FDA Activity Recap: August 2024 Features TCR T-Cell Therapy Approval, REMS Modification, the Lifting of a Clinical Hold, and More

Last month, August 2024, 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 the approval of Adaptimmune Therapeutics’ afamitresgene autoleucel (afami-cel, formerly ADP-A2M4) for the treatment of synovial sarcoma (SS), the agency modifying its Risk Evaluation and Mitigation Strategies (REMS) for autologous chimeric antigen receptor (CAR) T-cell immunotherapies, and a few other important actions. Our team has highlighted these below.

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

FDA Approves Adaptimmune’s TCR T-cell Therapy Afami-cel for Synovial Sarcoma

August 2, 2024 — The FDA has granted accelerated approval to Adaptimmune Therapeutics’ afami-cel, an investigational T-cell receptor (TCR) T-cell therapy marketed as Tecelra, for the treatment of SS. It is the first engineered T-cell therapy to be approved by the FDA for a solid tumor indication, indicated specifically for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA antigen(s) A*02:01P, -A*02:02P, -A*02:03P, or -A*02:06P positive, and whose tumor expresses the MAGE-A4 antigen as determined by FDA authorized companion diagnostic devices.

“Potentially life-threatening cancers such as synovial sarcoma continue to have a devastating impact on individuals, especially those for whom standard treatments have limited efficacy due to tumor growth and progression,” Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research (CBER), said in a statement. “The approval of this state-of-the-art immunotherapy technology provides a critical new option for a patient population in need and demonstrates the FDA’s dedication to the advancement of beneficial cancer treatments.”

Sandra D’Angelo, MD, Sarcoma Medical Oncologist and Cell Therapist, Memorial Sloan Kettering Cancer Center, and the SPEARHEAD clinical trial's principal investigator, noted that the therapy "uses each patient’s own immune cells to recognize and attack their cancer cells in a one-time infusion treatment" and "is significantly different than the current standards of care for advanced synovial sarcoma." She added that the FDA decision "represents a much-needed new option for people diagnosed with this sarcoma and an important milestone for the use of cell therapies in solid tumor cancers.”

FDA Modifies CAR-T Risk Strategies to Lower Healthcare Burden

August 6, 2024 — The FDA has modified its REMS for autologous CAR-T immunotherapies to minimize burdens on healthcare systems.

The REMS have been modified to remove the requirements for educational and training materials regarding the risks of cytokine release syndrome (CRS) and neurological toxicities associated with approved CAR T-cell therapies Abecma (idecabtagene vicleucel), Breyanzi (lisocabtagene maraleucel), Carvykti (ciltacabtagene autoleucel), Kymriah (tisagenlecleucel), Tecartus (brexucabtagene autoleucel), and Yescarta (axicabtagene ciloleucel).

The FDA notice stated that information about the risks of these adverse effects (AEs) are “conveyed adequately” on current product labeling as well as boxed warnings. The FDA also removed the requirement to report AEs suggestive of CRS or neurological toxicities to the REMS. Notably, the FDA recently required approved CAR-T labels to include boxed warnings for T-cell malignancies after treatment.

FDA Lifts Clinical Hold on Trial for 4D Molecular Therapeutics’ Fabry Disease Gene Therapy 4D-310

August 12, 2024 — The FDA has lifted a clinical hold on the phase 1/2 INGLAXA (NCT04519749) clinical trial for 4D Molecular Therapeutics (4DMT)’s 4D-310, an investigational adeno-associated virus (AAV) vector-based gene therapy being evaluated for the treatment of Fabry disease.

In light of the FDA’s decision, 4DMT plans to continue enrolling patients in INGLAXA before the end of 2024, according to an announcement from the company. Furthermore, 4DMT anticipates that it will provide an update on the program at some point in 2025.

The FDA originally placed the hold on INGLAXA in early 2023, according to a United States Securities and Exchange Commission FORM 8-K from February of that year. The hold came weeks after 4DMT announced it was halting enrollment in the phase 1/2 clinical trial of 4D-310 (NCT04519749) after 3 instances of treatment-related serious AEs of atypical hemolytic uremic syndrome that had resolved within 2 to 4 weeks. In 1 participant, a 69-year-old man with underlying kidney dysfunction, the AE was classified as a grade 4 dose-limiting toxicity and required temporary hemodialysis; the other 2 patients did not receive dialysis.

IN8bio Secures FDA Guidance on Bringing Gamma-Delta T-cell Therapy INB-100 to Pivotal AML Trial

August 14, 2024 — IN8bio has received guidance from the FDA regarding the path for bringing INB-100, an allogeneic gamma-delta T-cell therapy intended for use as a maintenance therapy after receiving haploidentical stem cell transplant (HSCT), to a registrational phase 2 clinical trial for acute myeloid leukemia (AML).

According to the company, the regulatory guidance came after a Type B meeting with the agency and pertains specifically to INB-100, which has been evaluated in multiple hematological malignancies, for the treatment of AML. With the guidance in mind, IN8bio intends to submit an investigational new drug (IND) application to the FDA in the first quarter of next year for a phase 2 trial that will utilize relapse-free survival as the primary end point. The company expects that it may be able to begin conducting the trial within the same year, pending clearance of the IND.

INB-100 is currently being evaluated in a phase 1 investigator-sponsored clinical trial (NCT03533816) for hematologic malignancies including AML, acute lymphoblastic leukemia, myelodysplastic/myeloproliferative neoplasms, and chronic myeloid leukemia. Alongside the announcement of the FDA’s guidance, IN8bio also reported newly updated results from the phase 1 trial that have a data cutoff of August 1, 2024. The company pointed out that all of the patients with AML treated in the trial (100%) remain in relapse-free survival. Furthermore, patients with other types of hematologic malignancies who were previously reported to have relapsed after treatment with INB-100 in a prior data update were noted to remain alive. IN8bio additionally stated that a 10-patient expansion cohort for the trial is currently enrolling participants and that it is expected to complete enrollment this year. Among the patients who have been treated in the expansion cohort so far, all remain in complete remission, with some having reached 90 days of posttransplant follow-up and 1 patient having reached almost 7 months of posttransplant follow-up.

FDA Clears Biosyngen’s CAR-T Therapy BRG01 for Pivotal Trial in EBV-Positive Nasopharyngeal Carcinoma

August 13, 2024 — Biosyngen’s CAR-T therapy BRG01 has been cleared by the FDA for a pivotal phase 2 clinical trial in patients with Epstein-Barr virus (EBV)-positive relapsed/metastatic nasopharyngeal carcinoma.

The FDA’s decision follows the Center for Drug Evaluation (CDE) of China’s National Medical Products Administration (NMPA) move in July 2024 to clear the company for a phase 2 pivotal clinical trial for BRG01 in China. As such, according to Biosyngen, BRG01 is the first cell therapy to move into a phase 2 clinical trial for relapsed/metastatic EBV-positive nasopharyngeal carcinoma in both the US and China.

"The approval of the phase 2 clinical trial for BRG01 is a testament to the robust preclinical data and strong early clinical results observed with this innovative therapy," Zhang Li, MD, MSc, the director of the Phase I Ward at the Sun Yat-Sen University Cancer Center and Deputy Director of the Lung Cancer Research Institute at Sun Yat-sen University, and principal investigator for the BRG01 clinical trial, said in a July 2024 statement, with regard to the trial’s clearance by the NMPA. "BRG01 has the potential to be a first-in-class T-cell therapy for EBV-positive tumors, and we are confident in its ability to deliver meaningful clinical benefits to patients with this difficult-to-treat malignancy.”