Safety Considerations for Tolebrutinib and Utility of BTK Inhibitors: Erik Wallstroem, MD, PhD

WATCH TIME: 5 minutes

"Clinicians should be aware that this compound class, including tolebrutinib, has the problem with drug-induced liver injury, particularly during the early months of treatment, requiring intense monitoring."

Earlier this month, Sanofi announced topline data from its phase 3 HERCULES study (NCT04411641) with results showing that investigational tolebrutinib met its primary end point of reduction in disability among patients with non-relapsing secondary progressive multiple sclerosis (nrSPMS). Overall, treatment with the Bruton Tyrosine kinase (BTK) inhibitor resulted in significant effects on 6-month confirmed disability progression, which was defined as an increase of more than 1 point from baseline on Expanded Disability Status Scale (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.

In terms of safety, the preliminary analysis of liver safety was consistent with previous tolebrutinib studies. The drug, which remains also in development for relapsing forms of the disease, had its development program paused in 2022 because of reported cases of drug-induced liver injury. At the time, it affected not only HERCULES, but other trials, including GEMINI 1 and 2 of relapsing MS, PERSEUS in primary progressive MS, and URSA in generalized myasthenia gravis.

Erik Wallstroem, MD, PhD, global head of neurology development at Sanofi, recently sat down with NeurologyLive® to discuss the safety profile of tolebrutinib, emphasizing the need for careful monitoring, particularly during the early months of initiating the therapy. In addition, he provided context on the potential of tolebrutinib to address unmet needs in nrSPMS and the broader implications of BTK inhibitors in understanding MS pathology, including the concept of "smoldering" MS and central nervous system-related immune mechanisms.

REFERENCE
1. Press Release: Tolebrutinib meets primary endpoint in HERCULES phase 3 study, the first and only to show reduction in disability accumulation in non-relapsing secondary progressive multiple sclerosis. News release. Sanofi. September 2, 2024. Accessed September 9, 2024. https://www.sanofi.com/en/media-room/press-releases/2024/2024-09-02-05-00-00-2938875