CHMP Recommends BTK Inhibitor Tolebrutinib as Treatment for Nonrelapsing Secondary Progressive MS

Data from the phase 3 HERCULES trial have led the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) to recommend approval of tolebrutinib (Cenrifki; Sanofi) for patients with nonrelapsing secondary progressive multiple sclerosis (nrSPMS), marking a potential new option in a population with limited disease-modifying therapies.¹

Secondary progressive MS without relapses is characterized by gradual and irreversible accumulation of disability, often driven by compartmentalized inflammation within the central nervous system. Unlike relapsing forms of MS, where peripheral immune activity is more prominent, nrSPMS is thought to be sustained by chronic microglial activation and smoldering inflammation behind an intact blood-brain barrier, contributing to progressive neurodegeneration.

Tolebrutinib is an oral, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor designed to target both peripheral B cells and innate immune signaling within the CNS. By inhibiting BTK, the therapy may reduce proinflammatory signaling in microglia and B cells, addressing a key mechanism believed to underlie disability progression in progressive MS.¹ The agent has previously received Breakthrough Therapy designation from the FDA for nrSPMS based on early evidence of efficacy in slowing disability accumulation.²

The CHMP recommendation is primarily supported by findings from the phase 3 HERCULES trial (NCT04411641), which enrolled 1131 patients aged 18 to 60 years with nrSPMS and Expanded Disability Status Scale (EDSS) scores between 3.0 and 6.5. Participants were randomized 2:1 to receive once-daily tolebrutinib 60 mg or placebo. Led by Robert J. Fox, MD, a staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, treatment with tolebrutinib significantly delayed time to 6-month confirmed disability progression, reducing risk by 31% compared with placebo (HR, 0.69; 95% CI, 0.55–0.88; P = .0026).²

Additional secondary outcomes further supported the primary findings. The proportion of patients achieving confirmed disability improvement was nearly doubled in the tolebrutinib group compared with placebo (10% vs 5%; HR, 1.88; 95% CI, 1.10–3.21), suggesting potential for not only slowing progression but also modest functional gains in a subset of patients.²

Subgroup analyses have provided further context on which patients may benefit most from therapy. In particular, individuals with higher baseline paramagnetic rim lesion burden, a radiographic marker associated with chronic active lesions, demonstrated greater reductions in disability progression risk. These findings reinforce the hypothesis that tolebrutinib’s CNS-penetrant mechanism may preferentially target smoldering inflammatory processes driving progression.

Supportive data from the phase 3 GEMINI 1 and 2 trials in relapsing MS have also helped contextualize the drug’s clinical profile. Although these studies did not meet their primary endpoint of reducing annualized relapse rate compared with teriflunomide, they demonstrated a 29% reduction in 6-month confirmed disability worsening, suggesting a consistent effect on progression-related outcomes across disease phenotypes.³

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Safety findings across the clinical program have been generally consistent. The most commonly reported adverse events included infections such as COVID-19 and upper respiratory tract infections.¹ However, liver enzyme elevations and drug-induced liver injury (DILI) have emerged as notable risks. In HERCULES, elevations greater than three times the upper limit of normal occurred in 4.1% of tolebrutinib-treated patients compared with 1.6% of those receiving placebo, with rare cases of more severe elevations observed early in treatment.² These findings highlight the need for careful hepatic monitoring in clinical practice.

The broader development program has also underscored variability across progressive MS populations. In the phase 3 PERSEUS trial in primary progressive MS, tolebrutinib did not meet its primary endpoint, suggesting that the magnitude of benefit may depend on underlying disease biology and the degree of ongoing inflammatory activity. Despite this, the consistent signal observed in nrSPMS has reinforced interest in BTK inhibition as a strategy to address progression.

From a clinical perspective, the CHMP recommendation represents a potentially meaningful step forward in the management of progressive MS. Current disease-modifying therapies have limited efficacy in patients without active relapses, leaving a substantial unmet need for treatments that directly target the mechanisms driving disability accumulation. If approved, tolebrutinib would represent a novel, mechanism-based option aimed at slowing progression in this difficult-to-treat population.

A final decision from the European Commission is expected in the coming months.¹

REFERENCES
1. Sanofi. Cenrifki (tolebrutinib) recommended for EU approval by CHMP for secondary progressive multiple sclerosis. News release. April 24, 2026. https://www.globenewswire.com/news-release/2026/04/24/3280641/0/en/press-release-sanofi-s-cenrifki-tolebrutinib-recommended-for-eu-approval-by-the-chmp-to-treat-secondary-progressive-multiple-sclerosis-without-relapses.html
2. Tolebrutinib meets primary endpoint in HERCULES phase 3 study. News release. Sanofi. September 2, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875
3. Oh J, Arnold DL, Cree BAC, et al. Efficacy and safety of tolebrutinib vs teriflunomide in relapsing multiple sclerosis: results from the phase 3 GEMINI 1 and 2 trials. Presented at: ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark.