Sanofi confirms delay to tolebrutinib’s FDA review in nrSPMS

Sanofi announced that the US FDA review of its investigational Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib for non-relapsing secondary progressive multiple sclerosis (nrSPMS) will extend beyond the previously communicated target action date of December 28, 2025. Ongoing discussions with the FDA suggest a decision is now anticipated after Q1 2026, with updated guidance expected by the end of March.

Sanofi attributed the shift to regulatory dialogue and additional data filings. Specifically, in response to the FDA’s request, the company submitted an expanded access protocol for tolebrutinib in nrSPMS, designed to potentially provide eligible patients early access to the therapy during the review period. Sanofi reiterated its confidence in tolebrutinib’s risk-benefit profile for this progressive MS subtype, where disability accumulates independently of relapses and treatment options remain limited.

Tolebrutinib’s mechanism and development context

Tolebrutinib is an oral, brain-penetrant BTK inhibitor intended to target smoldering neuroinflammation, a key driver of disability progression in progressive MS. This mechanism aims to modulate innate and adaptive immune responses within the central nervous system, potentially slowing neurodegeneration beyond inflammatory relapse control. Sanofi’s regulatory strategy for nrSPMS is grounded in Phase 3 evidence (notably HERCULES and related trials) demonstrating disability progression delays versus placebo, which previously supported the FDA’s Breakthrough Therapy designation and Priority Review status.

The review delay comes amid mixed clinical signals for tolebrutinib across MS populations. Recent announcements highlighted a failure of the PERSEUS trial in primary progressive MS to meet its key endpoint of delaying disability progression, underscoring divergent outcomes across MS subtypes and complicating the broader development narrative. Despite these setbacks, Sanofi maintains that insights from these data will inform future research and regulatory discussions.

Key takeaways

The industry will continue to monitor the evolving regulatory timeline, which bears on tolebrutinib’s competitive positioning as one of the few brain-penetrant BTK inhibitors in advanced MS development. Tolebrutinib is also the subject of Phase 3 trials in relapsing MS (RMS) and primary progressive MS (PPMS) in addition to nrSPMS.

Other BTK inhibitors under development for MS include Roche’s fenebrutinib, Novartis’s remibrutinib, Merck’s evobrutinib, and InnoCare/Biogen’s orelabrutinib, all at or planning for the Phase 3 study stage