Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)

Summary

Primary Objective: To determine the efficacy of SAR442168 compared to placebo in delaying disability progression in NRSPMS Secondary Objective: To evaluate efficacy of SAR442168 compared to placebo on clinical endpoints, magnetic resonance imaging (MRI) lesions, cognitive performance, physical function, and quality of life To evaluate safety and tolerability of SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites in NRSPMS and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168

Timeline

Start

2020-09-24

Primary completion

2024-08-29

Completion

2024-08-29

Outcome

Met primary endpoint

paper A smaller percentage of participants in the tolebrutinib group than in the placebo group had confirmed disability progression sustained for at least 6 months (22.6% vs. 30.7%; PMID 40202696 ↗

registry analysis (superiority test); DB: Placebo vs DB: Tolebrutinib 60 mg; p = 0.0026; Hazard Ratio (HR) 0.693 (95% CI 0.546 to 0.880); NCT04411641 ↗

release “Positive results from the HERCULES phase 3 study showed that tolebrutinib, Sanofi’s oral brain-penetrant BTK inhibitor, met the primary endpoint of improvement over placebo” sanofi.com ↗

release “Recommendation based on the HERCULES phase 3 study which demonstrated that brain-penetrant Cenrifki (tolebrutinib) significantly delayed the onset of disability progression in non-relapsing SPMS” sanofi.com ↗

Publications

• Fox RJ, Bar-Or A, Traboulsee A, Oreja-Guevara C, Giovannoni G, Vermersch P, Syed S, Li Y, Vargas WS, Turner TJ, Wallstroem E, Reich DS; HERCULES Trial Group. Tolebrutinib in Nonrelapsing Secondary Progressive Multiple Sclerosis. N Engl J Med. 2025 May 15;392(19):1883-1892. doi: 10.1056/NEJMoa2415988. Epub 2025 Apr 8.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Tolebrutinib	Small molecule	60 mg	Oral

Indications