BTK Inhibitor Tolebrutinib Delayed Disability Progression in Individuals with nrSPMS

Tolebrutinib (Sanofi, Paris, France), a brain-penetrant Bruton tyrosine kinase (BTK) inhibitor, was shown to be effective in delaying disability progression for people with non-relapsing secondary progressive multiple sclerosis (nrSPMS). Compared with placebo, treatment with tolebrutinib was associated with a delay of 31% in time to onset of 6-month confirmed disability status (CDP), and improvements in disability for some participants. The results of the phase 3 HERCULES clinical study (NCT04411641) were presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

HERCULES was a double-blind, randomized phase 3 clinical trial evaluating the safety and efficacy of tolebrutinib treatment in people aged 18 to 60 years with nrSPMS and expanded disability status scale (EDSS) scores between 3.0 and 6.5. Participants were randomly assigned 2:1 to receive either tolebrutinib (n=752) or matched placebo (n=375) by oral daily dosing for 48 months. The primary endpoint was 6-month CDP, which was defined as a ≥1.0-point increase in EDSS for participants with a baseline EDSS score of ≤5.0, and a ≥5.0-point increase for participants with a baseline EDSS of >5.0. Secondary endpoints included change in 9-hole peg test and timed 25-foot walk (T25-FW) test at 3 months, as well as 3-month CDP assessed by EDSS score, the presence of MRI lesions, and change in cognitive function.

In terms of results:

• Compared with people treated with placebo, those who received tolebrutinib demonstrated a delayed time to onset of 6-month CDP of 31% (hazard ratio [HR], 0.69; 95% CI, 0.55 to 0.88; P=.0026).
• 10% of people who received tolebrutinib experienced confirmed disability improvement, compared with 5% of those treated with 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.
• Prior to the implementation of a revised study protocol, one participant who received tolebrutinib died after receiving a liver transplant.
• The safety profile of tolebrutinib was generally consistent with other BTK inhibitors used for the treatment of multiple sclerosis (MS).

“Secondary progressive multiple sclerosis is characterized by insidious worsening of disability over time, independent of relapses, and represents a critical unmet need because we don’t have effective treatments,” said Robert Fox, MD, Vice Chair of Research at the Cleveland Clinic’s Neurologic Institute, Chair of the HERCULES Glboal Steering Committee, and paid advisor to Sanofi for the HERCULES trial. “The results of HERCULES show clearly that tolebrutinib delayed disability progression in people with nrSPMS – and some people even improved disability – by uniquely targeting the biological processes driving disease progression in the brain.”