Cleveland Clinic-Led Trial is the First to Show a Delay in Confirmed Disability Progression in Non-relapsing Secondary Progressive Multiple Sclerosis

A Cleveland Clinic-led clinical trial of tolebrutinib, an investigational oral Bruton’s tyrosine kinase inhibitor, a group of drugs originally developed to treat lymphomas and related blood disorders, demonstrated a 31% delay in the onset of six-month confirmed disability progression (CDP) in patients with non-relapsing secondary progressive multiple sclerosis (SPMS).

The first peer-reviewed results of the Phase 3 HERCULES trial published online today in the New England Journal of Medicine and were simultaneously presented during a clinical trials plenary session at the American Academy of Neurology 2025 Annual Meeting in San Diego, and suggest that tolebrutinib is an effective treatment for non-relapsing SPMS, a form of the disease for which there are currently no U.S. Food and Drug Administration (FDA)-approved treatments.

“This is the first clinical trial showing a positive effect in delaying disability progression in non-relapsing SPMS, a later form of the disease where neurological function gradually worsens over time and disability increases relentlessly,” said Robert Fox, M.D., the paper’s lead author, chair of the HERCULES Global Steering Committee and a neurologist at the Mellen Center for MS Research and Treatment at Cleveland Clinic.

“The findings demonstrate the drug's impact on chronic neuroinflammation in the central nervous system, a key driver of this gradual disability observed in SPMS,” said Dr. Fox. “The drug offers the potential for a new class of medications for the treatment of MS, the leading cause of non-traumatic disability in young adults.”

While topline results of HERCULES were first presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting last September, the peer-reviewed paper offers new insights into the drug’s efficacy and safety profile.

Between Oct. 23, 2020, and Jan. 12, 2023, the randomized, double-blind, placebo-controlled trial enrolled 1,131 patients ages 18-60 at 264 sites across 31 countries. Patients with documented disability progression in the 12 months prior to screening and who had no clinical relapses in the 24 months before screening were randomly assigned at a 2:1 ratio to receive 60 mg oral tolebrutinib or a matching placebo tablet.

For the primary endpoint, the cumulative incidence of six-month confirmed disability progression was 22.6% in the tolebrutinib group versus 30.7% in the placebo group, which was a 31% reduction with tolebrutinib compared to placebo. In addition, the drug demonstrated a positive effect across several of its secondary endpoints in disability progression and MRI-related measures:

• A similar degree of risk reduction was observed in the time to three-month confirmed disability progression.
• A higher proportion of patients achieved improvement in disability with therapy, with a six-month confirmed disability improvement rate of 8.6% versus 4.5% with placebo.
• Measures of three-month sustained 20% increase in the timed 25-foot walk test favored tolebrutinib, but three-month sustained 20% increase in nine-hold peg test was not impacted by tolebrutinib. In clinical trials of MS, these are standard tests used to measure walking ability and upper limb dexterity, respectively.
• The mean annualized rate of new and/or enlarging T2-weighted lesions, a test used to measure disease activity, including inflammation and tissue damage, was reduced with tolebrutinib compared with placebo.

Adverse event rates were broadly comparable between the tolebrutinib and placebo groups, although serious adverse events were more frequent with tolebrutinib. Levels of alanine aminotransferase (ALT), an enzyme reflecting liver injury, above three times the upper limit of normal (ULN) were observed in 4% of tolebrutinib recipients versus 1.6% of placebo recipients over the course of the trial. ALT level increases above 20 times ULN were reported in 0.5% of tolebrutinib recipients versus 0% of placebo recipients, and one patient treated with tolebrutinib died of complications related to liver failure. Notably, all cases of severe ALT elevation occurred within 90 days of treatment initiation.

Tolebrutinib is currently under review by the FDA. “If approved, the drug will likely require intensive monitoring of liver function enzymes during the first three months of therapy, with less frequent monitoring thereafter,” says Dr. Fox. “It appears that about one in 200 patients will have severe elevation of liver enzymes during the first three months of use, so careful monitoring is important, and the drug should be stopped immediately in those with liver enzyme elevations.”

The HERCULES trial was sponsored by Sanofi, the developer of tolebrutinib. Dr. Fox reports consulting for, and receiving research support from, Sanofi and other pharmaceutical companies.