Tolebrutinib Receives FDA Breakthrough Therapy Designation for Progressive Multiple Sclerosis

Tolebrutinib Receives FDA Breakthrough Therapy Designation for Progressive Multiple Sclerosis

(IN BRIEF) The FDA has granted Breakthrough Therapy designation to tolebrutinib for treating adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS), following positive results from the HERCULES phase 3 study. The study showed tolebrutinib delayed disability progression by 31% and nearly doubled disability improvement rates compared to placebo. As the first brain-penetrant BTK inhibitor for MS to receive this designation, tolebrutinib represents a promising treatment for a condition with no approved therapies. Regulatory submissions are underway, with further clinical studies ongoing.

(PRESS RELEASE) PARIS, 13-Dec-2024 — /EuropaWire/ — The US Food and Drug Administration (FDA) has granted Breakthrough Therapy designation to tolebrutinib for the treatment of adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This milestone comes following promising results from the HERCULES phase 3 study, which demonstrated significant benefits for patients using tolebrutinib. Specifically, the drug delayed the time to onset of 6-month confirmed disability progression (CDP) by 31% compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Additionally, the number of participants experiencing confirmed disability improvement nearly doubled with tolebrutinib (10%) compared to placebo (5%) (HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021).

This designation marks the first time a brain-penetrant Bruton’s tyrosine kinase (BTK) inhibitor for multiple sclerosis has been recognized as a Breakthrough Therapy by the FDA. The designation aims to accelerate the development and review of drugs targeting serious or life-threatening conditions and requires preliminary clinical evidence of substantial improvement over existing treatments.

Dr. Erik Wallström, Global Head of Neurology Development at Sanofi, highlighted the significance of this development, stating, “This Breakthrough Therapy designation underscores tolebrutinib’s potential to address the critical unmet need of delaying disability progression in people living with multiple sclerosis. We are committed to working closely with the FDA to bring this innovative treatment to patients who currently lack approved therapies for non-relapsing secondary progressive multiple sclerosis.”

The study also reported that liver enzyme elevations (>3xULN) occurred in 4.1% of participants receiving tolebrutinib compared to 1.6% in the placebo group. A small proportion (0.5%) experienced peak ALT levels exceeding 20xULN, primarily within the first 90 days of treatment. All but one case resolved without requiring additional medical intervention. Enhanced monitoring protocols have since been implemented to mitigate the risk of severe liver-related side effects.

Regulatory submissions for tolebrutinib are in progress in the US and are being prepared for the European Union. Sanofi will announce regulatory acceptance as soon as submissions are finalized. Meanwhile, the PERSEUS phase 3 study, evaluating tolebrutinib in primary progressive MS, is ongoing, with results expected in the second half of 2025.

It is important to note that tolebrutinib remains under clinical investigation, and its safety and efficacy have yet to be evaluated by regulatory authorities.

About tolebrutinib
Tolebrutinib is an investigational, oral, brain-penetrant, and bioactive Bruton’s tyrosine kinase (BTK) inhibitor that achieves cerebrospinal fluid concentrations predicted to modulate B lymphocytes and disease-associated microglia. Tolebrutinib is being evaluated in phase 3 clinical studies for the treatment of various forms of multiple sclerosis and its safety and efficacy have not been evaluated by any regulatory authority worldwide. For more information on tolebrutinib clinical studies, please visit www.clinicaltrials.gov.

About HERCULES
HERCULES (clinical study identifier: NCT04411641) was a double-blind randomized phase 3 clinical study evaluating the efficacy and safety of tolebrutinib in participants with nrSPMS. nrSPMS was defined at baseline as having a SPMS diagnosis with an expanded disability status scale (EDSS) 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. Participants were randomized (2:1) 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 point from the baseline EDSS score when the baseline score is ≤5.0, or the increase of ≥0.5 point when the baseline EDSS score was >5.0. Secondary endpoints included 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, time to onset of confirmed disability improvement, 3-month change in 9 hole peg test and T25-FW test as well as the safety and tolerability of tolebrutinib.

About Sanofi
We are an innovative global healthcare company, driven by one purpose: we chase the miracles of science to improve people’s lives. Our team, across the world, is dedicated to transforming the practice of medicine by working to turn the impossible into the possible. We provide potentially life-changing treatment options and life-saving vaccine protection to millions of people globally, while putting sustainability and social responsibility at the center of our ambitions.
Sanofi is listed on EURONEXT: SAN and NASDAQ: SNY

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SOURCE: Sanofi