Sanofi gets double blow for MS drug tolebrutinib

Shares in Sanofi were sliding today after a double dose of bad news for its oral BTK inhibitor tolebrutinib, in development as a therapy for multiple sclerosis (MS).

Along with what looks set to be another delay in the FDA's review of tolebrutinib in non-relapsing secondary progressive MS (nrSPMS) – already delayed from 28th September to 28th December – the drug has also failed a phase 3 trial in primary progressive multiple sclerosis (PPMS).

The newly-revealed PERSEUS trial involved 767 patients aged 18 to 55 with a confirmed PPMS diagnosis and either limited access to or an insufficient response to Roche's Ocrevus (ocrelizumab).

The results showed that tolebrutinib "did not meet its primary endpoint in delaying time to 6-month composite confirmed disability progression (cCDP)" in PPMS, which accounts for around 10% of all MS cases.

Due to the disappointing outcome data, Sanofi said it would not pursue regulatory registration for PPMS. That could hand an advantage to Roche, whose rival oral BTK inhibitor fenebrutinib has hit the mark in phase 3 trials involving patients with both relapsing MS and PPMS, and is being prepared for filings next year.

"We are disappointed by today's results; however, we do believe that these results will improve our understanding of the underlying disease biology of multiple sclerosis," said Houman Ashrafian, head of R&D at the pharma group.

Sanofi pressed ahead with a filing for tolebrutinib in nrSPMS on the back of the HERCULES trial, which showed that tolebrutinib was able to delay the time to six-month disability progression by 31% compared to placebo in patients with nrSPMS, after the drug failed two phase 3 trials in relapsing form of MS.

There is a much greater need for new therapies for progressive forms of MS than in relapsing forms of the disease, so Sanofi's decision to proceed based on the HERCULES result made sense. It has been approved for nrSPMS – a larger patient population than PPMS – in the United Arab Emirates (UAE).

The renewed delay has nevertheless dented investor optimism about a positive outcome in the nrSPMS indication in the big US market, and shares in Sanofi were down a couple of percentage points at the time of writing, having previously lost around 5% of their value.

Sanofi said in a statement that it has submitted an expanded access protocol for tolebrutinib in nrSPMS and "expects further guidance from the FDA by the end of the first quarter of 2026."

Tolebrutinib was one of three oral BTK inhibitors that Sanofi acquired as part of its $3.7 billion buyout of Principia Biopharma in 2020, and was abandoned as a treatment for myasthenia gravis – another neuromuscular disorder – in 2023 for what the company said at the time were commercial reasons.

Another BTK inhibitor being developed for MS, Merck KGaA's evobrutinib, also failed late-stage testing and was abandoned.

Image by Dmitriy Gutarev from Pixabay