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


Clinical holds have been placed on BCMA-targeted CT053, GPRC5D-targeted CT071, and Claudin18.2-targeted CT041.

The FDA has placed clinical holds on 3 of CARsgen’s chimeric antigen receptor (CAR) T-cell therapies, CT053, also known as zevorcabtagene autoleucel (zevor-cel); CT071; and CT041 due to chemistry, manufacturing, and controls-related concerns that arose after an FDA inspection of the company’s manufacturing facility in Durham, North Carolina.1

CARsgen said in its notice of the clinical hold to the Hong Kong Stock Exchange that it plans to conduct a comprehensive review and improve its Current Good Manufacturing Practices (cGMP) at the facilityand 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.”1

The company just 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. Zevor-cel is an autologous, BCMA-targeted CAR T-cell therapy. The new data included 14 patients with a median age of 54 years (range, 34-62) that received a single infusion of zevor-cel (100 × 106 CAR+ T cells in 3 patients, 150 × 106 CAR+ T cells as the recommended phase 2 dose in 11 patients). The participants had a median of 6 prior lines of therapy, 50.0% had high-risk cytogenetics, 14.3% had extramedullary disease, 14.3% had ISS stage III, and no patients received bridging therapy.2

As of July 17, 2023, the median survival follow-up duration was 37.7 months (range, 14.8-44.2), overall response rate was 100% (95% CI, 76.8-100.0), and 11 (78.6%) patients achieved complete response (CR) or stringent complete response (sCR). Two (14.3%) patients achieved very good partial response and 1 (7.1%) patient had partial response. All patients who achieved CR or better had minimal residual disease negativity. The median progression-free survival was 25.0 months (range, 14.9-not evaluable [NE]) for all patients and 26.9 months (range, 15.5-NE) for patients with sCR/CR. The median duration of response was 24.1 months (range, 14.0-NE) for all patients and 26.0 months (range, 14.6-NE) for patients with sCR/CR. At data cutoff, 5 subjects, had ongoing responses, 7 had progressed and were still in survival follow-up, and 2 had died at month 42.6 and 32.6, respectively (deemed unrelated to zevor-cel).2

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All patients experienced treatment-related adverse events and grade 3 or 4 hematologic toxicity. Thirteen patients (92.9%) had cytokine release syndrome, all cases of which were grade 1 or 2.There have been no reports of immune effector cell-associated neurotoxicity syndrome, second primary malignancy, autoimmune disease, or replication competent lentivirus to date.2

CT071, a GPRC5D-targeting CAR, received investigational new drug (IND) application clearance from the FDA earlier this month for the treatment of r/r MM or r/r primary plasma cell leukemia.3 The therapy is being evaluated in an investigator-initiated trial (IIT) in China to assess its safety and efficacy (NCT05838131) and the company has stated that preliminary clinical data shows an acceptable safety profile with preliminary efficacy.3

The third CAR-T hit by the hold, CT041, targets Clauidin18.2 positive solid tumors and is focused on treating gastric, gastroesophageal junction and pancreatic cancer. A phase 2 trial started enrolling patients in May 2023. The therapy is also set to be evaluated in conjunction with Moderna’s mRNA cancer vaccine as announced in August 2023.4

1. Inside information announcement clinical hold in the U.S. due to CMC related questions. CARsgen. Letter.
2. Fu C, Chen W, Cai Z, et al. Three-Year Follow-up on Efficacy and Safety Results from Phase 1 Lummicar Study 1 of ZevorcabtageneAutoleucel in Chinese Patients with Relapsed or Refractory Multiple Myeloma. Presented at: ASH 2023 Annual Meeting & Exposition. December 9-12; San Diego, CA. Abstract 4845.
3. CARsgen's CT071 Received IND Clearance from the FDA for Treating Relapsed/Refractory Multiple Myeloma or Relapsed/Refractory Primary Plasma Cell Leukemia. News release. CARsgen. December 4, 2023. https://www.biospace.com/article/releases/carsgen-s-ct071-received-ind-clearance-from-the-fda-for-treating-relapsed-refractory-multiple-myeloma-or-relapsed-refractory-primary-plasma-cell-leukemia/
4. CARsgen collaborates with Moderna to evaluate CT041 in combination with an mRNA cancer vaccine. News release. CARsgen. August 21, 2023. https://www.carsgen.com/en/news/2023-08-21/
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