Tolebrutinib Achieves Primary Endpoint in Phase 3 HERCULES Study for Non-Relapsing Secondary Progressive Multiple Sclerosis

Sanofi has announced promising results from the HERCULES phase 3 clinical trial, indicating that tolebrutinib, an oral BTK inhibitor, successfully met its primary endpoint. This endpoint focused on delaying the onset of confirmed disability progression (CDP) in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This condition is characterized by a progressive accumulation of disability without clinical relapses for at least 24 months, alongside documented evidence of disability worsening over the past 12 months.

The HERCULES study defined nrSPMS patients as having an expanded disability status scale (EDSS) score ranging from 3.0 to 6.5 at baseline. The study's positive outcome marks a significant advancement for individuals with nrSPMS, a group for whom no approved therapies currently exist. These findings demonstrate that tolebrutinib can effectively delay disability progression in this patient population, addressing a critical unmet medical need.

Parallel to the HERCULES study, results from the GEMINI 1 and 2 phase 3 trials were less conclusive regarding the primary endpoint of reducing the annualized relapse rate (ARR) in patients with relapsing multiple sclerosis (RMS) when compared to teriflunomide. However, GEMINI trials did reveal that tolebrutinib showed a significant delay in the time to onset of confirmed disability worsening (CDW) over six months. This secondary endpoint aligns with the findings from HERCULES, reinforcing the potential of tolebrutinib in mitigating disability progression.

Houman Ashrafian, MD, PhD, the Head of Research & Development at Sanofi, lauded tolebrutinib as a ground-breaking potential treatment for disability accumulation in MS. He emphasized that addressing this aspect of the disease, driven by persistent neuroinflammation, represents a substantial unmet medical need for individuals with nrSPMS.

Further research is ongoing, with the PERSEUS phase 3 study currently evaluating tolebrutinib's efficacy in primary progressive MS, another form of the disease. Results from this study are expected in 2025.

Both the HERCULES and GEMINI studies are set to be presented at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Copenhagen on September 20, 2024. It is important to note that tolebrutinib is still under investigation, and its safety and efficacy have not yet been confirmed by any regulatory authority.

Multiple sclerosis (MS) is a chronic, immune-mediated disease that results in progressive neurodegeneration and irreversible disability over time. This condition significantly impairs physical and cognitive functions, leading to a gradual decline in health and quality of life. Current treatments primarily target the adaptive immune system, focusing on peripheral B and T cells, but often do not address mechanisms of disability accumulation within the central nervous system (CNS).

Relapsing MS (RMS) involves episodes of new or worsening symptoms followed by periods of partial or complete recovery. In contrast, non-relapsing secondary progressive MS (nrSPMS) is characterized by continuous disability accumulation without clinical relapses. Patients with nrSPMS experience various symptoms including cognitive impairment, balance issues, and loss of bodily functions.

Tolebrutinib's mechanism of action involves modulating B lymphocytes and activated microglia within the CNS, addressing the underlying neuroinflammatory processes linked to disability accumulation in MS. The HERCULES trial (NCT04411641) and GEMINI trials (NCT04410978 and NCT04410991) were double-blind, randomized studies aimed at evaluating the efficacy and safety of tolebrutinib in patients with different forms of MS.

Participants in these trials were randomized to receive either tolebrutinib or placebo, with primary and secondary endpoints measuring various aspects of disability progression and relapse rates. The HERCULES study focused on nrSPMS, with participants receiving tolebrutinib or placebo for up to 48 months, while GEMINI studies compared tolebrutinib with teriflunomide in RMS over a similar period.

In conclusion, tolebrutinib has shown significant promise as a treatment for delaying disability progression in non-relapsing secondary progressive MS. While results from trials in relapsing MS were less definitive regarding relapse rates, the consistent delay in disability worsening underscores the potential of this investigational drug. Further research and regulatory review will determine its future role in treating multiple sclerosis.