FDA Accepts Regulatory Submission for BTK Inhibitor Tolebrutinib for Non-Relapsing Secondary Progressive MS

The FDA has accepted Sanofi’s regulatory submission for tolebrutinib as a potential treatment for patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS) and to slow disability accumulation independent of relapse activity in adults, assigning the agent a PDUFA target date of September 28, 2025. If approved, tolebrutinib would become the first and only brain-penetrant Bruton tyrosine kinase (BTK) inhibitor marketed for the treatment of MS, and the first specific for nrSPMS.¹

Tolebrutinib, an oral, brain-penetrant therapy designed to target smoldering neuroinflammation, remains under review in the European Union as well. The regulatory submissions for the agent were based on findings from the phase 3 HERCULES study (NCT04411641) in nrSPMS and 2 phase 3 studies (GEMINI 1 [NCT04410978] and GEMINI 2 [NCT04410991]) in relapsing MS. In addition, it remains in development for patients with primary progressive MS, with ongoing study results from the phase 3 PERSEUS trial (NCT04458051) anticipated later this year.

"The totality of data across our clinical program validates our scientific understanding of smoldering neuroinflammation as a distinct inflammatory process in MS," Erik Wallström, MD, PhD, global head of neurology department at Sanofi, said in a statement.¹ "People living with non-relapsing secondary progressive multiple sclerosis or who experience disability independent of relapse activity suffer from disability that worsens over time due to persistent inflammation in the brain, known as smoldering neuroinflammation, which is the primary driver of disability. The demonstrated ability of tolebrutinib to delay disability by targeting underlying drivers of the disease represents a potential paradigm shift in treating these patients."

HERCULES, a double-blind, randomized study, comprised 1131 patients with nrSPMS who were randomly assigned 2:1 to either daily tolebrutinib or matching placebo for up to 48 months. In the study, treatment with tolebrutinib resulted in delayed time to onset of 6-month confirmed disability progression (CDP), the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55-0.88; P = .0026). On secondary end point, the number of patients who experienced confirmed disability improvement increased by nearly 2-fold, 10%, for those treated with tolebrutinib compared with 5% of those in the placebo group (HR, 1.88; 95% CI, 1.10-3.21; P = .021).²

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Data from HERCULES is what led to the FDA’s decision to grant breakthrough therapy designation to tolebrutinib in December 2024.³ Months later, a post-hoc analysis of the trial showed that the therapy has greater efficacy in patients with MS who have a higher number of paramagnetic rim lesions (PRLs). In HERCULES, treatment with the therapy led to a 54% reduced risk in 6-month CDW among patients with at least 4 baseline PRLs, the highest quartile group observed. In GEMINI, a similar risk mitigation was observed, with a 46% and 49% risk reduction in participants with 1-3 and at least 4 PRLs, respectively.⁴ Of note, this data is not connected to this FDA filing submission/acceptance for tolebrutinib.

Regarding these data, lead author Jiwoh Oh, MD, PhD, staff neurologist and medical director of the Barlo MS Program, St. Michaels Hospital, University of Toronto, told NeurologyLive that, "This finding has several clinical and clinical trial implications, particularly for trial design in the future. If we want to enrich clinical trial populations for people more likely to accumulate disability, PRLs could be considered as a measure to help with this—though, of course, these findings need to be validated."

The HERCULES and GEMINI trials had notable differences. HERCULES focused on patients with nrSPMS, while GEMINI included those with relapsing MS. In HERCULES, participants were randomly assigned to receive either tolebrutinib or placebo. Meanwhile, in the GEMINI trials, participants were randomized in a 1:1 ratio to receive either daily tolebrutinib and placebo or 14 mg of teriflunomide (Aubagio; Sanofi) and placebo. Although tolebrutinib in GEMINI did not meet its primary end point of reducing annualized relapse rate (ARR) compared with teriflunomide, it demonstrated promising results on a key secondary end point by significantly delaying the time to onset of 6-month CDW.⁵

REFERENCES
1. Press Release: Tolebrutinib regulatory submission accepted for priority review in the US for patients with multiple sclerosis. News release. Sanofi. March 25, 2025. Accessed March 25, 2025. https://www.globenewswire.com/news-release/2025/03/25/3048411/0/en/Press-Release-Tolebrutinib-regulatory-submission-accepted-for-priority-review-in-the-US-for-patients-with-multiple-sclerosis.html
2. Fox RJ, Bar-Or A, Traboulsee A, et al. Efficacy and Safety of Tolebrutinib Versus Placebo in Non-Relapsing Secondary Progressive Multiple Sclerosis: Results from the Phase 3 HERCULES Trial. Presented at: 2024 ECTRIMS; September 18-20; Copenhagen, Denmark. Abstract 4027.
3. Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis. News Release. Sanofi. Published December 13, 2024. Accessed March 25, 2025. https://www.sanofi.com/assets/dotcom/pressreleases/2024/2024-12-13-06-00-00-2996609-en.pdf
4. Oh J, Fox RJ, Arnold DL, et al. LB1.1. 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; West Palm Beach, FL. ABSTRACT LB1.1
5. GEMINI 1 and 2 Trials. Presented at: ECTRIMS Congress; September 18-20, 2024; Copenhagen, Denmark. Abstract 4026/O135