Last month, the FDA declined to approve Sanofi’s tolebrutinib for a specific form of multiple sclerosis. In a recently published complete response letter, the agency detailed its reasoning behind the rejection.
Following last month’s surprise rejection of Sanofi’s BTK inhibitor tolebrutinib in multiple sclerosis, the FDA has now made public its complete response letter to the company, in which it pointed to serious safety risks with the drug, as well as uncertainties regarding its efficacy.
“A favorable benefit-risk profile could not be established for any patient subpopulation,” the agency wrote in its CRL, dated Dec. 23, 2025. Sanofi and California-based partner Corcept Therapeutics were proposing tolebrutinib as a treatment for adult patients with non-relapsing secondary progressive multiple sclerosis (SPMS).
The FDA zeroed in on four main issues with tolebrutinib’s data package, one of which was the drug’s “serious risk of severe” drug-induced liver injury (DILI). Six such cases were detected among about 2,700 patients, according to the CRL. In one patient, this necessitated liver transplantation and ultimately led to death.
This safety signal, the FDA contended, “indicates a high level of hepatotoxic risk with tolebrutinib.” While the agency conceded that liver toxicities are known side effects of BTK inhibitors like tolebrutinib, “the risk of fatal DILI associated with tolebrutinib appears to be among the highest in the class.”
The FDA also flagged tolebrutinib’s efficacy, raising questions about its therapeutic benefit in certain patient subpopulations. The CRL noted that Sanofi was unable to distinguish between patients with active or non-active SPMS because it failed to collect historical MRI data.
Sanofi tried to provide such data in response to an information request from the FDA, but the MRI information were subject to “selection bias, as the data were only able to be collected from subjects who elected to enroll in and remained in the open-label extension study,” the letter read.
Nevertheless, an analysis of Sanofi’s follow-on submission suggested that tolebrutinib’s treatment effect was driven largely by patients with active SPMS, for which the FDA noted there are already approved therapies.
“The analyses raise substantial uncertainties about the SPMS population that is more likely to benefit from tolebrutinib,” the agency wrote. “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.”
Another critical issue for the FDA was the lack of conclusive evidence demonstrating tolebrutinib’s effectiveness at slowing the accumulation of disability in patients, independent of its ability to prevent relapses. Here, Sanofi was tripped up by the lack of established standards for this particular endpoint. “There are no widely accepted criteria for defining disability accumulation independent of relapse activity,” the FDA wrote in its rejection letter, noting that this particular endpoint “remains an emerging construct with multiple limitations.”
Taken together, these three shortcomings in the tolebrutinib package led to the FDA’s final sticking point, which is that tolebrutinib did not have a favorable risk-benefit profile in any tested patient subpopulation. In patients with active SPMS, the agency argued, tolebrutinib’s “benefits would not be anticipated to outweigh the risk of DILI” given the presence of approved alternatives.
Meanwhile, the drug’s lack of signal in terms of disease accumulation points to its unclear benefits in patients with non-active disease.
Despite the rejection, the FDA has left the door open to Sanofi, giving the pharma the opportunity to “identify a population for whom the potential benefits of your drug may outweigh the serious risk of severe DILI.”
