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Non-Relapsing Progressive MS and How Tolebrutinib Acts on It
Secondary progressive multiple sclerosis is the stage that can follow relapsing-remitting disease, sometimes decades after diagnosis, when symptoms worsen steadily instead of arriving as discrete attacks [5]. More than half of people with relapsing MS eventually transition to this course, and the disability they accumulate builds independently of relapses [3].
Tolebrutinib is the first therapy approved in Europe for the subset of those patients who have stopped relapsing altogether. Regulators define that subset by a clinical record rather than a scan: no relapses in the previous 2 years [2].
Quick Take & Core Data
- 31% relative risk reduction in the time to onset of six-month confirmed disability progression compared with placebo, at a hazard ratio of 0.69 [1].
- 1,131 adults with non-relapsing disease randomized within the international Phase 3 HERCULES trial [1].
- 38% fewer new or enlarging T2-hyperintense brain lesions per year, at 1.8 lesions versus 2.9 on placebo [2].
- 0.5% of the 754 treated participants had liver enzyme elevations above 20 times the upper limit of normal, all within 3 months of starting the drug [2].
Non-relapsing secondary progressive multiple sclerosis involves continuous, low-grade nerve-cell loss driven by chronic immune activity inside the central nervous system, a process researchers call smoldering neuroinflammation. Relapse-reducing therapies do little against it, because the damage is not arriving in the form of relapses.
Tolebrutinib, an oral brain-penetrant therapy, is a Bruton’s tyrosine kinase (BTK) inhibitor. Bruton’s tyrosine kinase controls signaling in B cells and in microglia, the immune cells resident in brain and spinal cord tissue.
The drug crosses the blood-brain barrier and reaches those cells where most disease-modifying therapies cannot. By dampening microglial activation inside central nervous system tissue rather than suppressing the immune system broadly, it acts on the inflammatory process that keeps destroying nerve fibers between relapses.
The approved dose is 60 mg taken orally once daily with a meal [2].
The HERCULES Clinical Evaluation
The international Phase 3 HERCULES trial enrolled adults aged 18 to 60 with a baseline Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 and no clinical relapses for at least 24 months, alongside documented disability accumulation during that period [4].
Investigators randomized 1,131 participants in a 2:1 ratio, with 754 receiving tolebrutinib and 377 receiving a matching placebo. The primary outcome measured time to confirmed disability progression sustained for at least 6 months.
Results published in the New England Journal of Medicine in April 2025 show that 22.6% of participants in the treatment group progressed, compared with 30.7% on placebo. That is a hazard ratio of 0.69 and a 31% reduction in risk [1].
Magnetic resonance imaging found 1.8 new or enlarging T2-hyperintense lesions per year on tolebrutinib versus 2.9 on placebo, a 38% reduction [2]. The trial did not establish a difference in overall brain volume loss.
What the Secondary Endpoints Showed
Two secondary measures moved in the drug’s favor without clearing the trial’s statistical bar. HERCULES tested its endpoints in a fixed hierarchical order, so neither result counts as formally significant. Both figures below come from the European product information rather than the primary publication.
Walking speed was one of them. A sustained 20% worsening on the timed 25-foot walk occurred in 41.1% of treated participants versus 49.6% on placebo, hazard ratio 0.77 [2].
Confirmed disability improvement was the other, at 8.6% of treated participants versus 4.5% on placebo, hazard ratio 1.88. That signal is the closest the trial comes to recovery of lost function, and it is not strong enough to support a claim of reversal.
Comparisons with Relapsing and Primary Progressive Disease
Two parallel Phase 3 trials, GEMINI I and GEMINI II, tested tolebrutinib against teriflunomide in 1,873 patients with relapsing MS. Both missed their primary endpoint: neither showed a significant improvement in annualized relapse rate.
A pre-specified pooled analysis of the two studies did find a 29% relative risk reduction in six-month confirmed disability worsening versus teriflunomide, and 77.9% of those events were progression independent of relapse activity [2]. Across all three trials the drug’s measurable effect falls on disability accumulation rather than on relapse frequency.
A third Phase 3 study, PERSEUS, randomized 767 patients with primary progressive MS and found no reduction in composite confirmed disability progression, at a hazard ratio of 1.01. Sanofi has said it will not pursue approval in primary progressive disease [3].
Other BTK inhibitors are in late-stage MS development. Fenebrutinib is in Phase 3 testing across relapsing and primary progressive disease, so the class will be judged on more than this one molecule [3].
