Tolebrutinib approved in the EU for secondary progressive multiple sclerosis without relapses

On June 23, 2026, the European Commission approved tolebrutinib for the treatment of adults with secondary progressive multiple sclerosis (SPMS) without relapses in the previous two years. The approval makes tolebrutinib the first disability-targeting therapy approved in the European Union (EU) specifically for this patient population and marks an important milestone in addressing disability progression in multiple sclerosis (MS).¹

Unmet need in non-relapsing secondary progressive multiple sclerosis

MS is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by progressive neurological disability. Many patients initially experience a relapsing-remitting disease course before transitioning to SPMS, a stage marked by gradual worsening of disability that occurs independently of relapses.²

Patients with non-relapsing SPMS (nrSPMS) often experience increasing mobility impairment, fatigue, cognitive decline, and loss of independence, substantially affecting quality of life. Treatment options capable of slowing disability accumulation in nrSPMS have remained limited.^1,2

Tolebrutinib: mechanism of action

Tolebrutinib is an oral, brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor specifically designed to target both peripheral immune cells and inflammatory processes within the central nervous system. By inhibiting BTK signaling in B-cells and myeloid cells, including microglia, tolebrutinib aims to reduce chronic neuroinflammation that contributes to disability accumulation in progressive MS.^1,2

Unlike many existing MS therapies that primarily focus on preventing relapses, tolebrutinib was developed to address the persistent inflammatory activity thought to drive progression independent of relapse activity.¹

Pivotal data: the HERCULES and GEMINI trials

The European Commission approval was primarily supported by results from the Phase III HERCULES trial (NCT04411641), a randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of tolebrutinib in patients with nrSPMS.^1,2

In the HERCULES trial, a total of 1,131 participants were randomized in a 2:1 ratio to receive either tolebrutinib 60 mg once daily (n = 754) or placebo (n = 377). Participants had documented evidence of disability accumulation during the previous 12 months, no clinical relapses during the previous 24 months, and an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5.¹˒² After a median follow-up of 133 weeks, a significantly lower proportion of patients experienced six-month confirmed disability progression (CDP) with tolebrutinib than with placebo (22.6% vs. 30.7%; hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.55–0.88; p = 0.003).²

Tolebrutinib was also evaluated in patients with relapsing multiple sclerosis (RMS) in the Phase III GEMINI trials (NCT04410978; NCT04410991). Across the clinical development program, the safety profile of tolebrutinib was generally consistent.¹ In HERCULES, serious adverse events occurred in 15.0% of patients receiving tolebrutinib compared with 10.4% receiving placebo.² The most commonly reported adverse events across studies included COVID-19 and upper respiratory tract infections.¹

We recently spoke with Celia Oreja-Guevara, MD, PhD, University Hospital San Carlos, Madrid, Spain, who discussed the HERCULES and GEMINI trials. Discussing the safety profile, Prof. Oreja-Guevara noted that ‘regarding the safety…all the hematological parameters in the blood are in the normal range and there was only a very mild decrease of the immunoglobulin IgM‘.

Clinical implications

The approval of tolebrutinib represents a significant advance for patients living with nrSPMS, a population that has historically faced limited treatment options despite substantial disability burden. By specifically targeting smoldering neuroinflammation within the central nervous system, tolebrutinib introduces a therapeutic strategy focused on slowing disability progression rather than solely reducing relapses. It is the first approved therapy in the EU specifically indicated for adults with nrSPMS, addressing a longstanding unmet need.^1,2

Written by Hannah Elkheir

Reviewed by Natalie Markova

References

1. Sanofi. Sanofi’s Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses. Available here. (Last accessed: 06/26/2026).
2. Fox RJ, Bar-Or A, Traboulsee A, et al.; HERCULES Trial Group. Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis. N Engl J Med. 2025;392(19):1883–1892.