Tolebrutinib Approved in EU for Nonrelapsing Secondary Progressive MS, Marking First Disability-Targeting Therapy in the Indication

The European Commission has approved tolebrutinib (Cenrifki; Sanofi) for the treatment of secondary progressive multiple sclerosis (SPMS) without relapses in the last two years, making it the first therapy specifically designed to target disability progression in this population.¹

The approval follows a positive opinion by the European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) issued in April 2026 and is based primarily on results from the phase 3 HERCULES trial in nonrelapsing SPMS (nrSPMS), with supporting data from the GEMINI 1 and 2 studies in relapsing MS.

The decision is a significant regulatory milestone for a drug whose path to market has been marked by setbacks, delays, and a divergence between European and US outcomes that leaves American patients without an approved option.

For context, tolebrutinib is an oral, brain-penetrant Bruton's tyrosine kinase (BTK) inhibitor designed to address smoldering neuroinflammation, a key driver of disability progression in progressive MS. Unlike earlier-generation BTK inhibitors developed for oncology, tolebrutinib crosses the blood-brain barrier, allowing it to inhibit microglial and B-cell signaling within the CNS, where compartmentalized inflammation is thought to sustain irreversible axonal injury in SPMS.¹ This mechanism distinguishes it from existing disease-modifying therapies, most of which target peripheral immune activity with limited effect on progression in the absence of active relapses.

HERCULES Efficacy Data

The HERCULES trial (NCT04411641) enrolled 1,131 patients aged 18 to 60 with nrSPMS, EDSS scores between 3.0 and 6.5, no clinical relapses in the prior 24 months, and documented disability accumulation during that period. Patients were randomized 2:1 to daily tolebrutinib 60 mg or placebo for up to 48 months. The primary endpoint was 6-month confirmed disability progression (CDP), defined as a 1.0-point EDSS increase from baseline for scores of 5.0 or lower, or a 0.5-point increase for scores above 5.0.

Treatment with tolebrutinib significantly delayed the onset of 6-month CDP compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026), a 31% relative risk reduction.² A key secondary finding showed that patients on tolebrutinib were nearly twice as likely to achieve confirmed disability improvement as those on placebo (10% vs 5%; HR, 1.88; 95% CI, 1.10-3.21).² Post-hoc analyses suggested the treatment effect may be greater in patients with higher baseline paramagnetic rim lesion (PRL) counts, a radiographic marker of chronic active lesions, with a 54% reduction in 6-month confirmed disability worsening observed in the highest-quartile PRL subgroup.³

Supportive data from the GEMINI 1 and 2 trials in relapsing MS did not meet their primary endpoints of reducing annualized relapse rate versus teriflunomide, but showed consistent reductions in 6-month confirmed disability worsening, reinforcing the signal seen in HERCULES across MS phenotypes.²

Safety

The most common adverse events across the clinical program were COVID-19 and upper respiratory tract infections. Drug-induced liver injury (DILI) is an identified risk, with liver enzyme elevations greater than three times the upper limit of normal observed in 4.1% of tolebrutinib-treated patients versus 1.6% on placebo in HERCULES.² Strict hepatic monitoring is required during treatment, and Sanofi has noted that Germany will be the first market where Cenrifki is made commercially available, accompanied by a Risk Management Program and Patient Support Program.¹

A Rocky Regulatory Path

The EU approval comes after a prolonged and difficult regulatory journey in the US. In September 2025, the FDA extended its review period for tolebrutinib's new drug application after additional information constituted a major amendment, pushing the PDUFA decision date to December 28, 2025.⁴ That date came and went without approval. The setback was compounded in December 2025 when the phase 3 PERSEUS trial in primary progressive MS failed to meet its primary endpoint of delaying 6-month composite confirmed disability progression, eliminating the prospect of a PPMS indication and raising broader questions about the drug's regulatory future in the US.⁵

"We are disappointed by today's results; however, we do believe that these results will improve our understanding of the underlying disease biology of multiple sclerosis," said Houman Ashrafian, Executive Vice President and Head of Research and Development at Sanofi, in a statement released at the time of the PERSEUS failure.⁵

The US NDA for nrSPMS remains pending, and Sanofi has not announced an updated PDUFA date or confirmed whether it intends to resubmit. For now, the EU approval means that tolebrutinib will be available to patients with nrSPMS across Europe, while US patients with the same diagnosis continue to have no approved treatment targeting the underlying mechanisms of their disability accumulation. Tolebrutinib is also approved in Australia and the United Arab Emirates for nrSPMS.¹

The broader question for US neurologists remains unresolved: whether the HERCULES data, which the EMA found sufficient to support approval, will ultimately satisfy FDA evidentiary standards, particularly in light of the PERSEUS failure and the FDA's prior concerns that prompted the review extension. No timeline has been publicly communicated.

REFERENCES
1. Sanofi's Cenrifki (tolebrutinib) approved in the EU as the first disability-targeting medicine for secondary progressive multiple sclerosis without relapses. News release. Sanofi. June 23, 2026. Accessed June 25, 2026. https://www.globenewswire.com/news-release/2026/06/23/sanofi-cenrifki-tolebrutinib-eu-approval-nrspms
2. Tolebrutinib meets primary endpoint in HERCULES phase 3 study. News release. Sanofi. September 2, 2024. Accessed June 25, 2026. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875
3. Oh J, Fox RJ, Arnold DL, et al. Paramagnetic rim lesions as a prognostic and predictive biomarker in the tolebrutinib phase 3 trials for disability outcomes. Presented at: 2025 ACTRIMS Forum; February 27-March 1, 2025; West Palm Beach, FL. Abstract LB1.1.
4. Update on the US regulatory review of tolebrutinib in non-relapsing, secondary progressive multiple sclerosis. News release. Sanofi. September 22, 2025. Accessed June 25, 2026. https://www.globenewswire.com/news-release/2025/09/22/3153624/0/en/Press-Release-Update-on-the-US-regulatory-review-of-tolebrutinib-in-non-relapsing-secondary-progressive-multiple-sclerosis.html
5. Sanofi provides update on tolebrutinib in primary progressive multiple sclerosis. News release. Sanofi. December 15, 2025. Accessed June 25, 2026. https://www.sanofi.com/assets/dotcom/pressreleases/2025/2025-12-15-06-05-00-3205094-en.pdf