Sanofi calls FDA rejection of potential MS blockbuster tolebrutinib “unexpected” amid evolving agency views on benefit–risk

The FDA issued a complete response letter (CRL) on Dec. 23, 2025, rejecting Sanofi’s BTK inhibitor tolebrutinib for adults with non‑relapsing secondary progressive multiple sclerosis (nrSPMS).1 2 10

The FDA concluded that no patient subpopulation showed a favorable benefit–risk profile, citing serious safety concerns and unclear efficacy.1 2

Key FDA concern:
an “unusually high” risk of severe drug‑induced liver injury (DILI), including cases meeting Hy’s Law and at least one death, which the agency said could not be adequately managed by Sanofi’s proposed REMS.1 2

The FDA described the DILI risk with tolebrutinib as idiosyncratic and possibly among the highest in the BTK inhibitor class.2

On efficacy, the FDA said Sanofi had not provided sufficient evidence that tolebrutinib slows disability accumulation independent of relapse activity, an endpoint it called an emerging construct with multiple limitations.1 2

Because Sanofi lacked complete historical MRI data, the FDA found uncertainty about benefit across SPMS subgroups, noting that observed treatment effects appeared driven mainly by active SPMS, a group that already has approved therapies.1 2

In public comments, Sanofi said the CRL represented a “significant and meaningful change in direction” from earlier FDA feedback and expressed surprise and disappointment, arguing that disability progression in MS remains a major unmet need and that tolebrutinib had previously received breakthrough therapy designation.3

Sanofi characterized the FDA’s position as reflecting “evolving perspectives” on endpoints like disability progression and on acceptable liver‑toxicity risk in MS, contrasting this with what the company saw as earlier, more positive regulatory interactions.1 3 9

Separately, Sanofi reported that tolebrutinib failed the Phase 3 PERSEUS trial in primary progressive MS, undermining its broader “blockbuster” potential and leading the company to scrap approval plans for that indication.5

Despite the rejection, the FDA indicated it is open to further discussions and invited Sanofi to identify a more clearly benefiting population and provide additional safety analyses, including data from the Perseus trial and an ongoing extension study.1 2