Allogene Discontinues ALLO-647 Following Patient Death in CAR-T Trial

Allogene Therapeutics has announced the discontinuation of its investigational anti-CD52 monoclonal antibody, ALLO-647, following a patient death in a pivotal CAR-T cell therapy trial. The decision marks a significant shift in the company's approach to lymphodepletion and highlights the ongoing challenges in developing safe and effective cell therapies.

Patient Death and Trial Implications

The male patient, enrolled in the ALPHA3 pivotal study evaluating cemacabtagene ansegedleucel (cema-cel) for first-line consolidation large B-cell lymphoma (LBCL), died on Day 54 after receiving cema-cel, ALLO-647, and standard lymphodepletion with fludarabine and cyclophosphamide (FC). The grade 5 adverse event was attributed to ALLO-647, with liver failure resulting from disseminated adenovirus infection during a state of immunosuppression.

In response, Allogene has decided to discontinue ALLO-647 entirely. The ALPHA3 trial will now proceed as a two-arm study, utilizing only the standard FC approach for lymphodepletion before cema-cel treatment. David Chang, M.D., Ph.D., President, CEO, and cofounder of Allogene, stated, "Today's update is prompted by this unfortunate circumstance but marks a clear and confident step forward."

Strategic Shift and Future Outlook

The discontinuation of ALLO-647 aligns with Allogene's ongoing transition towards its next-generation platform, Dagger. This novel technology aims to reduce reliance on standard lymphodepletion by enhancing the allogeneic CAR-T cells' resistance to host rejection.

Chang emphasized the potential benefits of this change, noting that "administering cema-cel after FC lymphodepletion in an outpatient setting will speed up enrollment while streamlining any potential regulatory review." The company expects to conduct a futility analysis in the first half of 2026, which will guide further development decisions.

Industry Implications and Safety Considerations

This development underscores the critical importance of patient safety in clinical trials, particularly in first-line settings where the goal is to improve cure rates. It also highlights the complexities involved in developing allogeneic CAR-T therapies and the ongoing challenge of balancing efficacy with safety.

As the pharmaceutical industry continues to pursue innovative cell therapies, events such as this serve as a reminder of the need for rigorous safety monitoring and the ability to adapt trial designs in response to unexpected outcomes. Allogene's transparent communication and swift action in this case may set a precedent for how companies handle similar situations in the future.