BTK Inhibitor Tolebrutinib Slows Disability Progression in Phase 3 HERCULES Study of Non-Relapsing Secondary Progressive MS
Tolebrutinib, a brain-penetrant BTK inhibitor, achieved the primary endpoint in the HERCULES study, significantly reducing disability accumulation in patients with non-relapsing secondary progressive multiple sclerosis.
Houman Ashrafian, MD, PhD
Sanofi has announced topline data from its phase 3 HERCULES study (NCT04411641) of its investigational agent tolebrutinib, with results showing that treatment with the agent met its primary end point of reduction in disability accumulation among patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The company plans to present study results from HERCULES, as well as its phase 3 GEMINI 1 and 2 studies (NCT04410978; NCT04410991) of tolebrutinib in relapsing MS at the upcoming European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting in Copenhagen, Demark, September 20, 2024.1
HERCULES was a randomized, double-blind study that assessed the efficacy and safety of tolebrutinib, a Bruton Tyrosine kinase (BTK) inhibitor in patients with nrSPMS, defined as those with an Expanded Disability Status Scale (EDSS) score between 3.0 and 6.5, no clinical relapses for the previous 24 months, and documented evidence of disability accumulation in the previous 12 months. Overall, the study met its primary end point, which was 6-month confirmed disability progression (CDP) defined as an increase of more than 1 point from baseline on EDSS when the baseline score is less than 5, or the increase or at least 0.5 point when the baseline EDSS score was greater than 5.0.
nrSPMS refers to patients with MS who have stopped experiencing confirmed relapses but continue to experience accumulation of disability, which may comprise fatigue, cognitive impairment, balance and gait issues, loss of bowel and/or bladder function, sexual dysfunction, and other problems. Tolebrutinib, an oral, brain-penetrant BTK inhibitor, is designed to achieve cerebrospinal fluid concentrations predicted to modulate B lymphocytes and disease-associated microglia. To date, there are no approved BTK inhibitors for relapsing and non-relapsing forms of MS.
"Tolebrutinib represents an unprecedented breakthrough as a potential first-in-disease treatment option with clinically meaningful benefit in disability accumulation," Houman Ashrafian, MD, PhD, head of Research & Development at Sanofi, said in a statement.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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Sanofi also announced that tolebrutinib did not meet its primary end point in the phase 3 GEMINI studies; however, it did demonstrate effects on the secondary end point of 6-month CDW. The GEMINI trials randomly assigned patients with relapsing forms of MS to either tolebrutinib and placebo daily or 14 mg teriflunomide (Aubagio; Sanofi) and placebo. Teriflunomide, one of the more relatively newly approved disease-modifying therapies, has been on the market since 2012.
In the GEMINI trials, the primary end point was comparing annualized relapse rate, defined as the number of confirmed adjudicated protocol defined relapses, over a 36-month period between the 2 study groups. Tolebrutinib is also being studied in a phase 3 trial of primary progressive MS, dubbed PERSEUS (NCT04458051), that is currently ongoing with study results anticipated in 2025. PERSEUS, a large-scale study of patients aged 18-55 years, primarily assesses the treatment’s effect on time to onset of CDP.
In a previously completed phase 2b trial (NCT03889639) of patients with relapsing-remitting MS or SPMS, tolebrutinib-treated patients demonstrated a dose-dependent reduction in the number of new gadolinium-enhancing (GdE) lesions. In the 16-week, double-blind, placebo-controlled, crossover study, the 60-mg dose of tolebrutinib was the most efficacious, with an observed mean number of lesions of 0.13 (SD, 0.43) compared to 1.03 (SD, 2.50) for placebo. Furthermore, 28 of the 31 participants (90%) who received the 60-mg dose had no new GdE lesions after 12 weeks of treatment, compared with 44 of 59 participants (75%) in cohort 2 placebo period observed at week 4.2
In June 2022, the FDA placed a partial hold on the phase 3 development of tolebrutinib because of drug-induced liver injuries in patients who received the drug in ongoing trials, which included the GEMINI studies, PERSEUS, HERCULES, and URSA, a study in generalized myasthenia gravis.3 A month before the announced hold, Sanofi revised global study protocols to both update safety monitoring and enrollment criteria to exclude those with preexisting factors related to hepatic dysfunction. As a result of the hold, new enrollment of the studies was paused, and dosing for any patient who had been in a study for less than 60 days was suspended.
