Tolebrutinib Achieves Primary Endpoint in HERCULES Phase 3 Trial, Demonstrating Reduction in Disability for Non-Relapsing Secondary Progressive Multiple Sclerosis
In a significant breakthrough, the HERCULES Phase 3 trial has revealed that tolebrutinib successfully achieved its primary endpoint by delaying the onset of confirmed disability progression (CDP) in individuals with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This is especially notable for a population that currently lacks approved treatment options and has considerable unmet medical needs.
HERCULES Study Success
The HERCULES trial results demonstrated that tolebrutinib, an oral brain-penetrant BTK inhibitor developed by Sanofi, effectively delayed the time to onset of confirmed disability progression compared to a placebo in patients with nrSPMS. The study defined nrSPMS at baseline as a diagnosis of SPMS with an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, no clinical relapses in the prior 24 months, and documented evidence of disability progression within the past year. Initial safety data related to liver function from the study were consistent with previous tolebrutinib trials.
Mixed Results in GEMINI 1 and 2 Trials
However, in the GEMINI 1 and 2 Phase 3 studies, tolebrutinib did not meet the primary endpoint of reducing the annualized relapse rate (ARR) when compared to teriflunomide in patients with relapsing forms of multiple sclerosis. Despite this, the key secondary endpoint analysis revealed that pooled data showed a significant delay in the onset of confirmed disability worsening (CDW) over six months, which aligns with the positive findings from the HERCULES trial.
Future Outlook
The findings from these Phase 3 studies will be pivotal in future discussions with global regulatory bodies. Additionally, results from the ongoing PERSEUS Phase 3 study, which is assessing time to onset of CDP in primary progressive MS, are expected by 2025.
The results of the HERCULES and GEMINI 1 and 2 studies will be presented at the upcoming European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) conference in Copenhagen, Denmark, scheduled for September 20, 2024. It is important to note that tolebrutinib is still under clinical investigation, and its safety and efficacy have not yet been confirmed by regulatory authorities.
Understanding Multiple Sclerosis and the Unmet Needs
Multiple sclerosis (MS) is a chronic, immune-mediated, neurodegenerative disorder that leads to the gradual accumulation of irreversible disabilities. This progressive impairment affects both physical and cognitive functions, resulting in a declining quality of life and reduced life expectancy for those affected.
A significant unmet need in MS treatment is the management of disability accumulation. Current therapies primarily target peripheral B and T cells, with less focus on innate immunity, which is believed to play a crucial role in disability progression. Existing treatments for MS mainly focus on the adaptive immune system and often do not directly target the central nervous system (CNS) to provide clinical benefits.
MS Subtypes and Tolebrutinib's Mechanism of Action
Relapsing MS (RMS) refers to individuals who experience episodes of new or worsening symptoms, known as relapses, followed by periods of partial or complete recovery. In contrast, non-relapsing secondary progressive MS (nrSPMS) refers to those who no longer experience relapses but continue to accumulate disability, with symptoms such as fatigue, cognitive decline, balance and gait issues, and other functional impairments.
Tolebrutinib operates by modulating both B lymphocytes and activated microglia within the CNS, addressing the underlying mechanisms of disability accumulation related to ongoing neuroinflammation in the brain and spinal cord.
About the GEMINI 1 & 2 Trials
GEMINI 1 (NCT04410978) and GEMINI 2 (NCT04410991) were randomized, double-blind Phase 3 clinical trials designed to evaluate the efficacy and safety of tolebrutinib compared to teriflunomide in patients with relapsing forms of MS. Participants were randomly assigned (1:1) to receive either tolebrutinib with a placebo or 14 mg of teriflunomide with a placebo daily.
The primary endpoint for both trials was the annualized relapse rate (ARR) over approximately 36 months, defined as the number of confirmed, adjudicated, protocol-defined relapses. Secondary endpoints included time to onset of 6-month confirmed disability worsening (CDW), total number of new or enlarging T2 hyperintense lesions detected by MRI, total number of Gd-enhancing T1 hyperintense lesions detected by MRI, and the safety and tolerability of tolebrutinib.
About the HERCULES Trial
HERCULES (NCT04411641) was a randomized, double-blind Phase 3 clinical trial focused on assessing the efficacy and safety of tolebrutinib in participants with nrSPMS compared to a placebo. At baseline, nrSPMS was defined by an SPMS diagnosis with an EDSS score between 3.0 and 6.5, no clinical relapses in the past 24 months, and documented evidence of disability accumulation within the prior 12 months. Participants were randomly assigned (1:1) to receive either a daily oral dose of tolebrutinib or a matching placebo for up to 48 months.
The primary endpoint was the 6-month confirmed disability progression (CDP), defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score was ≤5.0, or an increase of ≥0.5 point when the baseline EDSS score was >5.0. Secondary endpoints included changes in the 9-hole peg test and T25-FW test, time to onset of 3-month CDP as assessed by EDSS score, total number of new or enlarging T2 hyperintense lesions detected by MRI, changes in cognitive function from baseline as assessed by the Symbol Digit Modalities Test and the California Verbal Learning Test, as well as the safety and tolerability of tolebrutinib.
About Tolebrutinib
Tolebrutinib is an investigational, orally administered, brain-penetrant, and bioactive Bruton’s tyrosine kinase (BTK) inhibitor that achieves cerebrospinal fluid (CSF) concentrations believed to modulate B lymphocytes and disease-associated microglia.
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