Novartis, Bristol Myers pause autoimmune CAR-T trials

Novartis and Bristol Myers Squibb have paused multiple clinical trials of their CAR-T cell therapies for autoimmune diseases. The halts follow reports of serious safety events, including three participant deaths in a Novartis study due to a severe immune reaction. Bristol Myers reported observing transient but reversible inflammatory events, according to a company spokesperson.

The news triggered immediate stock declines for several other companies developing autoimmune cell therapies, including Kyverna Therapeutics, Cabaletta Bio, Allogene Therapeutics, CRISPR Therapeutics, and Fate Therapeutics. Shares later recovered. The developments have prompted Wall Street analysts to assess the potential impact on the entire field. Leerink Partners analyst Thomas Smith noted the results have raised some investor questions regarding the broader autoimmune cell therapy landscape.

The safety events and manufacturing questions

CAR-T therapies are approved for cancers like leukemia and myeloma, where they engineer a patient's own immune cells to attack diseased cells. A significant drawback has been their complex and lengthy manufacturing, which can take weeks. Both Novartis and Bristol Myers have been testing a faster production method to grow the modified cells more quickly. Multiple analysts have suggested this accelerated manufacturing strategy could be a factor in the recent safety issues.

Jefferies analyst Roger Song highlighted this concern in a client note. He wrote that this is particularly important, as autoimmune diseases have more activated immunity at baseline that could be dangerously amplified by CAR-T treatment. In contrast, companies like Cabaletta, Kyverna, and Autolus Therapeutics use more traditional, established manufacturing processes for their candidate therapies.

How other developers differentiate their approaches

Kyverna Therapeutics moved quickly to distinguish its lead therapy after the news broke. On Tuesday, the company stated its drug, mivocabtagene autoleucel, has a distinct construct design and is produced using a well-established, validated manufacturing process. Kyverna's therapy is currently under regulatory review.

Other developers are use different technological platforms they believe are safer. Companies like Allogene and Fate Therapeutics are developing allogeneic therapies, which use cells from healthy donors rather than from the individual patient. Analyst Roger Song wrote that these therapies contain a different mix of cell types, potentially leading to a more controlled effect with a lower risk of severe inflammatory responses.

TD Cowen analyst Phil Nadeau detailed Cabaletta Bio's specific approach. He noted the company invested in a standardized, nine-day production process designed to minimize immune related toxicities and prioritize patient safety. Nadeau wrote that Cabaletta has not seen any cases of the potentially deadly immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) reactions observed in the Novartis trials. Cabaletta's trials in lupus and other conditions have so far recorded low rates of immune and neurological adverse events. He added that given the difference in protocols, they see limited read-through from the Novartis and Bristol Myers safety issues.

Adjusting trial protocols for safety

Analysts also pointed out that the recent events could lead to more cautious patient selection in future trials. For example, Song noted that Cabaletta's trials exclude patients who have had a recent infection or a harmful inflammatory event to reduce risk.

William Blair analyst Sami Corwin suggested that greater awareness among physicians will be key. She wrote on Monday that they believe greater physician awareness of symptoms and treatments specifically for IEC-HS will improve the management and outcomes of this adverse event over the longer term. The field continues to advance, with one program from Kyverna headed for an approval decision and others in late-stage testing, even as it grapples with these new safety questions.