Sanofi Reveals MS Data from Tolebrutinib’s Mixed Phase 3, Eyes ‘24 Approval

Sanofi has revealed promising data from the phase 3 HERCULES trial, which may revive its multiple sclerosis (MS) drug candidate, tolebrutinib. The BTK inhibitor has shown a 31% delay in the onset of confirmed disability progression, prompting the company to seek approval later this year.

Earlier in the month, Sanofi announced topline data from three phase 3 trials of tolebrutinib, with mixed results: one success in non-relapsing secondary progressive MS and two failures in relapsing MS. The detailed findings were presented at the European Committee for Treatment and Research in Multiple Sclerosis conference.

In the successful non-relapsing secondary progressive MS trial, tolebrutinib delayed the time to onset of six-month confirmed disability progression by 31% compared to placebo, achieving the study's primary endpoint. Additionally, 10% of patients in the tolebrutinib group experienced confirmed disability improvement, compared to 5% in the placebo group.

Sanofi’s safety analysis highlighted that 4.1% of patients on tolebrutinib had liver enzyme levels at least three times the upper limit of normal, compared to 1.6% in the placebo group. In 0.5% of patients, liver enzyme ALT levels exceeded 20 times the normal limit. These elevations occurred within the first 90 days of treatment. All but one case of liver enzyme elevation resolved without further medical intervention; however, one patient required a liver transplant and later died due to postoperative complications. This incident occurred before Sanofi implemented stricter monitoring protocols. Liver injury reports led the FDA to impose a partial hold on tolebrutinib in 2022, a challenge also encountered by other BTK drug developers.

Sanofi plans to initiate global filings for approval based on the current data this year, with liver toxicity as a significant consideration. The failure of tolebrutinib in two relapsing MS trials might also be a critical discussion point. Sanofi emphasized the distinction between the successful non-relapsing secondary progressive MS trial and the failed relapsing MS trials, explaining that non-relapsing secondary progressive MS is genetically and clinically distinct.

In the failed relapsing MS trials, tolebrutinib did not significantly improve annualized relapse rates compared to Aubagio, failing the primary endpoints. However, a pooled analysis of a secondary endpoint indicated a 29% delay in the time to onset of six-month confirmed disability worsening. Sanofi suggested that this significant difference in disability accumulation, but not in relapses, implies that tolebrutinib might address smoldering neuroinflammation, which manifests as progression independent of relapses. The company has been raising awareness about smoldering neuroinflammation throughout the development of tolebrutinib.

The liver safety signal persisted in the relapsing MS trials, with 5.6% of participants on tolebrutinib showing liver enzyme levels at least three times the upper limit of normal. This figure, although higher than in the non-relapsing study, is lower compared to the Aubagio control arms, which stood at 6.3% in the relapsing MS trials.

A fourth study is currently evaluating tolebrutinib in primary progressive MS, with data expected in the second half of 2025. The forthcoming results will further determine the future of tolebrutinib as a potential treatment for various forms of multiple sclerosis.