In a decisive regulatory action dated December 2025, the U.S. Food and Drug Administration (FDA) issued a complete response letter formally rejecting Sanofi SA's new drug application for tolebrutinib. The drug was intended to treat adult patients suffering from non-relapsing secondary progressive multiple sclerosis (nrSPMS), an under-addressed subset of multiple sclerosis lacking approved therapies.
The FDA's communication was publicly released but provided limited detail in its initial announcement. Upon closer examination of the complete response letter, key concerns centered around both the efficacy of tolebrutinib in its target population and, more critically, significant safety risks identified during clinical development.
The regulatory agency articulated that a "favorable benefit-risk profile" could not be demonstrated for any subgroup of patients considered, effectively halting the prospect of approval at this time. This conclusion was grounded in the agency’s assessment of emerging safety data alongside ambiguous efficacy signals.
Detailed Safety Concerns: Serious Risk of Liver Injury
The FDA’s review uncovered a serious safety threat: severe drug-induced liver injury (DILI). During clinical trials, six cases fulfilling Hy's Law criteria—clinical evidence indicating a high likelihood of significant hepatotoxicity—were documented among approximately 2,700 subjects enrolled in the tolebrutinib Phase 3 development program. One patient even succumbed following a liver transplant prompted by drug-related liver failure. These findings alerted the agency to a pronounced and potentially life-threatening hepatotoxic risk directly linked to tolebrutinib treatment.
Further underscoring the magnitude of this safety concern, the FDA noted elevated liver enzyme levels among trial participants. Within the first six months of blinded treatment in Study EFC16645, 3.6% of patients receiving tolebrutinib exhibited aminotransferase elevations exceeding three times the upper limit of normal, compared to 1.9% in the placebo group. This differential signals a drug-related hepatotoxicity trend requiring heightened caution.
Sanofi had proposed a risk evaluation and mitigation strategy (REMS) to address these safety risks, aiming to monitor and manage potential liver injuries. However, the FDA concluded that the proposed mitigation measures were inadequate to effectively control or reduce the serious risk of severe DILI associated with the drug.
Uncertain Clinical Benefit Fails to Offset Safety Risks
Sanofi maintained that the benefit-risk balance for tolebrutinib was positive in the treatment of nrSPMS patients due to the absence of existing approved options. Nevertheless, the FDA disagreed with this appraisal, stating it was unable to identify any patient subgroup for which the clinical benefit could be convincingly established and shown to outweigh the serious risks of hepatotoxicity.
In addition to safety concerns, the FDA expressed reservations about the efficacy evidence, particularly regarding the drug’s ability to slow disability progression independently of relapse activity. Analysis of trial data failed to clarify this effect convincingly, diminishing support for a clinically meaningful benefit for the target population.
The agency concluded that "substantial evidence of effectiveness has not been established in a clinically identifiable population for whom the benefits potentially outweigh the risks," reinforcing the overall unfavorable regulatory standing.
Market and Investor Response
Following the FDA’s announcement, Sanofi’s shares showed a modest increase of 0.53%, trading at $47.76 in premarket activity on the subsequent Tuesday, as per Benzinga Pro data. The market reaction suggests cautious investor sentiment reflecting both the setback in drug approval and broader confidence in Sanofi's pipeline and business operations.
Contextual Takeaways
This regulatory outcome underlines the FDA’s rigorous evaluation standards regarding patient safety and the imperative to balance efficacy with acceptable risk, particularly in vulnerable populations with limited treatment options. While Sanofi’s aspirations to address an unmet medical need in nrSPMS remain clear, the unresolved safety liabilities—most notably severe liver toxicity—and uncertain clinical benefits present formidable barriers requiring further investigation before resubmission or alternative strategies.