Investigational tolebrutinib shows efficacy for non-relapsing secondary progressive multiple sclerosis (SPMS)

Results from a Phase 3 study of treatment with investigational tolebrutinib show a 31% delay in the onset of six-month confirmed disability progression (CDP) in patients with non-relapsing secondary progressive multiple sclerosis (SPMS).

The findings from the HERCULES trial were published on April 8, 2025 in the New England Journal of Medicine and were simultaneously presented at the American Academy of Neurology 2025 Annual Meeting in San Diego.

SPMS is 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 lead author Robert Fox, M.D., chair of the HERCULES Global Steering Committee and a neurologist at the Mellen Center for MS Research and Treatment at Cleveland Clinic in Cleveland, Ohio.

“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 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.”

As background, the authors noted that in multiple sclerosis progressive neurologic impairment, or disability accrual, can develop. Current disease-modifying therapies show limited effect on disability accrual unrelated to relapses, which is thought to be partially caused by unresolved neuroinflammation within the central nervous system.

Tolebrutinib is an oral, brain-penetrant Bruton’s tyrosine kinase inhibitor that targets myeloid cells (including microglia) and B cells in both the periphery and central nervous system.

In this placebo-controlled trial, subjects with nonrelapsing secondary progressive multiple sclerosis were randomized in a 2:1 ratio, to receive tolebrutinib (60 mg once daily) or matching placebo.

The primary end point was confirmed disability progression sustained for at least 6 months.

A total of 1131 subjects were enrolled and randomized — 754 to tolebrutinib and 377 to placebo.

The median follow-up was 133 weeks.

The investigators reported that a statistically significant smaller percentage of the tolebrutinib-treated subjects than placebo subjects had experienced confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; P=0.003).

Serious adverse events occurred in 15.0% of the tolebrutinib-treated subjects and in 10.4% of those in the placebo group.

The researchers reported that levels of alanine aminotransferase (ALT), an enzyme reflecting liver injury, at above three times the upper limit of normal (ULN) were detected in 4% of tolebrutinib-treated subjects versus 1.6% of placebo recipients. ALT level increases above 20 times ULN were detected in 0.5% of tolebrutinib-treated and in no placebo subjects. One subject treated with tolebrutinib died of complications related to liver failure.

All cases of severe ALT elevation occurred within 90 days of the start of treatment.

“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,” said. 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 authors concluded, “In participants with nonrelapsing secondary progressive multiple sclerosis, the risk of disability progression was lower among those who received treatment with tolebrutinib than among those who received placebo.”