indication in the management of patients with transfusion-dependent β-thalassemia.

The bluebird therapy consists of autologous CD34+ hematopoietic stem cells collected by plerixafor mobilization and apheresis, transduced with BB305 lentiviral vector (LVV) encoding the human beta-A-T87Q globin gene. Hematologic malignancy has occurred in patients treated with lovo-cel, and as such, a black box warning is included in the label for the therapy with information regarding this risk. The FDA noted that patients receiving lovo-cel should have lifelong monitoring for these malignancies.

FDA Approves bluebird bio's Lovo-Cel Gene Therapy for Sickle Cell Disease

FDA Approves bluebird bio's Lovo-Cel Gene Therapy for Sickle Cell Disease

FDA Approves Exa-cel, Vertex and CRISPR Therapeutics’ Gene Therapy, for Sickle Cell Disease

FDA Approves Exa-cel, Vertex and CRISPR Therapeutics’ Gene Therapy, for Sickle Cell Disease

FDA Blocks CARsgen’s 3 Clinical Stage CAR-Ts Over CMC Concerns

December 19, 2023 — In mid-December, the agency announced it had placed clinical holds on 3 of CARsgen’s CAR T-cell therapies: CT053, which is also known as zevorcabtagene autoleucel (zevor-cel); CT071; and CT041, because of chemistry, manufacturing, and controls-related concerns that arose after an inspection of the company’s manufacturing facility in Durham, North Carolina.4

CARsgen said in its notice of the clinical hold to the Hong Kong Stock Exchange that it planned to conduct a comprehensive review and improve its Current Good Manufacturing Practices (cGMP) at the facility and is “committed to working closely with the FDA to address the findings to ensure the smooth progress and production quality for clinical trials and launching applications.”

Prior to this news, the company had recently presented data on zevor-cel from the phase 1b LUMMICAR study 1 (NCT03975907) conducted in China in patients with relapsed/refractory multiple myeloma (r/r MM) at the 2023 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 9-12, in San Diego, California.

FDA Blocks CARsgen’s 3 Clinical Stage CAR-Ts Over CMC Concerns

REFERENCES
1. FDA investigating serious risk of T-cell malignancy following BCMA-directed or CD19-directed autologous chimeric antigen receptor (CAR) T cell immunotherapies. News release. FDA. November 28, 2023. Accessed January 8, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-t-cell-malignancy-following-bcma-directed-or-cd19-directed-autologous
2. BrainStorm Cell Therapeutics announces outcome of FDA meeting on NurOwn in ALS. News release. BrainStorm Cell Therapeutics Inc. December 7, 2023. Accessed December 21, 2023. https://ir.brainstorm-cell.com/2023-12-07-BrainStorm-Cell-Therapeutics-Announces-Outcome-of-FDA-Meeting-on-NurOwn-R-in-ALS
3. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. News release. FDA. December 8, 2023. Accessed January 8, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapies-treat-patients-sickle-cell-disease
4. Inside information announcement clinical hold in the U.S. due to CMC related questions. CARsgen. Letter. Accessed January 8, 2024. https://www1.hkexnews.hk/listedco/listconews/sehk/2023/1212/2023121201146.pdf
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