BTK Inhibitor Tolebrutinib Receives Breakthrough Therapy Designation for nrSPMS

Tolebrutinib (Sanofi, Paris, France), an investigational, oral, bioactive brain-penetrant Bruton tyrosine kinase (BTK) inhibitor, has been granted Breakthrough Therapy designation by the Food and Drug Administration (FDA) for the treatment of adults with non-relapsing secondary progressive multiple sclerosis (nrSPMS). The designation was granted based on positive data from the phase 3 HERCULES clinical study (NCT04411641) showing that treatment with tolebrutinib was effective in delaying disability progression for people with nrSPMS.

HERCULES was a double-blind, randomized, phase 3 clinical study evaluating the safety and efficacy of tolebrutinib treatment in adults with nrSPMS. Participants received treatment with either tolebrutinib (n=752) or matched placebo (n=375) by oral daily dosing for 48 months. Researchers assessed 6-month confirmed disability progression (CDP) as a primary endpoint, defined as a ≥1.0-point increase in expanded disability status scale (EDSS) scores for participants with a baseline score of ≤5.0 and a ≥5.0-point increase for participants with a baseline EDSS of >5.0.

• Compared with placebo, tolebrutinib treatment delayed time to onset of 6-month CDP progression by 31% (hazard ratio [HR], 0.69; 95% CI, 0.55 to 0.88; P=.0026).
• 10% of participants treated with tolebrutinib experienced confirmed disability improvement, compared with 5% of those who received placebo (HR, 1.88; 95% CI, 1.10 to 3.21; nominal P=.021).
• 4.1% of people treated with tolebrutinib showed an increase in in liver enzyme elevations (3x the upper limit of normal [ULN]) compared with 1.6% of those treated with placebo.

“This Breakthrough Therapy designation demonstrates the potential for tolebrutinib to delay disability progression, a critical unmet need for people living with multiple sclerosis,” said Erik Wallstöm, MD, PhD, Global Head of Neurology Development at Sanofi. “We look forward to working with the FDA during the regulatory review of this first of its kind medicine in non-relapsing secondary progressive multiple sclerosis where there are currently no approved treatments available.”

Tolebrutinib is currently also under investigation as a treatment for primary progressive multiple sclerosis (PPMS) in the ongoing phase 3 PERSEUS clinical study (NCT04458051).

Breakthrough Therapy designation is intended to expedite the development and review of drugs that treat serious conditions with positive preliminary clinical evidence. Products that receive Breakthrough Therapy designation are granted all the features of Fast Track designation as well as guidance in an efficient drug development program.