Results from HERCULES will form the basis for future discussions with global regulatory authorities, according to Sanofi.
Tolebrutinib has successfully met its primary endpoint of improvement over placebo in delaying time to onset of confirmed disability progression (CDP) in patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS) in the HERCULES phase 3 clinical trial. It has become the first and only study to achieve this clinical effect in the patient population, according to a Sanofi news release.1
Sanofi logo on building / Robert - stock.adobe.com
Disability accumulation represents a significant unmet medical need in people with nrSPMS, a population for which there are currently no approved therapies. Whereas existing multiple sclerosis (MS) treatments primarily target peripheral B and T cells, many neglect the central nervous system (CNS) and innate immunity, thought to play a key driver of disability.2
About HERCULES
Trial Name: Nonrelapsing Secondary Progressive Multiple Sclerosis (NRSPMS) Study of Bruton's Tyrosine Kinase (BTK) Inhibitor Tolebrutinib (SAR442168) (HERCULES)
Clinicaltrials.gov Identifier: NCT04411641
Sponsor: Sanofi
Summary: [This is a study] to determine the efficacy of SAR442168 compared to placebo in delaying disability progression in NRSPMS.
Tolebrutinib offers a potential solution. As an investigational, brain-penetrant, Bruton’s tyrosine kinase inhibitor, it modulates both B lymphocytes and activated microglia in the CNS. This dual approach addresses the underlying mechanisms of disability accumulation in MS linked to smoldering neuroinflammation in the brain and spinal cord.
“Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation,” said Houman Ashrafian, MD, PhD, head of research and development at Sanofi, in the release.1 “Addressing disability accumulation, thought to be driven by smoldering neuroinflammation, remains the greatest unmet medical need in people with non-relapsing secondary progressive MS today.”
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HERCULES (NCT04411641) was a randomized, double-blind phase 3 clinical study evaluating the efficacy and safety of tolebrutinib in participants with nrSPMS compared to placebo. nrSPMS was defined as having a SPMS diagnosis with an expanded disability status scale (EDSS) score between 3.0 and 6.5, no clinical relapses in the previous 24 months, and documented evidence of disability accumulation in the previous 12 months.
Participants were randomized (1:1) to receive either an oral daily dose of tolebrutinib or matching placebo for up to approximately 48 months.
The primary endpoint was 6-month CDP defined as the increase of 1.0 or more point from the baseline EDSS score when the baseline score was 5.0 or less, or the increase of 0.5 or more points when the baseline EDSS score was below 5.0.
Secondary endpoints included 3-month change in 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 as detected by MRI, change in cognitive function at the EOS compared to baseline as assessed by the Symbol Digit Modalities Test and by the California Verbal Learning Test as well as the safety and tolerability of tolebrutinib.
Previously, tolebrutinib missed the mark in the randomized, double-blind, phase 3 clinical studies GEMINI 1 (NCT04410978) and GEMINI 2 (NCT0441099). The trials, which evaluated the efficacy and safety of tolebrutinib compared to teriflunomide in patients with relapsing forms of MS (RMS), did not show significance in the primary endpoint of reducing annualized relapse rate over Sanofi’s own teriflunomide (Aubagio). However, secondary analyses of pooled 6-month confirmed disability worsening data demonstrated a considerable delay in time to onset, which overlapped with positive CDP data observed in HERCULES.
According to Sanofi, HERCULES results will form the basis for future discussions with global regulatory authorities. Study results for HERCULES, GEMINI 1, and GEMINI 2 will be presented at the European Committee for Treatment and Research in Multiple Sclerosis medical meeting in Copenhagen, Denmark, on September 20, 2024.
Further, Sanofi’s PERSEUS phase 3 trial investigating time to onset of CDP in primary progressive MS is currently underway. Study results are expected to be available in 2025.
Sanofi's optimism about tolebrutinib has remained steadfast since the company began enrolling patients in clinical trials in 2022, saying in a news release, "Sanofi remains confident in the future of tolebrutinib as a potentially transformative oral treatment option for people living with MS."3
RMS refers to people with MS who have recurring episodes of new or worsening symptoms followed by periods of improvement. nrSPMS refers to individuals with MS who haven’t had confirmed relapses but continue to experience worsening symptoms such as fatigue, cognitive difficulties, balance issues, bladder or bowel problems, sexual dysfunction, and others.1
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