Oral evobrutinib, a highly selective Bruton tyrosine kinase inhibitor, may have a beneficial effect on reducing nerve damage in multiple sclerosis (MS), based on how it has been found to reduce the levels of a key blood biomarker, according to a post hoc analysis of a placebo-controlled clinical trial reported at the 2021 annual meeting of the American Academy of Neurology.
Dr. Jens Good
Jens Good, MD, from the biomedicine department at Basel University Hospital, Switzerland, said the conclusion was based on the reduction in blood levels of the neurofilament light chain (NfL), a biomarker of neuroaxonal damage, in treated patients. “These data on the effect of evobrutinib on NfL dynamics are the first to be reported of a BTK inhibitor investigated for MS,” Kuhle said. Evobrutinib targets beta and myeloid cells, including macrophages and microglia, to disrupt NfL production.
The analysis consisted of three treatment arms in addition to the placebo arm: 25 and 75 mg daily and 75 mg twice daily. The post hoc analysis included 166 patients in all arms, with 148 evaluated at week 24.
Kuhle said the 75 mg twice daily group had significantly lower blood NfL levels as early as week 12, with reduced levels maintained until week 24, the last time the blood was assessed. study, specifically reductions of 18.9% (Pg = 0.01) and 16.8% (Pg = 0.040) compared with placebo, respectively.
However, the 75 mg once daily dose also showed significant reductions compared to placebo: 15.4% (Pg = 0.043) and 14.1% (Pg = .10) at 12 and 24 weeks, respectively, Kuhle said. “No significant differences were observed with the 25 mg group once daily,” he said.
“These results are promising and indicate that evobrutinib at an effective dose of 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in MS,” he said.
In an interview, Kuhle explained the importance of lower NfL levels. “The hope is that detecting subclinical disease activity in a sensitive and comprehensive manner will lead to more effective treatment of the individual patient with MS,” he said.
The findings may also inform future studies of evobrutinib in MS, he said. “Neurofilaments and neurons are the key substrate for permanent disability in MS and other neurodegenerative diseases,” Kuhle said. “It is expected that normalization of NfL to levels in healthy controls of the same age should be the appropriate treatment goal for individual patients.”
NfL could be an “easily accessible and modifiable biomarker” for use in recurrent and progressive MS clinical trials, he said. The researchers plan to use NfL measures in the extension phase of the trial.
“An important next step is the development of reliable, age-adjusted benchmarks for NfL measurements in the blood to move this biomarker toward individual application in clinical practice,” he added, noting that his group has already collected more than 10,000 serum samples from more than 5,000 healthy controls to do so.
Dr. Fredrik Piehl
The analysis adds to the growing body of evidence supporting the use of NfL levels in the blood to evaluate the effectiveness of disease-modifying therapies on neuroaxonal degeneration in MS. Fredrik Piehl, MD, Ph.D., professor at Karolinska University Hospital in Stockholm.
“However,” he added, “this is a short-term phase 2 trial that lacks an active comparator. It has been suggested that BTK inhibitors have a double action, acting on the periphery on the immune response. adaptive, but also improves local brain tissue inflammation. “
Additional longer-term studies, active comparators, and advanced neuroimaging will be needed to validate the effect of BTKs on NfL levels in MS, Piehl said.
The study was sponsored by EMD Serono Research and Development Institute, a subsidiary of Merck. Kuhle has no relevant financial relationships to reveal. Piehl reported financial relationships with Biogen, Novartis, Sanofi, Merck, Actelion, Alexion, Argenx, Roche / Genentech, Genzyme, UCB and Parexel.
This article originally appeared on MDedge.com, which is part of the Medscape professional network.
