Sanofi seeks approval after MS therapy slows disease by 31%

Sanofi is seeking global regulatory approval for tolebrutinib following the release of positive Phase III data in non-relapsing secondary progressive multiple sclerosis (MS). The HERCULES Phase III trial (NCT04411641) results revealed that the Bruton tyrosine kinase (BTK) inhibitor delayed the time to six-month disability progression by 31% compared to a placebo. Sanofi aims to use these findings to support marketing applications to global regulatory bodies before the end of 2024. The findings were disclosed at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2024 conference, held from September 18-20 in Copenhagen, Denmark.

Sanofi has experienced mixed outcomes with tolebrutinib. Although the HERCULES study met its primary endpoint, the therapy did not demonstrate significant efficacy in patients with relapsing forms of MS. Earlier this month, Sanofi announced positive results from the HERCULES study, but two other Phase III trials – GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) – failed to show an improvement over Sanofi’s older therapy, Aubagio (teriflunomide).

One significant setback for Sanofi was the partial clinical hold placed by the US Food and Drug Administration (FDA) on Phase III trials evaluating tolebrutinib in MS and myasthenia gravis last year, including the HERCULES study. This clinical hold was instituted following reports of liver injury associated with tolebrutinib. Elevated liver enzymes are a well-documented side effect of BTK inhibitors.

The placebo-controlled HERCULES Phase III trial included 1,127 patients with non-relapsing secondary progressive MS. Among these patients, those with confirmed improvements in disability doubled to 10% with tolebrutinib, compared to 5% in the placebo group. Liver enzymes were elevated in 4.1% of participants in the tolebrutinib arm, compared to 1.6% in the placebo arm. Sanofi has since revised the study’s protocol to be more stringent in monitoring liver toxicities. The company noted that “all but one case of liver enzyme elevations resolved without further medical intervention,” although one patient in the tolebrutinib arm received a liver transplant and subsequently died due to post-operative complications.

Results from the GEMINI 1 and 2 trials were also presented at the ECTRIMS conference. Both tolebrutinib and Aubagio demonstrated improvements in annualized relapse rates, but no differences were observed between the two in a pooled analysis. Tolebrutinib also delayed the time to six-month disability progression by 29%.

Additionally, Sanofi is evaluating tolebrutinib in patients with primary progressive MS in a Phase III PERSUS trial (NCT04458051). Preliminary results from this study are expected in the latter half of the next year. Earlier this year, the company suspended the development of tolebrutinib for myasthenia gravis and terminated the Phase III trial (NCT05132569), citing “strategic” considerations.

In summary, while Sanofi has faced challenges with tolebrutinib, including mixed efficacy results and liver toxicity issues, the company remains optimistic about securing global regulatory approval for its use in non-relapsing secondary progressive MS, supported by promising data from the HERCULES Phase III trial. Further evaluations in primary progressive MS and other strategic decisions will continue to shape the future of tolebrutinib’s development.