Slowly Expanding Lesions in MS Reduced With BTK Inhibitor

Evobrutinib, a highly selective Bruton's tyrosine kinase inhibitor (BTK) targeting B cells and myeloid cells, reduced the volume of slowly expanding lesions (SELs) in people with relapsing multiple sclerosis (MS), a post hoc analysis of a phase II trial showed.

Treatment with investigational evobrutinib reduced SEL volume compared with placebo, with the highest effect seen with 75 mg twice daily (P=0.047), reported Douglas Arnold, MD, of NeuroRx Research in Montreal, in a scientific session at the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress.

"This is the first evidence that a BTK inhibitor impacts brain lesions associated with chronic inflammation and tissue loss," Arnold said.

Primary results in the evobrutinib phase II trial showed that relapsing MS patients who received 75 mg of evobrutinib had significantly fewer gadolinium-enhancing lesions during weeks 12 through 24 than those who received placebo. Further analysis showed that evobrutinib 75 mg twice daily produced a significant reduction of neurofilament light, a marker of axonal damage, compared with placebo.

SELs are a potential result of accumulating neuronal damage and occur independently of acute inflammation associated with gadolinium-enhancing lesions. Also known as smoldering lesions, SELs are an emerging imaging marker of chronic tissue loss in MS. They are likely driven by sustained microglia or macrophage activity, resulting in the progressive accumulation of irreversible tissue damage and axonal loss, Arnold noted.

On MRI, SELs can be identified as areas within pre-existing T2 lesions that show gradual, radial expansion. "These are areas of ongoing tissue damage within chronic lesions and at least a subset of histologically-defined chronic active lesions that show expansion over time," Arnold said. SEL activity and ongoing damage within SELs can predict long-term disability.

In the post hoc analysis, evobrutinib reduced SEL volume relative to placebo in a dose-dependent manner from baseline through week 48, with volume decreasing by -136.5 mm³ (P=0.505), -246.0 mm³ (P=0.192), and -474.5 mm³ (P=0.047) for evobrutinib 25 mg once daily, 75 mg once daily, and 75 mg twice daily, respectively.

"The effect of evobrutinib on SEL volume was especially apparent in patients with more advanced disease and greater T2 lesion volume," Arnold said.

What wasn't clear was whether the reduction in SEL volume with evobrutinib was due to a decrease in new cells or whether present cells showed a reduction in expansion, observed ECTRIMS session chair Jan Bauer, PhD, of the Medical University of Vienna in Austria.

"In this particular instance, we didn't actually measure new cells," Arnold said. "We measured cells that were present in the baseline chronic T2 lesion volume. This was affecting chronic activity in pre-existing lesions."

The suppression of SEL volume suggests evobrutinib may have an effect on myeloid cells including microglia and macrophages within the central nervous system, Arnold noted. "Progressive accumulation of irreversible neural tissue damage and axonal loss associated with SELs may be predictive of long-term clinical progression," he added.

Evobrutinib is one of several BTK inhibitors currently being tested in MS. The EVOLUTION phase III trials of evobrutinib in relapsing MS are underway with enrollment recently completed, drug maker Merck KGaA announced.

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