Sanofi’s application for its BTK inhibitor tolebrutinib as a treatment for multiple sclerosis has been rejected by the U.S. Food and Drug Administration (FDA), according to a complete response letter released by the agency. The FDA cited significant safety concerns and unclear evidence of benefit as reasons for the decision.
“A favorable benefit-risk profile could not be established for any patient subpopulation,” the FDA stated in its letter dated December 23, 2025. Sanofi, along with its partner Corcept Therapeutics, had sought approval for tolebrutinib in adult patients with non-relapsing secondary progressive multiple sclerosis (SPMS).
The agency highlighted four main issues with the data provided on tolebrutinib. One key concern was a “serious risk of severe” drug-induced liver injury (DILI). Six cases were identified among roughly 2,700 patients in clinical trials, including one case that resulted in liver transplantation and death.
According to the FDA, this finding “indicates a high level of hepatotoxic risk with tolebrutinib.” While acknowledging that liver toxicity is known among BTK inhibitors, the agency noted that “the risk of fatal DILI associated with tolebrutinib appears to be among the highest in the class.”
The FDA also questioned whether there was enough evidence showing that tolebrutinib provides therapeutic benefit across different patient groups. The company was unable to separate patients with active versus non-active SPMS due to missing historical MRI data.
Sanofi attempted to provide additional MRI information following an FDA request, but these data were limited because they came only from participants who joined and remained in an open-label extension study. The agency said this introduced “selection bias.”
An analysis of these follow-up submissions indicated that any observed treatment effect was mainly seen in patients with active SPMS—a group for which other approved therapies already exist.
“The analyses raise substantial uncertainties about the SPMS population that is more likely to benefit from tolebrutinib,” wrote the FDA. “Given the serious and unusually high risk of severe DILI, it is critical to have certainty about efficacy in a population in whom this level of DILI risk could be considered acceptable.”
A further issue was insufficient proof that tolebrutinib slowed disability progression independently from preventing relapses. The FDA pointed out there are no widely accepted standards for measuring disability accumulation apart from relapse activity: “There are no widely accepted criteria for defining disability accumulation independent of relapse activity,” it wrote, adding that this endpoint “remains an emerging construct with multiple limitations.”
Based on these findings, regulators concluded that none of the tested patient groups showed a positive balance between benefits and risks when using tolebrutinib. For those with active SPMS—where alternative treatments exist—the potential advantages did not outweigh concerns over DILI.
For patients without active disease, lack of evidence regarding impact on disease progression left benefits unclear.
Despite denying approval at this time, the FDA indicated Sanofi may resubmit if it can define a group where potential benefits might outweigh serious risks: The agency has given Sanofi an opportunity “to identify a population for whom the potential benefits of your drug may outweigh the serious risk of severe DILI.”
