Novartis, BMS Pause CAR-T Autoimmune Trials

Novartis and Bristol Myers Squibb have paused trials of their respective CAR T-cell therapies for autoimmune diseases. The suspensions follow reports of severe adverse events, including three patient deaths in the Novartis program.

Novartis halted enrollment and treatment in trials of its therapy, rapcabtagene autoleucel (rap-cel), after three fatal cases of immune effector cell-associated hemophagocytic syndrome (IEC-HS). Bristol Myers Squibb separately stopped its program for zolacabtagene autoleucel (zola-cel) due to unspecified transient and reversible inflammatory events. BMS confirmed the report to MedPage Today but declined to provide further details. Novartis did not immediately respond.

Scope of the Affected Trials

ClinicalTrials.gov lists multiple trials for the paused therapies. Novartis has nine trials for rap-cel targeting a wide range of autoimmune conditions and two forms of hematologic cancer. Bristol Myers Squibb has three listed trials for zola-cel.

The targeted autoimmune conditions for each therapy are listed below.

Background and Prior Success

CAR T-cell therapy was originally developed for oncology, specifically B cell-driven cancers like lymphoma. The process involves extracting a patient's T cells, engineering them to target specific cells, and reinfusing them. This approach has shown remarkable success in achieving long-lasting remissions for some cancer patients.

Rheumatologists became interested in its potential for autoimmune diseases, which also involve abnormal B-cell activity. Early results in autoimmune patients were described as astonishing, with remissions seen in individuals who had failed all conventional treatments.

Known and Emerging Risks

The therapy is not without risk. A harsh conditioning regimen is required before reinfusion. Common side effects include infections and cytokine release syndrome, which is often mild and treatable. More severe immune-related problems, like immune effector cell-associated neurotoxicity syndrome (ICANS), have also been observed in rheumatology patients.

However, IEC-HS had not been previously reported in autoimmune disease patients receiving CAR-T therapy. It is a known, though rare, side effect in hematologic cancer applications. FDA-approved CAR-T products for cancer carry a boxed warning about this risk.

Company Statements and Implications

Bristol Myers Squibb framed its trial halt as a minor setback. In a statement to MedPage Today, the company said the adverse events were identified during routine study surveillance. "To date, the overall safety profile of zola-cel remains consistent with the known profile of CAR T therapies," the statement read. "We are focused on completing our evaluation and resuming enrollment as quickly as possible."

The situation is more serious for Novartis due to the three deaths. The impact will depend on how many patients had been treated. One Novartis trial in SLE and lupus nephritis aims to enroll 179 participants. Another in systemic sclerosis targets 96, and a vasculitis trial aims for 126. Approximately 60 more are planned across other autoimmune trials. Current recruitment progress is unclear.

Fatal adverse events are viewed differently in autoimmune disease trials versus cancer trials. Autoimmune conditions are generally not considered immediately life-threatening, raising the tolerance for risk. This changes the calculus for safety.

The pauses mark a significant moment for a field that had been buoyed by early promise. Researchers and companies must now carefully evaluate these serious safety signals.