Sanofi SA (SNY) ran into a serious regulatory roadblock in December 2024 when the FDA issued a complete response letter rejecting its experimental multiple sclerosis drug tolebrutinib. The rejection came down to a simple but critical calculation: the agency couldn't find any patient group where the drug's benefits clearly outweighed its risks, particularly the risk of severe liver damage.
The drug was intended to treat non-relapsing secondary progressive multiple sclerosis in adults, a patient population that currently has limited treatment options. Sanofi's initial press release about the rejection was notably sparse on details, but the FDA went ahead and publicly released the complete response letter itself, laying out both efficacy and safety concerns in stark terms.
The Liver Problem
Here's where things get serious. The FDA identified a concerning pattern of severe drug-induced liver injury during clinical trials. Out of approximately 2,700 subjects in the Phase 3 program, six cases met what's known as Hy's Law criteria, a clinical benchmark that signals high hepatotoxic risk. One of those patients died after requiring a liver transplant.
The numbers get more granular when you look at liver enzyme elevations. In the first six months of double-blind treatment in one study, 3.6% of patients taking tolebrutinib experienced aminotransferases more than three times the upper limit of normal, compared to 1.9% on placebo. That's nearly double the rate.
Sanofi proposed a risk evaluation and mitigation strategy to manage these liver concerns, but the FDA determined it wouldn't be adequate to address the severity of the problem.
The Unmet Need Argument Fails
Sanofi made what seems like a reasonable argument: patients with non-relapsing secondary progressive MS don't have approved treatment options, so even a drug with risks might offer a favorable benefit-risk profile given the lack of alternatives.
The FDA wasn't buying it. The agency wrote bluntly that it "was unable to identify a population for which the benefit could be clearly established and for which that benefit would be anticipated to outweigh the serious risk of severe DILI to support approval."
Beyond the liver safety issues, the FDA also flagged uncertainties about whether the drug actually slows disability accumulation independent of relapse activity, which raises questions about the efficacy evidence itself.
The regulatory agency's bottom line: "Overall, substantial evidence of effectiveness has not been established in a clinically identifiable population for whom the benefits potentially outweigh the risks."
As of Tuesday premarket trading, Sanofi shares were up 0.53% at $47.76, suggesting investors had largely anticipated the rejection or don't see it as materially impacting the company's broader business.