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SAN DIEGO — Tolebrutinib, a novel Bruton’s tyrosine kinase (BTK) inhibitor that targets neuroinflammation, slowed disability progression by 31% in patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS), results of a multi-center phase 3 study showed.

“Although tolebrutinib was associated with increased risks of respiratory complications and elevated liver enzymes, it also demonstrated several functional benefits, including a slowed decline in walking ability and a significant reduction in the annualized rate of new, or enlarging, T2 lesions.”

This study is believed to be the first to demonstrate a significant slowing of disability progression in patients with nrSPMS, a condition for which there are currently no US Food and Drug Administration (FDA)–approved treatments.

“For years we been saying to patients that there really is nothing we can do to slow progression of their disease, but now we have something, and that’s truly exciting”, lead investigator, Robert J. Fox, MD, chair of the HERCULES Global Steering Committee and a neurologist at the Mellen Center for MS Research and Treatment, Cleveland Clinic, Cleveland, told Medscape Medical News.

The findings were presented on April 8, 2025, at the American Academy of Neurology 2025 annual meeting and published simultaneously in The New England Journal of Medicine.

Targeting Neuroinflammation

About 85% of MS cases begin as the relapsing-remitting form, and over 10-20 years, a large proportion of patients transition to secondary progressive MS, where relapses subside and are gradually replaced by a steady decline in function, said Fox.

Tolebrutinib is an oral, brain-penetrant, and bioactive inhibitor of BTK, a key signaling molecule involved in neuroinflammation. It is designed to reduce activation and proinflammatory responses in B cells and myeloid cells within the central nervous system (CNS), as well as their counterparts in the peripheral immune system.

Several BTK inhibitors are under investigation in MS as well as other autoimmune diseases.

The HERCULES trial enrolled 1131 adults with nrSPMS, with a mean age of approximately 49 years and no relapses in the previous 24 months. Participants had documented disability progression within the past 12 months and an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5.

Participants were randomly assigned to receive either oral tolebrutinib (60 mg daily) or a matching placebo. The two groups were similar in demographic and disease characteristics.

Most participants (74%) had previously received at least one disease-modifying therapy (DMT), and 12.7% had gadolinium-enhancing T1 lesions at baseline.

The median follow-up was 133 weeks. Overall, 76.9% of participants in the tolebrutinib group and 76.7% of those in the placebo group completed the trial.

The primary endpoint was confirmed disability progression (CDP), defined as an increase in EDSS score of at least 1.0 point for those with a baseline score ≤ 5.0, or at least 0.5 points for those with a baseline score > 5.0, sustained for a minimum of 6 months.

The primary endpoint was confirmed disability progression (CDP), defined as an increase in the EDSS score of 1.0 or more points (if the baseline score was ≤ 5.0) or 0.5 or more points (if the baseline score was > 5.0), that was sustained for at least 6 months.

Slowed Disease Progression

Confirmed disability progression occurred in 22.6% of participants in the tolebrutinib group compared with 30.7% of those in the placebo group (hazard ratio [HR], 0.69; 95% CI, 0.55 - 0.88; P = .003).

For the secondary endpoint — time to 3-month CDP — the study showed a 24% risk reduction in the tolebrutinib group vs placebo (27.6% vs 34.2%; HR, 0.76; 95% CI, 0.61-0.94; P = .01).

The treatment did not appear to improve arm function. The percentage of participants with a 20% increase in the score on the nine-hole peg test that was sustained for at least 3 months was 19.0% in the tolebrutinib group and 19.6% in the placebo group (HR 0.97; 95% CI, 0.74-1.29; P = .84).

However, it did seem to preserve walking ability. The percentage of participants with a 20% increase in the score on the timed 25-foot walk sustained for at least 3 months was 41.1% in the tolebrutinib group and 49.6% in the placebo group (HR, 0.77; 95% CI, 0.64-0.92).

Fox noted it was somewhat surprising that the treatment appeared to slow deterioration in walking ability but had no effect on arm function.

“We wouldn’t have expected it to affect one and not the other, so we definitely need to dive into that data a bit more to understand the nuances of patient subpopulations,” he said.

All disability-progression events were independent of relapse activity, the investigators noted.

“What’s really revolutionary is that we’re slowing down progression in this population, which has never been shown before, and we’re slowing down progression even though the effect on the relapsing aspect of MS is not very big,” said Fox.

Confirmed disability improvement was observed in 8.6% of participants treated with tolebrutinib compared with 4.5% of those treated with placebo (HR, 1.88; 95% CI, 1.10-3.21).

Tolebrutinib was associated with fewer new or enlarging T2 lesions (adjusted rate ratio, 0.62; 95% CI, 0.43-0.90; P = .011). Brain volume loss was similar between the two groups, which Fox noted was somewhat unexpected.

There was a slight increase in certain adverse events in the tolebrutinib group compared with that in the placebo group, including respiratory infections such as COVID-19, nasopharyngitis, and influenza.

Serious adverse events occurred in 15.0% of participants receiving tolebrutinib vs 10.4% of those receiving placebo. The number of deaths was similar in both groups, at 0.3%.

Elevated Liver Enzymes

Elevations in liver enzymes — specifically alanine aminotransferase (ALT) levels greater than three times the upper limit of normal (ULN) — were observed in 4.0% of participants in the tolebrutinib group compared with 1.6% of those in the placebo group.

A small proportion of participants receiving tolebrutinib (0.5%) experienced ALT elevations exceeding 20 times the ULN, all of which occurred within the first 90 days of treatment; no such cases were reported in the placebo group.

The vast majority of these cases resolved without lasting effects; however, one individual who required a liver transplant died. As a result, frequent liver monitoring during the first 90 days of treatment has been incorporated into the treatment protocol.

“We have to warn patients that this treatment can irritate the liver, and we need to monitor for it; it will mean weekly blood monitoring for first 3 months. We believe if we monitor carefully and identify the liver enzyme elevation early, we can intervene and stop it from progressing to liver failure,” said Fox.

Other trials have not shown a treatment benefit of tolebrutinib in patients with relapsing MS. “The pathology driving progression is probably quite different than the pathology driving relapses,” said Fox.

Sanofi, the study’s sponsor, has submitted its regulatory application to the FDA, and a decision is expected within 6 months, said Fox.

Penetrating the Blood-Brain Barrier

Commenting on the findings for Medscape Medical News, Barbara Giesser, MD, a neurologist specializing in MS, and professor emeritus of clinical neurology, University of California at Los Angeles, said the study is “important and very well done.”

What largely distinguishes the new class of BTK inhibitors from current disease modifying treatments is their ability to penetrate the blood-brain barrier and act on cells within the CNS, said Giesser.

She noted that these cells contribute to a mechanism of nerve damage known as smoldering inflammation, which is believed to play a major role in disease progression and the accumulation of disability.

The significant 31% reduction in the risk for disability progression at 6 months observed in the treatment group aligns with earlier data from smaller trials, which suggest that BTK inhibitors may slow — and potentially prevent — disability progression independently of their effects on relapses, said Giesser.

She expressed hope that the new findings will lead to broader access to treatments for nrSPMS. “Currently, the DMTs that have indications for SPMS are only authorized for SPMS with relapses,” she said.

This study was supported by Sanofi. Fox reported consulting for AB Science, Biogen, Bristol Myers Squibb, EMD Serono, Genentech, Greenwich Biosciences, Immunic, INmune Bio, Eli Lily and Company, Janssen, Novartis, Sanofi, Siemens, and TG Therapeutics; and receiving research support from Biogen, Novartis, and Sanofi. Geisser reported no relevant conflicts of interest.