Tolebrutinib for Progressive MS: HERCULES Data, FDA Rejection, and EU Recommendation

Tolebrutinib received an FDA complete response letter in December 2025 and a positive EU CHMP opinion in April 2026. Here is what neurology clinicians should weigh before treating non-relapsing secondary progressive MS.

April 26, 2026 · 4 min read

Why Tolebrutinib Is in the News Right Now

Tolebrutinib’s regulatory path took a sharp turn this month. On April 24, 2026, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued a positive opinion recommending approval of the oral Bruton’s tyrosine kinase (BTK) inhibitor for secondary progressive multiple sclerosis (SPMS) without relapses, branded in Europe as Cenrifki.

That recommendation arrived four months after the US Food and Drug Administration (FDA) issued a complete response letter (CRL) for the same drug on December 23, 2025. The FDA cited a serious risk of severe drug-induced liver injury (DILI), uncertainty about whether benefit extends across the non-relapsing SPMS (nrSPMS) population, and an inability to identify any subpopulation with a favorable benefit-risk profile.

The Background

nrSPMS is the phase of multiple sclerosis in which patients no longer experience clinical relapses but continue to accumulate disability — fatigue, cognitive decline, gait and bladder dysfunction — driven by chronic neuroinflammation rather than acute attacks. There are no FDA-approved disease-modifying therapies (DMTs) specific to this group.

Tolebrutinib is an oral, brain-penetrant BTK inhibitor that targets myeloid cells, including microglia, behind the blood-brain barrier. Sanofi acquired the molecule in 2020 through its $3.7 billion buyout of Principia Biopharma. The FDA granted breakthrough therapy designation in December 2024 and priority review in March 2025.

The Evidence So Far on Tolebrutinib

The case for tolebrutinib rests primarily on the HERCULES trial (NCT04411641), published in NEJM in May 2025. HERCULES randomized 1,131 patients with nrSPMS in a 2:1 ratio: 754 to tolebrutinib 60 mg once daily and 377 to placebo, with median follow-up of 133 weeks.

Tolebrutinib delayed time to 6-month confirmed disability progression by 31% (22.6% vs 30.7%; hazard ratio [HR] 0.69; 95% confidence interval [CI] 0.55–0.88; p=0.003). Confirmed disability improvement, a secondary endpoint, occurred in 10% of tolebrutinib patients versus 5% on placebo (HR 1.88; 95% CI 1.10–3.21).

Safety, however, complicated the picture. Liver enzyme elevations (alanine aminotransferase > 3× upper limit of normal) occurred in 5.6% of the tolebrutinib group, with 0.5% experiencing peak ALT > 20× ULN — all within the first 90 days of treatment. Serious adverse events occurred in 15.0% of tolebrutinib patients versus 10.4% on placebo. One participant in the tolebrutinib arm died from postoperative complications after a liver transplant deemed treatment-related.

Across Sanofi’s broader phase 3 program of roughly 2,700 patients, the FDA later identified six cases meeting Hy’s law criteria — a marker of severe hepatotoxicity risk — and characterized the DILI risk as among the highest in the BTK inhibitor class. The PERSEUS trial of tolebrutinib in primary progressive MS missed its primary endpoint in late 2025, and Sanofi withdrew that application. The GEMINI 1 and 2 trials in relapsing MS also failed to beat teriflunomide on annualized relapse rate.

Where Experts Disagree on Tolebrutinib

The FDA and EMA reached strikingly different conclusions on the same dataset. The FDA’s CRL emphasized that a baseline-MRI subgroup analysis suggested the therapeutic effect was driven mostly by patients with active SPMS — a population already eligible for approved DMTs — leaving benefit in true nrSPMS uncertain.

“A favorable benefit-risk profile could not be established for any patient subpopulation.” — US Food and Drug Administration, Complete Response Letter (December 2025)

The CHMP took a different view, judging the HERCULES results adequate to recommend EU approval paired with strict liver-monitoring requirements. HERCULES investigators have argued tolebrutinib represents a new class of therapy targeting smoldering neuroinflammation, the dominant biology of progressive MS — a domain where existing DMTs have limited effect.

An independent Institute for Clinical and Economic Review (ICER) analysis in May 2025 raised separate concerns: the absence of pre-specified subgroup data on active versus inactive SPMS, and the practical burden of weekly hepatic monitoring on patients with high disability who may struggle to attend frequent lab visits.

The Practical Question for Clinicians

The practical question is what neurology clinicians treating progressive MS should plan now, given that tolebrutinib is unavailable in the US and not yet fully approved in the EU. Three steps are reasonable.

First, document the natural history carefully. Confirm whether a patient meets the strict nrSPMS definition — no clinical relapses for at least 24 months, documented disability progression in the prior 12 months, and an Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5 — using objective MRI data when available. This documentation will matter if a BTK inhibitor becomes available in this indication.

Second, anticipate intensive hepatic monitoring. The amended HERCULES protocol required weekly ALT/AST testing during weeks 2–12, monthly during months 3–12, and quarterly thereafter. Any future label is likely to require comparable surveillance. Practices should plan workflow, lab logistics, and patient counseling accordingly. Patients with baseline liver disease, alcohol use, or hepatotoxic comedications would be reasonable candidates to exclude.

Third, follow the resubmission pipeline. Sanofi maintains an expanded access protocol in the US and is in dialogue with the FDA. Other BTK inhibitors — including fenebrutinib and remibrutinib — have phase 3 readouts expected in MS over the next two years.

What to Watch For

Sanofi’s response to the FDA CRL on tolebrutinib — whether resubmission targets a more selective nrSPMS subgroup paired with a strengthened risk evaluation and mitigation strategy
The European Commission’s final decision on Cenrifki, expected in the coming months
Long-term hepatic safety data from the HERCULES open-label extension and the active US expanded access program
Phase 3 readouts from competing BTK inhibitors in MS (fenebrutinib, remibrutinib) that may reframe the class benefit-risk profile

Sources

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. Fox et al., NEJM 2025 — HERCULES Trial Primary Publication
Sanofi. Sanofi provides update on tolebrutinib regulatory submission in non-relapsing secondary progressive multiple sclerosis. Press release, December 24, 2025. Sanofi FDA Complete Response Letter Announcement (December 24, 2025)
Reuter E. FDA cites severe liver injury risk, unclear benefit behind Sanofi’s MS drug rejection. FierceBiotech, January 6, 2026. FierceBiotech — FDA CRL Details on Tolebrutinib (January 2026)
Sanofi. Sanofi’s Cenrifki (tolebrutinib) recommended for EU approval by the CHMP to treat secondary progressive multiple sclerosis without relapses. Press release, April 24, 2026. Sanofi Cenrifki CHMP Positive Opinion (April 24, 2026)
Institute for Clinical and Economic Review. The Effectiveness and Value of Tolebrutinib for Secondary Progressive Multiple Sclerosis. ICER Evidence Report, May 2025. ICER Evidence Report — Tolebrutinib for SPMS (May 2025)
NeurologyLive. FDA Accepts Regulatory Submission for BTK Inhibitor Tolebrutinib for Non-Relapsing Secondary Progressive MS. March 25, 2025. NeurologyLive — Tolebrutinib FDA Submission Acceptance
Pharmacy Times. Tolebrutinib Receives FDA CRL for Nonrelapsing Secondary Progressive Multiple Sclerosis. April 22, 2026. Pharmacy Times — Tolebrutinib CRL Coverage and Hepatic Monitoring Considerations