Results of Phase III HERCULES, GEMINI 1 and 2 Trials Lead to FDA Priority Review for Tolebrutinib for Non-Relapsing Secondary Progressive MS

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Results from the Phase III HERCULES (NCT04411641) trial and Phase III GEMINI 1 (NCT04410978) and GEMINI 2 trials (NCT04410991) have led to the FDA granting Priority Review status to a regulatory submission for tolebrutinib (Sanofi) in the treatment of non-relapsing secondary progressive multiple sclerosis (nrSPMS) and to limit disability accumulation independent of relapse activity in adult patients.^1-4

The investigational, orally administered Bruton’s tyrosine kinase inhibitor was developed to target smoldering neuroinflammation, which is among the primary drivers of disability progression in patients with multiple sclerosis (MS), according to Sanofi.

“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 Development, Sanofi, said in a press release. “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.”¹

In December 2024, the FDA granted Breakthrough Therapy Designation to tolebrutinib for nrSPMS based on positive findings from the HERCULES trial.⁵

Trial Design

HERCULES

The double-blind, randomized, HERCULES trial compared tolebrutinib’s efficacy and safety in patients with nrSPMS versus placebo. Enrollment criteria included an SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5, no clinical relapses across the prior 24-month period, and documented evidence of disability progression over the preceding 12 months. Participants were randomly assigned in a 2:1 ratio to receive a daily dose of oral tolebrutinib or matching placebo for about 48 months.

The trial’s primary endpoint was six-month confirmed disability progression (CDP), which was defined as increase of ≥1.0 point from baseline EDSS score if score is ≤5.0, or increase of ≥0.5 point if baseline EDSS score was >5.0. The trial’s secondary endpoints included safety and tolerability; time to onset of three-month CDP as per EDSS score; amount of new or enlarging T2 hyperintense lesions detected by MRI; time to onset of confirmed disability improvement; and three-month change in 9-hole peg test and T25-FW test.

GEMINI 1 and GEMINI 2

Both GEMINI 1 and 2 were double-blind, randomized trials that compared the efficacy and safety of tolebrutinib versus Aubagio (teriflunomide) in patients with relapsing MS. For both GEMINI 1 and 2, patients were randomly assigned in a 1:1 ratio to receive daily tolebrutinib and placebo or teriflunomide at a dose of 14 mg and placebo daily.

Both trials had a primary endpoint of annualized relapse rate for up to about 36 months, which was defined as amount of confirmed adjudicated protocol defined relapses. The trial’s secondary endpoints included time to onset of confirmed disability worsening (CDW) across at least six months and defined as an increase of ≥1.5 points from baseline EDSS score if the score is 0; increase of ≥1.0 point from baseline EDSS score when score is 0.5 to ≤5.5; or increase of ≥0.5 point from baseline EDSS score when baseline score was >5.5. Secondary endpoints also included increase of total number of new and/or enlarging T2 hyperintense lesions detected by MRI from baseline through trial end date, amount of Gd-enhancing T1 hyperintense lesions detected by MRI from baseline through trial end date, and safety and tolerability.

“The findings from these studies, as well as additional clinical and preclinical studies, support the differentiated mechanism of tolebrutinib to target disability progression independent of relapse activity, and the scientific hypothesis that smoldering neuroinflammation represents a key inflammatory process in MS and is a critical driver of disability accumulation,” Sanofi stated in a press release.¹

The FDA has assigned the application for tolebrutinib with Prescription Drug User Fee Act target action date of September 28, 2025.

References

1. 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.sanofi.com/en/media-room/press-releases/2025/2025-03-25-06-00-00-3048411

2. Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES) (HERCULES). ClinicalTrials.gov. Updated February 3, 2025. Accessed March 25, 2025. https://clinicaltrials.gov/study/NCT04411641

3. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 1) (GEMINI 1). ClinicalTrials.gov. Updated September 19, 2024. Accessed March 25, 2025. https://clinicaltrials.gov/study/NCT04410978

4. Relapsing Forms of Multiple Sclerosis (RMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (GEMINI 2) (GEMINI 2). ClinicalTrials.gov. Updated September 9, 2024. Accessed March 25, 2025. https://clinicaltrials.gov/study/NCT04410991

5. Tolebrutinib designated Breakthrough Therapy by the FDA for non-relapsing secondary progressive multiple sclerosis. Sanofi. December 13, 2024. Accessed March 25, 2025. https://www.sanofi.com/en/media-room/press-releases/2024/2024-12-13-06-00-00-2996609