Multiple sclerosis: Tolebrutinib slows progression of disabilities

In multiple sclerosis (MS), acute and smoldering inflammatory processes occur in the brain, leading to progressive disability. Despite treatment with disease-modifying therapies, many patients experience an increase in disability, regardless of disease flare-ups. Smoldering neuroinflammation is thought to be responsible for this.

"Disability progression, measured using the Expanded Disability Status Scale (EDSS), can be slow for many years, but then suddenly increase when neurobiological reserves are exhausted," explained Professor Dr. Ralf Gold of the Katholisches Klinikum Bochum at a Sanofi press conference last Wednesday. With the chronicity of MS, physical limitations increase, and cognition, mental flexibility, and endurance are often also affected. Unlike other forms of MS, there is currently no approved treatment for people with non-relapsing secondary progressive MS (nrSPMS).

The BTK inhibitor tolebrutinib could prove useful in this context. Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase expressed in B cells, macrophages, and microglia, among others. It is involved in the regulation of B cell maturation and function, as well as in cytokine release. Inhibition of the enzyme disrupts signaling pathways essential for microglial activation and B cell function.

Tolebrutinib crosses the blood-brain barrier after oral administration. "Therefore, the 60 mg dose appears to be sufficient to reach microglia in the central nervous system," said the MS expert.

The effect of tolebrutinib was demonstrated in the recently published, randomized phase III HERCULES study . 1,131 patients with nrSPMS were included, of whom 754 received the drug (60 mg once daily) and 377 received placebo. The primary endpoint was the time to onset of confirmed disability progression (CDP) at six months. The median follow-up time was 133 weeks.

Over an observation period of up to 45 months, physical function deteriorated by 26.9 percent with tolebrutinib and 37.2 percent with placebo; the difference was significant. The relative risk reduction for the six-month CDP was 31 percent. According to Gold, this represents a delay of approximately one to one and a quarter years.

In addition to slowing disease progression, 10 percent of patients in the active group even showed an improvement in physical function (compared to 5 percent in the placebo group); this was a secondary endpoint. In addition, the risk of new T2 lesions on magnetic resonance imaging decreased by 38 percent.