FDA Grants Tolebrutinib Breakthrough Therapy for Nonrelapsing Secondary Progressive Multiple Sclerosis

Author(s):

Isabella Ciccone, MPH

Fact checked by:

Marco Meglio

Key Takeaways

Tolebrutinib received FDA breakthrough therapy designation for nrSPMS, showing significant efficacy in delaying disability progression.
The HERCULES phase 3 study reported a 31% delay in 6-month confirmed disability progression with tolebrutinib versus placebo.
Tolebrutinib treatment resulted in nearly double the rate of confirmed disability improvement compared to placebo.
Liver enzyme elevations were observed, requiring monitoring, especially in the early treatment phase.
Findings from HERCULES may impact SPMS treatment and align with GEMINI studies in relapsing MS.

Findings from the ongoing PERSEUS phase 3 study of tolebrutinib in primary progressive multiple sclerosis are anticipated to be reported in the second half of 2025.

Erik Wallström, MD, PhD

(Credit: Sanofi)

According to a new announcement, the FDA has granted breakthrough therapy designation to Sanofi’s tolebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, for patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The company noted that regulatory submissions for tolebrutinib are being finalized for the United States and prepared for Europe, with confirmation to follow once a submission has been accepted.¹

This is designation was based on findings from the HERCULES phase 3 study (NCT04411641), which showed that treatment with tolebrutinib delayed the 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) in patients with nrSPMS.^2,3Additional results of the secondary end points revealed that the number of patients who experienced confirmed disability improvement increased by nearly 2-fold, 10%, for those treated with tolebrutinib compared with 5% those in the placebo group (HR, 1.88; 95% CI, 1.10-3.21; nominal P = .021).

"We think that tolebrutinib compares favorably in terms of being able to effectively target BTK in the CNS based on the combination of potency and brain penetration," Erik Wallström, MD, PhD, global head of neurology development at Sanofi, told NeurologyLive^® in a recent interview. "Clinicians should be aware that this compound class, including tolebrutinib, has the problem with drug-induced liver injury, particularly during the early months of treatment, requiring intense monitoring."

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 CDP, as measured by EDSS, and secondary end points included other measures of disability, MRI outcomes and safety.

In the preliminary analysis of HERCULES, investigators reported a slight increase of some adverse events among tolebrutinib-treated patients. Researchers noted that liver enzyme elevations (>3xULN) were experienced by 4.1% of patients who received tolebrutinib compared with 1.6% in the placebo group, which is an adverse effect previously reported with other BTK inhibitors in MS. In addition, 0.5% of patients in the tolebrutinib group had peak ALT increases of >20xULN, all which occurred in the first 90 days of treatment. All of the cases of liver enzyme elevations, with the exception of one, resolved without any further medical intervention needed.

At the 2024 European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress, held September 18-20, in Copenhagen, Denmark,Robert J. Fox, MD, 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.

REFERENCES
1. Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis. News Release. Sanofi. Published December 13, 2024. Accessed December 13, 2024. https://www.sanofi.com/assets/dotcom/pressreleases/2024/2024-12-13-06-00-00-2996609-en.pdf
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. 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 December 13, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875