Sanofi has shared data from the phase 3 HERCULES trial that could rescue its multiple sclerosis (MS) drug candidate tolebrutinib, linking the BTK inhibitor to a 31% delay in time to onset of confirmed disability progression. The drugmaker plans to seek approval this year.
Earlier this month, Sanofi posted topline data from three phase 3 trials of the BTK inhibitor, reporting one win in non-relapsing secondary progressive MS and two failures in relapsing MS. Now, the French drugmaker has shared the numbers behind the headline findings at the European Committee for Treatment and Research in Multiple Sclerosis conference.
In the successful non-relapsing trial, the time to onset of six-month confirmed disability progression was delayed by 31% in the tolebrutinib group compared to the placebo arm. That result delivered the study’s hit on its primary endpoint. Sanofi also reported a difference in the number of patients who experienced confirmed disability improvement in the tolebrutinib arm, 10%, and the placebo group, 5%.
Sanofi’s safety and tolerability analysis showed 4.1% of people on tolebrutinib had liver enzyme levels of at least three times the upper limit of normal, compared to 1.6% of the patients taking placebo. In 0.5% of people on tolebrutinib, levels of the liver enzyme ALT peaked at more than 20 times the upper normal limit. All those increases happened in the first 90 days of treatment.
All but one case of liver enzyme elevations resolved without further medical intervention. One patient needed a liver transplant and died of postoperative complications. The death happened before Sanofi put more stringent monitoring in place. Reports of liver injury led the FDA to slap a partial hold on tolebrutinib in 2022. Developers of other BTK drug candidates have faced similar problems.
Sanofi plans to start global filings for approval on the strength of the data this year. The liver toxicity will be one area of focus. Tolebrutinib’s failure to move the needle in two relapsing MS trials may be another talking point. Sanofi sought to separate the successful and failed trials when it shared the topline results, arguing non-relapsing secondary progressive MS is a genetically and clinically distinct condition.
The drugmaker also shared data from the two failed trials in relapsing MS. There was no significant improvement in annualized relapse rates compared to Aubagio, causing the studies to miss their primary endpoints, but a pooled analysis of a secondary endpoint linked tolebrutinib to a 29% delay in the time to onset of six-month confirmed disability worsening across the two relapsing MS studies.
Sanofi said the significant difference in disability accumulation, but not relapses, suggests tolebrutinib “may address smoldering neuroinflammation, which manifests as progression independent of relapses.” The drugmaker has sought to raise awareness of smoldering neuroinflammation during the development of tolebrutinib.
The liver safety signal was present in the relapsing MS trials. Across the two studies, 5.6% of participants receiving tolebrutinib had liver enzyme levels of at least three times the upper limit of normal. While the figure is higher than in the non-replasing study, it is lower than the result for the Aubagio control arms, 6.3%, in the replasing MS trials.
A fourth study is assessing tolebrutinib in primary progressive MS. Sanofi expects to have data from that phase 3 trial in the second half of 2025.