Novartis suspended multiple studies of a CAR T candidate after three patients who received the therapy suffered fatal cases of immune effector cell-associated hemophagocytic syndrome. BMS, meanwhile, paused some CAR T trials after separately observing “transient and reversible inflammatory events” with its therapy.
Three patients have died after receiving Novartis’ CAR T candidate rapcabtagene autoleucel, prompting the pharma to suspend several immunology and neurology studies of the investigational therapy. Bristol Myers Squibb has taken a similar move, voluntarily freezing autoimmune trials for its own CAR T asset zolacabtagene autoleucel after observing “transient and reversible inflammatory events,” the company told William Blair analysts.
“Emergence of [adverse events] in NVS and BMY autoimmune trials highlight risks but could reduce competition in a crowded CAR-T space,” the analysts wrote in a note to investors on Monday afternoon.
A Novartis spokesperson confirmed the pause to BioSpace in an email statement on Monday afternoon, adding that the decision stemmed from three cases of “serious immune effector cell-associated hemophagocytic syndrome (IEC-HS).” These events then led to complications that eventually proved fatal.
BMS, acting “out of an abundance of caution,” has also decided to voluntarily freeze at least some studies of zolacabtagene autoleucel (zola-cel), a spokesperson confirmed to BioSpace via email. The pause will allow the pharma to review clinical data across zola-cel’s development program.
The pause for Novartis’ rapcabtagene autoleucel (rap-cel) affects the Phase 2 AUTOGRAPH studies in various autoimmune conditions, such as systemic lupus erythematosus, systemic sclerosis and idiopathic inflammatory myopathies, the company’s spokesperson said. Novartis is also suspending Phase 1/2 trials looking at rap-cel’s safety, efficacy and cellular kinetics in patients with rheumatoid arthritis, generalized myasthenia gravis and certain types of multiple sclerosis.
Studies of rap-cel in cancer are unaffected by the pause, Novartis said. The pharma is currently analyzing the safety data to identify all factors that could have led to the complications. The pharma is also engaging with independent data committees to come up with better safety measures, such as tighter monitoring, earlier identification and appropriate management, the spokesperson added.
As for BMS, it remains unclear if the suspension covers all of zola-cel’s studies. The pharma has several programs for the asset, including for myasthenia gravis, multiple sclerosis, rheumatoid arthritis and other immune indications. “We are focused on completing our evaluation and resuming enrollment as quickly as possible,” the spokesperson said.
The exact nature of the safety events that prompted BMS’s move to pause hasn’t been disclosed. The pharma didn’t report deaths linked to zola-cel, though William Blair pointed out that at least one case of IEC-HS has previously been reported for the CAR T candidate.
“IEC-HS is a rare but serious side effect that has been reported with CD19 and BCMA CAR-T therapies across blood cancer indications,” William Blair explained.
While the exact causes of the IEC-HS cases remain unknown, the analysts noted that rapid manufacturing—a feature of both rap-cel and zola-cel—could play a role. “Rapid manufacturing could be driving increased cell expansion and the reported toxicities,” they posited, but added that “other factors could be playing a role . . . such as specific indications or patients harboring a predisposition to a hyperinflammatory state.”
The firm cautioned that “it is difficult to extrapolate the risk of this side effect to all ongoing CAR-T programs in development for autoimmune diseases,” but listed several companies that are developing CD19 CAR Ts for autoimmune diseases. These include Autolus, Cabaletta Bio, CRISPR Therapeutics, Kyverna Therapeutics and Allogene Therapeutics.
The analysts speculate how “different safety profiles may provide advantages if Bristol Myers and Novartis are limited in the development of their CAR-T programs for autoimmune diseases.”
