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BTK Inhibitor Cuts Marker of Neuronal Damage in Relapsing MS

— Novel agent lowered neurofilament light chain levels, may help reduce neuroaxonal damage

Last Updated April 23, 2021
MedpageToday

The investigational agent evobrutinib significantly reduced serum levels of neurofilament light chain (NfL) in patients with relapsing multiple sclerosis (MS), a post hoc analysis of a phase II trial showed.

Treatment with the highly selective Bruton's tyrosine kinase inhibitor (BTK), which targets B cells and myeloid cells, at a dose of 75 mg twice daily resulted in a 16.8% decline in blood NfL levels versus no decline in patients assigned to placebo (P<0.01), according to Jens Kuhle, MD, PhD, of the Multiple Sclerosis Centre at University Hospital Basel in Switzerland.

The reduction in NfL levels was observed as early as 12 weeks, and those reduced levels were maintained through the 24-week trial, he reported at the American Academy of Neurology virtual meeting.

Treatment with once-daily evobrutinib at 75 mg produced a significant 15.4% reduction of NfL versus placebo (P<0.05), while treatment with a 25-mg once-daily dose was similar to placebo.

"These results indicate evobrutinib 75 mg twice daily has a beneficial effect on reducing neuroaxonal damage in multiple sclerosis patients," Kuhle stated, adding that the data on NfL dynamics are the first to be reported for any BTK inhibitor investigated for MS.

Primary results of the phase II trial showed that evobrutinib at a once-daily dose of 75 mg significantly reduced T1 gadolinium-enhancing lesions during weeks 12 through 24 compared with placebo, while the once-daily 25-mg dose and twice-daily 75-mg dose failed to do so.

For the current post hoc analysis, Kuhle and colleagues assessed NfL levels in the blood as a marker of neuroaxonal damage, with a proposed prognostic value for monitoring disease progression.

They enrolled 267 individuals for the overall study, and included 166 of them in the NfL evaluation study, with 50 having received placebo. The rest received evobrutinib, at doses of 25-mg once-daily (n=40), 75-mg once-daily (n=37), and 75-mg twice-daily (n=39). Kuhle said the baseline demographics were similar in the modified intention-to-treat population and in the NfL evaluation group.

Deborah Hall, MD, PhD, of Rush University in Chicago, told ľֱ that NfL levels "have been found to be a promising biomarker for several central nervous system disorders. Although we don't directly treat abnormal levels, it is an important marker of disease that could inform treatment in the future."

But Hall, who was not involved in the study, cautioned that NfL level markers are not ready for prime time. "We are still early in trying to determine how we will use this information appropriately in the clinic."

"These encouraging findings add to the substantial literature on potential use of neurofilament light chain levels as a marker of multiple sclerosis disease activity, and more specifically as a biomarker of treatment response to evobrutinib at the population level," added John Corboy, MD, of the University of Colorado Denver.

"The Bruton's tyrosine kinase inhibitors are an exciting class of molecules that could have significant impact on both adaptive and innate immune system dysfunction in multiple sclerosis, especially as it affects neurodegeneration and progressive disease," Corboy told ľֱ. "Markers such as neurofilament light chain levels may play an important role as outcome measures in this regard, but it remains a major challenge to determine how we will use neurofilament light chain data in individual patients."

In September 2019, evobrutinib's developer announced the initiation ofof the agent in relapsing MS.

Disclosures

The study was supported by EMD Serono Research and Development Institute/Merck KGaA.

Kuhle disclosed no relevant relationships with industry. Co-authors disclosed relevant relationships with EMD Serono, Bayer, Biogen, Celgene, Genentech, Genzyme, Janssen, Minoryx, Novartis, Roche, Sanofi, Santhera, AbbVie, and Eisai.

Primary Source

American Academy of Neurology

Kuhle J, et al "The effect of evobrutinib, a BTK inhibitor, on blood neurofilament light chain levels in relapsing multiple sclerosis" AAN 2021.