The HERCULES study focused on the efficacy and safety of tolebrutinib in individuals with non-relapsing secondary progressive MS. Credit: CC7/Shutterstock.

Sanofi has announced the outcomes of Phase III clinical trials of its investigational oral brain-penetrant BTK inhibitor, tolebrutinib, aimed at treating multiple sclerosis (MS).

These studies, namely HERCULES, GEMINI 1, and GEMINI 2, have provided mixed results, with the HERCULES trial meeting its primary endpoint while the GEMINI trials did not.

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The HERCULES study focused on the efficacy and safety of tolebrutinib in individuals with non-relapsing secondary progressive MS (nrSPMS) compared to a placebo.

The primary measure of success was the six-month confirmed disability progression (CDP), which tolebrutinib successfully delayed in comparison to the placebo.

GEMINI 1 and GEMINI 2 were both designed to assess the therapy’s performance against teriflunomide in patients with relapsing forms of MS.

Despite not meeting the primary goal of reducing the annualised relapse rate (ARR), pooled data from secondary endpoints suggested a significant delay in the onset of confirmed disability worsening (CDW), aligning with the positive CDP findings from HERCULES.

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The GEMINI studies had a 1:1 randomisation of participants to either receive tolebrutinib and a placebo or 14mg of teriflunomide and a placebo daily.

The primary endpoint was the ARR over approximately 36 months, with secondary endpoints including time to onset of CDW confirmed over at least six months, as well as the total number of new or enlarging T2 hyperintense lesions and Gd-enhancing T1 hyperintense lesions as detected by MRI.

While the GEMINI trials did not demonstrate a reduction in ARR when compared to teriflunomide, the analysis of the key secondary endpoint of pooled six-month CDW data revealed a notable delay in time to onset.

This finding is consistent with the CDP data observed in the HERCULES trial, providing a measure of support for tolebrutinib’s potential efficacy.

Sanofi research and development head Houman Ashrafian said: “Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation.

“Addressing disability accumulation, thought to be driven by smoldering neuroinflammation, remains the greatest unmet medical need in people with non-relapsing secondary progressive MS today.”