FDA starts review of Sanofi's MS hope tolebrutinib

Sanofi's oral BTK inhibitor tolebrutinib is heading towards an FDA decision in September as a potential treatment for multiple sclerosis (MS) after a priority review by the US regulator.

Tolebrutinib is vying to become the first brain-penetrant BTK inhibitor to both treat non-relapsing secondary progressive MS (nrSPMS) and to slow the progression of disability caused by the disease, independent of relapse activity.

The FDA review – which is due to be completed by 28th September – revolves around the results 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. It has been awarded breakthrough status for this indication.

Sanofi's decision to file for nrSPMS only comes after tolebrutinib failed to achieve its primary objective in two other phase 3 trials – GEMINI 1 and 2 – that involved patients with relapsing forms of MS.

Treatment options for progressive MS are more limited, however, and Sanofi is hoping that tolebrutinib can become the first medicine to target so-called 'smouldering' neuroinflammation. While relapsing forms are characterised by sudden attacks associated with advancing disability, in non-relapsing patients the decline tends to be more continuous and driven by underlying nerve inflammation.

Data from the GEMINI studies will be used to support the application for nrSPMS, while a fourth phase 3 trial called PERSEUS in patients with primary progressive MS (PPMS) is still ongoing, with results due in the second half of this year.

"The demonstrated ability of tolebrutinib to delay disability by targeting underlying drivers of the disease represents a potential paradigm shift in treating these patients," commented Erik Wallström, Sanofi's global head of neurology development.

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 were commercial reasons.

The candidate is one of several oral BTK drugs that have been in clinical development for MS, including Merck KGaA's evobrutinib – which failed two phase 3 trials and was abandoned for MS – as well as Roche's fenebrutinib, Novartis' remibrutinib, and InnoCare Pharma's orelabrutinib.

Among the others, fenebrutinib is in phase 3 for PPMS, with results due in 2026, while remibrutinib is in phase 3 for relapsing MS and orelabrutinib generated positive results in relapsing-remitting forms of the disease that were presented at the ACTRIMS congress in February.

GlobalData has predicted that tolebrutinib will be the leading BTK inhibitor for MS by 2030, with forecasted sales of approximately $2.6 billion across seven of the largest pharma markets.

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