Sanofi’s Tolebrutinib Meets Primary Endpoint in Phase 3 MS Trial

After facing a 2022 FDA-imposed partial clinical hold due to liver toxicity issues, Paris-based Sanofi announced yesterday that the HERCULES phase 3 study of its investigational Bruton’s tyrosine kinase (BTK) inhibitor, tolebrutinib, met the primary endpoint of delaying time to onset of confirmed disability progression in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS).

The HERCULES trial randomized 1,131 participants with nrSPMS to receive oral tolebrutinib or placebo daily for up to 48 months. The study defined nrSPMS as having an SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5 and no clinical relapses during the 24 months before enrollment. The participants must also have documented evidence of disability accumulation during the 12 months prior to enrollment.

SPMS is the gradual succession of relapsing-remitting MS, which is the most common form of the disease. Someone with SPMS experiences steadily worsening MS-associated symptoms and disability. People with nrSPMS stop experiencing disease relapses but continue to have disability accumulation. This can be seen in symptoms such as balance, gait, and cognitive impairment, bowel, bladder, or sexual dysfunction, and increased fatigue. Currently, there is no approved treatment for this form of MS.

Sanofi is hoping to change that.

“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,” Houman Ashrafian, M.D., Ph.D., head of research and development at Sanofi, said in a press conference.

BTK is a protein expressed in B-cells and myeloid cells, which play an integral role in MS pathology. Tolebrutinib is an oral central nervous system penetrant that is thought to modulate B-cells and microglia associated with MS disease progression. The BTK inhibitor is being evaluated for use in various forms of MS.

The GEMINI 1 and GEMINI 2 phase 3 studies evaluated the safety and efficacy of tolebrutinib versus Aubagio (teriflunomide) in patients with relapsing forms of MS. Aubagio is a pyrimidine synthesis inhibitor FDA-approved to treat relapsing forms of MS. Genzyme Corporation, a Sanofi company, manufactures the drug. The studies did not meet the primary endpoint of reducing the annualized relapse rate in up to 36 months. However, analysis of pooled data of secondary endpoint of 6-month confirmed disability worsening (CDW) demonstrated a significant delay in time to onset of CDW.

Results from the HERCULES trial, as well as those from the GEMINI 1 and 2 studies, will be presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) medical meeting in Copenhagen, Denmark, on September 20, 2024.