Tolebrutinib Falls Short in Phase 3 PERSEUS Study, Forcing Decision to Redact Regulatory Submission

According to a company update, Sanofi’s tolebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, did not meet its end points in the phase 3 PERSEUS study (NCT04458051) of patients with primary progressive multiple sclerosis (PPMS), and a regulatory submission is therefore not expected. In addition, it’s been reported that the FDA has pushed back its review of the agent as a treatment for non-relapsing secondary progressive MS (nrSPMS).^1,2

More detailed results from the global, double-blind, randomized trial are expected to be presented at an upcoming meeting. In the release, it was noted that tolebrutinib did not meet its primary end point of delaying time of onset of 6-month composite confirmed disability progression (CDP) compared with placebo in the study cohort, which included those aged 18-55 with an Expanded Disability Status Scale (EDSS) of between 2.0 and 6.5.

"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," Houman Ashrafian, executive vice president and head of Research & Development at Sanofi, said in a statement.¹

PERSEUS was a parallel-group, multicenter, event-driven trial that featured 767 patients with PPMS, a mean EDSS score of 4.9 (median, 5.0; n = 766), and a mean time of 4.2 years since PPMS diagnosis.³ While tolebrutinib failed to demonstrate efficacy on the primary outcome of 6-month composite CDW, the drug did show a consistent safety profile, an encouraging finding. With that said, this includes drug-induced liver injury, an identified risk of tolebrutinib, which is handled with strict monitoring and prompt management.¹

In the trial, patients were randomized 2:1 to either tolebrutinib at 60 mg doses of placebo, with more patients treatment-naïve than not (59%). Coming into the study, most patients (89%) had no gadolinium-enhancing lesions, and the cohort’s median T2 lesion volume was 10.8 cm³.³

On the same day as the negative results, reports came out that Sanofi will await a decision on tolebrutinib as a treatment for nrSPMS toward the end of Q1 2026.² The drug manufacturer was originally targeting a decision in September of this year, but the FDA pushed back its review period after additional information constituted a major amendment to the new drug application (NDA).⁴ The application is supported by data from the phase 3 HERCULES study (NCT04411641) in nrSPMS, as well as the phase 3 GEMINI 1 and 2 trials (NCT04410978; NCT04410991) of patients with relapsing MS.

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HERCULES, the primary supportive study for tolebrutinib in nrSPMS, was a double-blind, randomized trial that enrolled 1,131 patients with Expanded Disability Status Scale scores ranging from 3.0 to 6.5, no clinical relapses in the preceding 24 months, and documented disability progression during that period. Participants were randomized 2:1 to receive daily tolebrutinib or matching placebo for up to 48 months.

Results from HERCULES showed that treatment with tolebrutinib significantly delayed the time to 6-month confirmed disability progression, the primary end point, by 31% compared with placebo (HR, 0.69; 95% CI, 0.55–0.88; P = .0026). The investigational BTK inhibitor also nearly doubled the likelihood of confirmed disability improvement, a key secondary outcome (HR, 1.88; 95% CI, 1.10–3.21; P = .021). In a post hoc analysis, greater treatment effects were observed in patients with higher baseline paramagnetic rim lesion counts, with a 54% reduction in the risk of 6-month confirmed disability worsening among those with at least 4 lesions, the highest quartile. Consistent findings were seen in the GEMINI study, where risk reductions of 46% and 49% were reported in patients with 1–3 lesions and at least 4 lesions, respectively.^5,6

Ashrafian added, "We extend our deepest appreciation to the study participants, their families, and healthcare professionals who support our scientific and innovative vision. Our commitment to the multiple sclerosis community remains unchanged, as do our efforts to pursue novel advancements that address existing unmet needs and we remain confident in the value tolebrutinib can bring to those living with non-relapsing secondary progressive multiple sclerosis."¹

REFERENCES
1. Sanofi provides update on tolebrutinib in primary progressive multiple sclerosis. Sanofi. News release. December 15, 2025. Accessed December 15, 2025. https://www.sanofi.com/assets/dotcom/pressreleases/2025/2025-12-15-06-05-00-3205094-en.pdf
2. Sanofi shares fall 6% after double setback for MS drug tolebrutinib. GlobalData Yahoo!Finance. December 15, 2025. Accessed December 15, 2025. https://finance.yahoo.com/news/sanofi-shares-fall-6-double-124715173.html
3. Fox RJ, Reich DS, Traboulsee A, et al. (DMT37) Baseline Characteristics in the Tolebrutinib Phase 3 Primary Progressive Multiple Sclerosis PERSEUS Clinical Trial. Presented at: 2025 CMSC Annual Meeting; May 28-31. Phoenix, AZ. Abstract DMT37
4. Press release: update on the US regulatory review of tolebrutinib in non-relapsing, secondary progressive multiple sclerosis. News release. Sanofi. September 22, 2025. Accessed December 15, 2025. 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. 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, 2024; Copenhagen, Denmark. Abstract 4027.
6. 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, 2025; West Palm Beach, FL. Abstract LB1.1