The ODAC hearing on Novartis’ breakthrough CAR-T therapy, tisagenlecleucel, was overwhelmingly positive, as the Committee unanimously recommended approval of the therapy for relapsed or refractory pediatric and young adult patients with b-cell ALL. The hearing paved the way for an efficient regulatory approval of Novartis’ CAR-T therapy, and also provided insight into opportunities for future CAR-T therapies to more directly address lingering issues raised in the ODAC session:
Cytokine Release Syndrome (CRS) Management Strategy
- Context: The safety profile of tisagenlecleucel was a focal point of the hearing, while the prevalence, severity, and management of CRS was consistently highlighted as a primary concern. One notable question that arose during the hearing focused on the potential value of prophylactic tocilizumab to manage CRS, however this approach was not explored in Novartis’ trials.
- Opportunity: As discussed during the hearing, the use of prophylactic immunosuppressives may potentially conflate measurement of response to CAR-T therapy. Nonetheless, the discussion indicates there may be opportunity for CAR-T researchers to compare and contrast varying approaches to immunosuppressive use to better understand how to manage events in a clinical setting.
Post-marketing Risk Evaluation Plan
- Context: As part of the ODAC discussion, Novartis provided a detailed outline of its proposed post-marketing registry, consisting of 20-year follow-up in treated patients to monitor the “type, frequency, and severity of adverse events and laboratory abnormalities.”
- Opportunity: The proposed study will be limited to patients who receive the drug within 5 years of market introduction, excluding those who may have initially been eligible but ultimately weren’t treated for various reasons. Accordingly, the study design can be expanded out to all patients deemed CAR-T drug-treatable to collect more robust data on real-world complications related to manufacturing malfunction or patient progression during the waiting period.
Manufacturing and Adverse Event Management Limitations
- Context: In an effort to optimize AE management post-approval, Novartis will limit the launch of tisagenlecleucel to FACT accredited sites with ability to perform allogenic-Stem Cell Transplant (SCT). Novartis will directly manage safety training and will limit the launch to a network of 30-35 sites.
- Opportunity: Novartis’ staged introduction of tisagenlecleucel to just 30-35 initial sites further demonstrates the opportunity for multiple CAR-T manufacturers to succeed in this promising field. While all manufacturers are competing over a similar patient pool in relapsed/refractory b-cell malignancies, the AE management and manufacturing demands are such that it may not be possible for one organization to address the full spectrum of patient needs.