The Promising Results of Tolebrutinib for Secondary Progressive Multiple Sclerosis Treatment: Robert J. Fox, MD

WATCH TIME: 2 minutes

"We have finally identified a therapy that slows the insidious progression of secondary progressive [multiple sclerosis], giving hope to slow this form of the disease."

Tolebrutinib (Sanofi), a Bruton’s tyrosine kinase (BTK) inhibitor that targets B cells and microglia, has the potential to modulate both peripheral and central pathologic processes in multiple sclerosis (MS) that lead to disability accumulation. Currently, the BTK inhibitor is being assessed in the phase 3 HERCULES trial (NCT04411641) for non-relapsing secondary progressive MS (nrSPMS). At the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, September 18-20, in Copenhagen, Denmark, new results from the trial presented provided a comprehensive assessment of the treatment’s efficacy and safety in patients with nrSPMS.^1,2

HERCULES comprised of 1131 patients aged between 18 to 60 years with nrSPMS (mean age was, 48.9 years; women, 62%) and Expanded Disability Status Scale (EDSS) score of 3.0–6.5. Eligible participants also had inclusive, documented proof of disability progression in the prior 12 months and no clinical relapses in the prior 24 months before screening. In the study, investigators randomized participants 2:1 to receive 60-mg once daily oral tolebrutinib or matching placebo. The primary end point of the trial was time to onset of 6-month confirmed disability progression, as measured by EDSS, and secondary end points included other measures of disability, MRI outcomes and safety.

Presented by lead author Robert J. Fox, MD, and colleagues, the mean time since relapsing-remitting MS symptom onset reported was 17.3 years, and the mean time since the most recent relapse observed was 7.5 years. A majority of the patients included in the study had previously received at least 1 disease-modifying therapy (77%) and the mean EDSS score was 5.53 at baseline (median 6.0; interquartile range 5.0–6.3).

At baseline, 12.8% of patients in HERCULES had gadolinium-enhancing T1 lesions and the cohort had a mean T2 lesion volume of 18.9 cm3 (SD, 14.6). During ECTRIMS, Fox, a staff neurologist at the Mellen Center for Multiple Sclerosis at Cleveland Clinic, sat down with NeurologyLive^® to discuss how the previously reported findings of HERCULES could potentially impact current treatment options for SPMS. He also talked about what makes this new therapy different from existing treatments for MS. Moreover, Fox spoke about how the results from the phase 3 GEMINI 1 and 2 studies (NCT04410978; NCT04410991) of tolebrutinib in relapsing MS confirm the outcomes observed in the HERCULES trial.

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REFERENCES
1. 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.
2. Press Release: Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis. News release. Sanofi. September 2, 2024. Accessed September 19, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875