FDA Grants Breakthrough Status to Sanofi’s Tolebrutinib for Non-Relapsing Secondary Progressive MS

The U.S. Food and Drug Administration has awarded Breakthrough Therapy status to tolebrutinib for treating adult patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). This decision stems from promising results in the HERCULES phase 3 trial, where tolebrutinib showed a 31% reduction in the time to 6-month confirmed disability progression when compared to placebo (HR 0.69; 95% CI 0.55-0.88; p=0.0026). Additionally, analysis of secondary outcomes revealed that participants on tolebrutinib experienced nearly twice the rate of confirmed disability improvement (10%) versus those on placebo (5%) (HR 1.88; 95% CI 1.10 to 3.21; nominal p=0.021).

The Breakthrough Therapy designation is intended to speed up the development and review processes in the U.S. for medications targeting severe or life-threatening conditions. For a drug to qualify, clinical evidence must indicate a considerable improvement over existing treatments.

Erik Wallström, MD, PhD, Sanofi’s global neurology development head, noted, “Receiving this Breakthrough Therapy status highlights tolebrutinib’s potential to address the critical unmet need of preventing disability progression for those living with multiple sclerosis. We are eager to collaborate closely with the FDA during the review of this pioneering treatment for non-relapsing secondary progressive MS, a condition with no currently approved treatments.”

Elevations in liver enzymes (>3xULN) were noted in 4.1% of participants on tolebrutinib versus 1.6% on placebo. A small fraction (0.5%) in the tolebrutinib group showed ALT increases >20xULN, predominantly within the first 90 days. Most liver enzyme elevations were resolved without additional medical interventions. Enhanced monitoring frequency has diminished serious liver complications.

The finalization process for tolebrutinib’s regulatory submissions in the U.S. is in progress, with preparations underway for the EU. As with other drugs, Sanofi will confirm when the regulatory submission is accepted. Results from the ongoing PERSEUS phase 3 study in primary progressive MS are awaited in the second half of 2025.

Currently, tolebrutinib is an investigational treatment, and regulatory authorities have not assessed its safety and effectiveness.

Multiple sclerosis is a chronic disease affecting the immune system and the nervous system, leading to lasting disabilities. These impairments in physical and cognitive abilities can progressively worsen a patient’s health and quality of life. The unmet medical need in MS is stopping disability. Therapies mainly target peripheral B and T cells, but innate immunity, thought to contribute to disability, remains largely unaddressed. Existing or late-stage MS treatments usually focus on the adaptive immune system and may not act directly within the central nervous system for clinical benefits.

nrSPMS individuals experience ongoing disability without relapses, showing symptoms like fatigue, cognitive challenges, balance issues, bowel and bladder function loss, and sexual dysfunction, among others.

Tolebrutinib is a brain-penetrant oral Bruton’s tyrosine kinase (BTK) inhibitor being researched in phase 3 studies for multiple sclerosis treatment, with its regulatory evaluation yet to be conducted globally.

HERCULES (clinical study identifier: NCT04411641) was a double-blind, randomized phase 3 study examining tolebrutinib’s effectiveness and safety in nrSPMS participants, identified at baseline by an expanded disability status scale (EDSS) between 3.0 and 6.5, no relapses in the past 24 months, and documented disability accumulation in the last year. Participants were randomized (2:1) for either an oral daily dose of tolebrutinib or a matching placebo for about 48 months.

The study’s primary endpoint was 6-month CDP, defined by a =1.0 point increase from baseline EDSS when the baseline was =5.0, or a =0.5 point increase when >5.0. Secondary endpoints assessed included time to 3-month CDP onset, new or enlarged T2 hyperintense lesions via MRI, confirmed disability improvement, changes in the 9-hole peg and T25-FW tests, and overall safety and tolerability of tolebrutinib.