25th April 2025
The phase 3 studies of oral BTK-inhibitor tolebrutinib have been published in The New England Journal of Medicine. The results provide evidence for tolebrutinib as an effective treatment for non-relapsing secondary progressive MS,* for which no treatment is currently approved.
Tolebrutinib inhibits an enzyme called “Bruton’s tyrosine kinase,” which reduces the activation of B cells –cells that play a role in the immune response that affects the brain and spinal cord in MS. Tolebrutinib also penetrates the brain and spinal cord, and regulates immune cells in the brain called microglia, which have been linked to MS progression.
The HERCULES Study
The phase 3 HERCULES trial compared tolebrutinib with placebo in 1,131 people with non-relapsing secondary progressive multiple sclerosis. Individuals treated with tolebrutinib had a 31% lower risk of disability progression than those treated with placebo. Significantly more people experienced improvements on the Expanded Disability Status Scale (EDSS) in the tolebrutinib group than in the placebo group.
Imaging studies showed significant reductions in new areas of tissue damage but not in brain tissue volume loss (atrophy). Secondary outcomes were recently presented at the Annual Meeting of the American Academy of Neurology Meeting, showing that tolebrutinib appeared to improve lower extremity function more than placebo, but did not improve upper extremity function significantly more than placebo.
“The ongoing HERCULES study shows promising results for tolebrutinib as a viable treatment for people with secondary progressive MS,” said Ruth Ann Marrie, co-chair of the International Progressive MS Alliance’s Scientific Steering Committee. “The potential of a treatment that slows disease progression provides incredible hope for improving the quality of life of people living with progressive MS.”
On March 25, 2025, Sanofi, Inc. announced that its regulatory submission of tolebrutinib to treat non-relapsing secondary progressive MS and to slow disability accumulation independent of relapse activity in adult patients was accepted for priority review by the U.S. Food and Drug Administration. The FDA will make its decision on or before September 28, 2025. No disease-modifying therapy is specifically approved to treat this group.
The GEMINI Studies
In the GEMINI studies, tolebrutinib was compared to teriflunomide (Aubagio®, Sanofi) in 1,873 people with relapsing MS (974 in GEMINI 1 and 899 in GEMINI 2). The primary endpoint in the GEMINI trials was annualized relapse rate, used to measure the average number of relapses a group of patients experience in a year.
Tolebrutinib did not reduce relapses significantly more than Aubagio® (teriflunomide, Sanofi). However, similar to the HERCULES study, tolebrutinib delayed time to disability progression. Participants treated with tolebrutinib had a 29% lower risk of disability progression compared to teriflunomide.
The PERSEUS Study
A fourth phase 3 study, the PERSEUS study, is ongoing in 767 people with primary progressive MS. Results are expected later in 2025.
*In this study, non-relapsing secondary progressive multiple sclerosis was defined as disability progression during the 12 previous months and no clinical relapses for the past 24 months.