Tolebrutinib Hits Primary Goal in HERCULES Phase 3 Study, Showing Disability Reduction in Non-Relapsing SPMS

Positive results from Sanofi's HERCULES phase 3 study have demonstrated that tolebrutinib, an oral brain-penetrant BTK inhibitor, effectively delays the onset of confirmed disability progression (CDP) in individuals with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The study defined nrSPMS as having an SPMS diagnosis with an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, no relapses in the past 24 months, and documented disability accumulation over the past year. Preliminary liver safety results aligned with previous tolebrutinib studies.

Conversely, the GEMINI 1 and 2 phase 3 studies did not achieve the primary goal of reducing the annualized relapse rate (ARR) compared to teriflunomide in patients with relapsing forms of MS. However, secondary analysis showed a significant delay in the onset of disability, supporting the CDP findings in the HERCULES study. 

Dr. Houman Ashrafian, Sanofi's Head of Research & Development, hailed tolebrutinib as a groundbreaking potential treatment for addressing disability accumulation in nrSPMS, which is driven by chronic neuroinflammation and remains a critical unmet medical need.

The ongoing PERSEUS phase 3 study is currently evaluating the time to onset of CDP in primary progressive MS, with results expected in 2025. Findings from the HERCULES and GEMINI studies will be presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Copenhagen, Denmark, on September 20, 2024. Tolebrutinib is still under clinical investigation and has not been evaluated for safety and efficacy by any regulatory authority.

Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disease that gradually leads to irreversible disabilities, affecting physical and cognitive functions. This deterioration adversely impacts patients' health, quality of life, and life expectancy. Addressing disability accumulation in MS is crucial, as current therapies primarily target peripheral B and T cells, neglecting innate immunity, which is believed to be a major factor in disability accumulation. Most approved or experimental MS treatments focus on the adaptive immune system and do not directly act within the central nervous system (CNS) to offer clinical benefits.

Relapsing forms of MS (RMS) are characterized by episodes of new or worsening symptoms, known as relapses, followed by periods of partial or complete recovery. Non-relapsing secondary progressive MS (nrSPMS) involves the continued accumulation of disability without confirmed relapses, manifesting as symptoms like fatigue, cognitive impairment, balance and gait issues, loss of bowel and/or bladder function, and sexual dysfunction.

Tolebrutinib works by modulating B lymphocytes and activated microglia in the CNS, addressing the underlying mechanisms of disability accumulation linked to chronic neuroinflammation in the brain and spinal cord.

The GEMINI 1 and 2 studies (NCT04410978 and NCT04410991) were randomized, double-blind phase 3 clinical trials evaluating tolebrutinib against teriflunomide in patients with relapsing MS. Participants were randomized to receive either tolebrutinib and placebo or 14mg teriflunomide and placebo daily. The primary endpoint was the annualized relapse rate over approximately 36 months. Secondary endpoints included time to onset of confirmed disability worsening (CDW), total number of new or enlarging T2 hyperintense lesions, total number of Gd-enhancing T1 hyperintense lesions as detected by MRI, and the safety and tolerability of tolebrutinib.

The HERCULES study (NCT04411641) was a randomized, double-blind phase 3 clinical trial assessing tolebrutinib's efficacy and safety in nrSPMS patients compared to placebo. Participants had an SPMS diagnosis with an EDSS score between 3.0 and 6.5, no relapses in the last 24 months, and documented disability accumulation in the past 12 months. They were randomized to receive either tolebrutinib or placebo daily for up to 48 months. The primary endpoint was the 6-month CDP, with secondary endpoints including changes in cognitive function and the safety and tolerability of tolebrutinib.

Tolebrutinib is an investigational oral BTK inhibitor that penetrates the brain and modulates B lymphocytes and disease-associated microglia. It is being evaluated in phase 3 clinical studies for various forms of MS, and its safety and efficacy have not been reviewed by any regulatory authority.

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