On July 12th, 2017 the FDA’s Oncologic Drugs Advisory Committee (ODAC) discussed biologics license application (BLA) 125646 for tisagenlecleucel-T suspension (KYMRIAH™), developed by Novartis. The proposed indication for KYMRIAH™ is the treatment of pediatric and young adult patients, ranging in age from 3-25 years, with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).
KYMRIAH™ works by obtaining T-cells from a cancer patient with ALL, which are then used to create a specific chimeric T-cell receptor (CAR T) that reacts to the cancer. These chimeric molecules are then administered back into the cancer patient they were originally taken from. The goal of this therapy is to target CD19, which is commonly expressed on B-cells and B-cell precursors, but not on stem cells or other tissues that may be affected by treatment. When the chimeric antigens bind to CD19, they activate two domains, 4-1BB which enhances the proliferation of CAR T-cells, and the CD3-zeta signaling domain, which initiates T-cell activation and mediates anti-tumor activity.
The sponsor presented findings from their pivotal clinical trial, B2202, which examined the overall remission rate (ORR) within 3-months after KYMRIAH™ administration as the primary endpoint. The B2202 study was conducted in patients aged 3-21 years with relapsed/refractory B-cell ALL. After the completion of the study, the sponsor noted that KYMRIAH™ resulted in an 83% ORR within 3-months of administration. The sponsor concluded that KYMRIAH™ fills a significant unmet need in pediatric and young adult patients with relapsed/refractory B-cell ALL and that the therapy demonstrates a positive benefit/risk profile with a well-characterized safety profile.
The FDA presentation complimented the sponsor presentation in terms of efficacy and safety, as well as pointing out that there were only short-term safety assessments completed. The FDA suggested a comprehensive post-marketing plan to further monitor certain aspects of patient safety after KYMRIAH™ treatment.
The committee then reviewed the discussion and voting questions the FDA presented. The first discussion question had to do with the manufacturing process behind KYMRIAH™ and the overall control of product quality. Committee members discussed the complex nature of the manufacturing process, which carries an inherent risk for manufacturing failure. Other members discussed that although patient-specific products face unique challenges, the sponsor has the proper procedures in place to address any issue.
The discussion then focused on the generation of replication-competent retrovirus (RCR) and insertional mutagenesis, which several committee members expressed concern about, but others supported the notion that RCR is no longer a serious safety concern for tisagenlecleucel.
The committee then discussed the sponsor’s risk mitigation measures for serious risks of cytokine release syndrome (CRS) and neurotoxicity with tisagenlecleucel. Although the committee acknowledged that these are serious events, they believed that the sponsor addressed these issues appropriately in their risk mitigation plan. The committee also supported a 15-year follow-up to be conducted by the sponsor, to monitor for subsequent malignant transformation. The vote resulted in a unanimous positive outcome (10-0), supporting the positive benefit/risk profile of KYMRIAH™ in for the proposed indication.
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