Sanofi’s MS Drug Tripped Up By Toxicities, Unclear Profit, Rejection Letter Reveals

Following final month’s shock rejection of Sanofi’s BTK inhibitor tolebrutinib in a number of sclerosis, the FDA has now made public its full response letter to the corporate, through which it pointed to severe security dangers with the drug, in addition to uncertainties concerning its efficacy.

“A positive benefit-risk profile couldn’t be established for any affected person subpopulation,” the company wrote in its CRL, dated Dec. 23, 2025. Sanofi and California-based associate Corcept Therapeutics had been proposing tolebrutinib as a remedy for grownup sufferers with non-relapsing secondary progressive a number of sclerosis (SPMS).

The FDA zeroed in on 4 most important points with tolebrutinib’s information package deal, one in every of which was the drug’s “severe danger of extreme” drug-induced liver harm (DILI). Six such instances had been detected amongst about 2,700 sufferers, in line with the CRL. In a single affected person, this necessitated liver transplantation and in the end led to demise.

This security sign, the FDA contended, “signifies a excessive degree of hepatotoxic danger with tolebrutinib.” Whereas the company conceded that liver toxicities are recognized unintended effects of BTK inhibitors like tolebrutinib, “the danger of deadly DILI related to tolebrutinib seems to be among the many highest within the class.”

The FDA additionally flagged tolebrutinib’s efficacy, elevating questions on its therapeutic profit in sure affected person subpopulations. The CRL famous that Sanofi was unable to differentiate between sufferers with energetic or non-active SPMS as a result of it failed to gather historic MRI information.

Sanofi tried to offer such information in response to an info request from the FDA, however the MRI info had been topic to “choice bias, as the info had been solely capable of be collected from topics who elected to enroll in and remained within the open-label extension examine,” the letter learn.

However, an evaluation of Sanofi’s follow-on submission prompt that tolebrutinib’s remedy impact was pushed largely by sufferers with energetic SPMS, for which the FDA famous there are already accredited therapies.

“The analyses elevate substantial uncertainties concerning the SPMS inhabitants that’s extra more likely to profit from tolebrutinib,” the company wrote. “Given the intense and unusually excessive danger of extreme DILI, it’s essential to have certainty about efficacy in a inhabitants in whom this degree of DILI danger may very well be thought of acceptable.”

One other essential problem for the FDA was the dearth of conclusive proof demonstrating tolebrutinib’s effectiveness at slowing the buildup of incapacity in sufferers, impartial of its potential to stop relapses. Right here, Sanofi was tripped up by the dearth of established requirements for this explicit endpoint. “There aren’t any broadly accepted standards for outlining incapacity accumulation impartial of relapse exercise,” the FDA wrote in its rejection letter, noting that this explicit endpoint “stays an rising assemble with a number of limitations.”

Taken collectively, these three shortcomings within the tolebrutinib package deal led to the FDA’s closing sticking level, which is that tolebrutinib didn’t have a positive risk-benefit profile in any examined affected person subpopulation. In sufferers with energetic SPMS, the company argued, tolebrutinib’s “advantages wouldn’t be anticipated to outweigh the danger of DILI” given the presence of accredited options.

In the meantime, the drug’s lack of sign by way of illness accumulation factors to its unclear advantages in sufferers with non-active illness.

Regardless of the rejection, the FDA has left the door open to Sanofi, giving the pharma the chance to “determine a inhabitants for whom the potential advantages of your drug could outweigh the intense danger of extreme DILI.”