FDA CRL - Genzyme Corporation

On December 23, 2025, the FDA issued a Complete Response Letter to Genzyme Corporation regarding its New Drug Application for tolebrutinib, a treatment intended for non-relapsing secondary progressive multiple sclerosis (nrSPMS). The agency determined that the application cannot be approved in its current form because the drug’s benefits do not outweigh its significant safety risks. The primary concern is a substantial and unusually high risk of severe drug-induced liver injury (DILI). Clinical trials reported six cases of high-level liver toxicity, including one fatality, a rate that exceeds those of other approved multiple sclerosis therapies. The FDA found that Genzyme's proposed Risk Evaluation and Mitigation Strategy (REMS) was insufficient to prevent these life-threatening events, as severe liver injury occurred even with frequent monitoring. Additionally, the agency noted inconsistencies in efficacy data, suggesting that the drug's benefits were largely limited to a small subgroup of patients who already have access to other approved treatments. Under the regulatory framework of the Federal Food, Drug, and Cosmetic Act, Genzyme is required to identify a specific patient population with a favorable benefit-risk profile. Required actions include submitting a revised REMS, providing updated safety data from ongoing and completed studies to characterize the impact of liver monitoring, and performing additional analyses to prove efficacy in populations with high unmet needs.