Safety Signals and Monitoring Requirements
Liver injury is the constraint on this drug. Serious adverse events occurred in 15.0% of participants receiving tolebrutinib and 10.4% of those on placebo [1].
Alanine aminotransferase rose above three times the upper limit of normal in 4.0% of the treatment group and 1.6% of the placebo group [1]. Among the 754 treated participants, 0.5% had elevations above 20 times the upper limit of normal, and every one of those cases appeared within 3 months of starting the drug [2].
One participant developed liver failure, received a liver transplant, and died of a post-transplant complication [2]. The case occurred before the trials adopted tighter monitoring.
Across the wider tolebrutinib program, elevations above 20 times the upper limit of normal reached 0.5% to 0.8%, and Hy’s Law criteria for drug-induced liver injury were met in 0.4% of treated participants [3].
Monitoring is built around that 3-month window. BTK inhibitor trials in MS check liver enzymes weekly through the first 3 months of treatment [3]. The EU label carries additional-monitoring status.
Infections were more common on the drug. HERCULES recorded infections in 54.4% of treated participants versus 49.3% on placebo, and serious infections in 5.2% versus 3.5%, most often COVID-19 pneumonia [3].
Research Gap
The clearest limitation sits inside the trial’s own subgroup analysis. Among the 142 participants who had gadolinium-enhancing lesions on baseline MRI, a sign of residual focal inflammation, tolebrutinib cut progression risk by 65%. Among the 989 without such lesions, the reduction was 22%, and the confidence interval crossed 1.0 [2].
That leaves an open question about which patients benefit. The larger and more purely non-inflammatory group produced the weaker result, so the average 31% figure may be carried substantially by the minority with visible inflammation. Long-term follow-up in patients with no enhancing lesions has not settled it.
European and U.S. Regulatory Decisions
The CHMP issued a positive opinion on April 23, 2026, and the European Commission granted marketing authorisation on June 19, 2026, under the brand name Cenrifki [2]. The authorised indication covers adults with secondary progressive multiple sclerosis without relapses in the last 2 years.
The U.S. Food and Drug Administration reached the opposite conclusion. It issued a complete response letter in December 2025, declining the application in the same indication [6].
The agency’s position was that the hepatotoxicity risk could not be adequately managed by the Risk Evaluation and Mitigation Strategy Sanofi proposed.
Both regulators reviewed the same HERCULES data and the same liver findings. Europe judged the benefit sufficient to license the drug with additional monitoring. The United States did not.
Closing Thoughts
Tolebrutinib is evidence that a drug reaching immune cells behind the blood-brain barrier can slow disability in multiple sclerosis when relapses have stopped. That is a form of the disease no approved therapy had addressed.
The trade-off is explicit and measurable: a 31% reduction in progression risk against a rare but real risk of severe liver injury, which trial protocols managed with weekly liver enzyme testing through the first 3 months. European patients now face that trade-off as a choice. American patients do not have the option.
Whether the benefit holds in patients with no residual inflammatory lesions is the question long-term data will need to answer.
References
[1] Fox, R. J., Bar-Or, A., Traboulsee, A., Oreja-Guevara, C., Giovannoni, G., Vermersch, P., Syed, S., Li, Y., Vargas, W. S., Turner, T. J., Wallstroem, E., & Reich, D. S. (2025). Tolebrutinib in nonrelapsing secondary progressive multiple sclerosis. New England Journal of Medicine, 392(19), 1883–1892. https://doi.org/10.1056/NEJMoa2415988
[2] European Medicines Agency. (2026). Cenrifki (tolebrutinib): EPAR product information (EMEA/H/C/006386). https://www.ema.europa.eu/en/medicines/human/EPAR/cenrifki
[3] Lambe, J., & Fox, R. J. (2026). Bruton’s tyrosine kinase inhibitors in multiple sclerosis. Drugs, 86(7), 989–1012. https://doi.org/10.1007/s40265-026-02324-y
[4] Sanofi. (2025). Nonrelapsing secondary progressive multiple sclerosis (NRSPMS) study of Bruton’s tyrosine kinase (BTK) inhibitor tolebrutinib (SAR442168) (HERCULES) (Identifier NCT04411641). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04411641
[5] Multiple Sclerosis International Federation. (2025, April 10). Types of MS. https://www.msif.org/about-ms/types-of-ms/
[6] Pharmacy Times. (2026, January 5). Tolebrutinib receives FDA CRL for nonrelapsing secondary progressive multiple sclerosis. https://www.pharmacytimes.com/view/tolebrutinib-receives-fda-crl-for-nonrelapsing-secondary-progressive-multiple-sclerosis
