EU Approves Tolebrutinib as First Therapy to Target Disability Progression in Nonrelapsing SPMS

The European Commission has approved tolebrutinib (Cenrifki; Sanofi) for the treatment of adults with secondary progressive multiple sclerosis (SPMS) who have not experienced relapses within the previous 2 years. The oral therapy is the first medicine approved in the European Union specifically to target disability progression in this population.¹

This approval follows a positive recommendation from the European Medicines Agency Committee for Medicinal Products for Human Use and is primarily supported by findings from the phase 3 HERCULES trial (NCT04411641). Supporting evidence was provided by the phase 3 GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) trials in relapsing MS.^1,2

Addressing Disability Accumulation in Progressive MS

SPMS develops after an initial relapsing-remitting course of MS and is identified through the gradual accumulation of neurologic disability. Patients may experience worsening mobility, fatigue, cognitive impairment, and a loss of independence even when inflammatory relapses no longer occur.

This progression is believed to be partly driven by persistent—or “smoldering”— inflammation within the central nervous system (CNS). Because many available disease-modifying therapies primarily reduce relapses and new inflammatory activity, patients whose disease progresses without relapses have historically had limited treatment options.

Tolebrutinib is a once-daily, 60-mg oral Bruton tyrosine kinase (BTK) inhibitor designed to penetrate the blood-brain barrier. Although its precise therapeutic mechanism in MS is not fully understood, inhibition of BTK is thought to reduce activation of B cells, macrophages, and microglia in both the peripheral nervous system and CNS.²

Tolebrutinib is intended to address the inflammatory processes associated with disability accumulation, rather than focusing solely on relapse prevention by targeting immune activity in the brain and spinal cord.

HERCULES Demonstrates Reduced Disability Progression

The HERCULES trial was a randomized, double-blind, placebo-controlled phase 3 trial that included 1131 adults with nonrelapsing SPMS. Participants who were eligible had an Expanded Disability Status Scale score between 3.0 and 6.5, no clinical relapses during the 24 months prior to enrollment, and documented disability progression during the preceding year. Participants were randomly assigned 2:1 to receive oral tolebrutinib 60 mg once daily or placebo.³

The primary end point was disability progression confirmed for at least 6 months. During a median follow-up of 133 weeks, 6-month confirmed disability progression occurred in approximately 22.6% of patients receiving tolebrutinib compared with 30.7% of those receiving placebo. Additionally, tolebrutinib was shown to reduce the risk of disability progression by 31% compared with placebo (HR, 0.69 [95% CI, 0.55-0.88]; P = .003).³

Six-month confirmed disability improvement occurred in 8.6% of patients treated with tolebrutinib and 4.5% of patients receiving placebo. The annualized rate of new or enlarging T2 lesions detected through MRI was also lower with tolebrutinib than with placebo, at 1.84 and 2.95 lesions, respectively.³

The GEMINI 1 and GEMINI 2 data did not demonstrate superiority for tolebrutinib over teriflunomide (Aubagio; Genzyme Corporation) in reducing annualized relapse rates among patients with relapsing MS. However, pooled supporting findings suggested a reduction in the risk of 6-month confirmed disability worsening with tolebrutinib.⁴

Liver Monitoring Is Central to Safe Use

The most frequently reported adverse events across the clinical program included COVID-19 and upper respiratory tract infections. Increased liver enzyme levels were also observed, and drug-induced liver injury is an identified critical safety risk.¹

In HERCULES, alanine aminotransferase levels exceeding 3 times the upper limit of normal occurred in 4.0% of patients receiving tolebrutinib and 1.6% receiving placebo. Approximately 0.5% of tolebrutinib-treated patients developed elevations exceeding 20 times the upper limit of normal, occurring within the first 90 days of treatment.³

Strict adherence to required liver function monitoring and prompt management of enzyme elevations will therefore be essential. Pharmacists can help verify appropriate laboratory monitoring, screen for concomitant therapies associated with hepatotoxicity, reinforce once-daily administration with food, and counsel patients to promptly report symptoms that could indicate liver injury.

The approval grants an emerging therapeutic option for patients whose MS-related disability continues to worsen despite an absence of recent relapses. Its clinical use, however, will require coordinated monitoring among prescribers, pharmacists, and patients to balance the demonstrated reduction in disability progression against the risk of serious hepatic toxicity.

REFERENCES

1. Sanofi’s Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses. Sanofi. News release. June 23, 2026. Accessed June 25, 2026. https://www.sanofi.com/assets/dotcom/pressreleases/2026/2026-06-23-05-00-00-3315699-en.pdf

2. Cenrifki: summary of opinion and European public assessment report. European Medicines Agency. Updated June 25, 2026. Accessed June 25, 2026. https://www.ema.europa.eu/en/medicines/human/EPAR/cenrifki

3. Fox RJ, Bar-Or A, Traboulsee A, et al. Tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. N Engl J Med. 2025;392(19):1883-1892. doi:10.1056/NEJMoa2415988

4. Oh J, Arnold DL, Cree BAC, et al. Tolebrutinib versus teriflunomide in relapsing multiple sclerosis. N Engl J Med. 2025;392(19):1893-1904. doi:10.1056/NEJMoa2415985