Sanofi facing tolebrutinib setback in MS

Sanofi SA (France) faces major challenges with its experimental buton tyrosine kinase (BTK) inhibitor tolebrutinib in multiple sclerosis (MS). On Monday, the French pharma major reported significant setbacks: the Phase III PERSEUS study in primary progressive MS (PPMS) missed its primary endpoint, what further delayed the US approval for non-relapsing secondary progressive MS (nrSPMS).

Phase III failure in PPMS

The PERSEUS trial, enrolling 767 participants, assessed whether tolebrutinib could significantly delay six-month confirmed disability progression versus placebo. Sanofi confirmed the study did not meet its primary endpoint, though detailed efficacy data were not disclosed. As a result, the company will not pursue regulatory approval for PPMS and is evaluating potential impairments on tolebrutinib’s intangible asset value, following its acquisition in 2020 of Principia Biopharma, Inc. (USA, Cambridge, MA) for US$3.7bn.

Separately, US approval for nrSPMS has been postponed. Originally, the FDA aimed to deliver a decision by 28 September, later moved to 28 December after Sanofi submitted a “major amendment” including additional analyses. The company now expects updated guidance from the FDA by the end of March 2026. Sanofi continues to assert confidence in the risk-benefit profile of tolebrutinib and has submitted an expanded access protocol to allow eligible patients with nrSPMS access to the drug.

Competitive context

BTK inhibitors represent a promising immunological approach in MS by modulating B-cell and microglial activation, key drivers of progressive disease. The PPMS setback highlights the clinical challenges of developing effective therapies for this population.

Comparable programmes show mixed outcomes:

• Evobrutinib (Roche Holding AG, Switzerland, Basel) demonstrated efficacy in RRMS but limited signal in PPMS.

• Orelabrutinib (InnoCare Pharma / Beijing InnoCare Biopharma, China) and other BTK inhibitors are in Phase II/III with data in progressive MS pending.

These developments underscore the high translational hurdle of moving molecular targets into clinically meaningful outcomes in progressive MS. For Sanofi, the setback is both a clinical and strategic signal, as established therapies such as Ocrelizumab (Roche, Switzerland) and Siponimod (Novartis AG, Switzerland, Basel) already hold approval in progressive MS populations.

Sanofi positions the failure as a valuable contribution to understanding MS biology, informing future BTK inhibitor study designs and target selection.