Fenebrutinib curbs brain lesions in MS, Phase 2 study finds
BTK inhibitor shows potential for symptom control
Fenebrutinib significantly reduced the occurrence of new brain lesions with active inflammation in people with relapsing multiple sclerosis (MS), a Phase 2 clinical trial found.
In the open-label extension portion of the FENopta trial (NCT05119569), disease activity “remained very low” for nearly one year, researchers wrote, with 98% of patients being free of new inflammatory lesions and 96% experiencing no MS relapses.
Some 90% of patients saw no evidence of disease activity — a measure known as NEDA-3 — through one year of treatment. This means they had no new lesions, relapses, or sustained disability progression.
Two Phase 3 clinical trials, FENhance 1 (NCT04586010) and FENhance 2 (NCT04586023), are further assessing fenebrutinib’s effectiveness in various relapsing types of MS.
Findings from the Phase 2 study were published in The Lancet Neurology, in a paper titled, “Safety and efficacy of fenebrutinib in relapsing multiple sclerosis (FENopta): a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial and open-label extension study.” The work was funded by Roche, which is developing fenebrutinib through its subsidiary Genentech.
Blocking BTK to ease inflammation
Fenebrutinib is an oral medication that’s designed to block the activity of Bruton’s tyrosine kinase (BTK), an enzyme that’s crucial to activating several types of immune cells known to play a role in MS. By inhibiting BTK, the therapy aims to tamp down disease-driving inflammation.
FENopta enrolled 109 people with relapsing forms of MS. Most had relapsing-remitting MS, while three had active secondary progressive MS. Participants were randomly assigned to receive either 200 mg fenebrutinib or a placebo twice daily for 12 weeks (about three months).
The study’s main goal was to evaluate the effect of fenebrutinib on the development of new MS lesions with active inflammation, as measured by brain MRI scans at weeks four, eight, and 12.
Results showed that the combined number of new inflammatory lesions was 69% lower with fenebrutinib than with the placebo. The reduction went from 22% at four weeks, to 92% at eight weeks, to 90% at 12 weeks.
The cumulative number of new or enlarging lesions also was significantly lower — by 74% — with fenebrutinib than with a placebo, and lesions with irreversible nerve damage were reduced by 64%.
“In the current phase 2 FENopta trial, patients who received the BTK inhibitor fenebrutinib exhibited rapid and robust reductions in the mean number of new [actively inflamed] lesions (the primary outcome) and in the number of new or enlarging [total] lesions, compared with patients who received placebo,” the researchers wrote.
After the placebo-controlled part of the clinical trial, participants had the option to continue into a long-term extension in which all are being treated with fenebrutinib and monitored for long-term outcomes. During the first year of the extension study, 96% of patients were free from relapses, and most also remained free from new inflammatory lesions.
Fenebrutinib’s impact on lesions “is consistent with results from phase 2 trials of several approved high-efficacy disease-modifying therapies for relapsing multiple sclerosis,” the team wrote.
Safety data from FENopta showed that fenebrutinib was generally well tolerated. No serious side effects were reported during the placebo-controlled study. Data showed that some patients given fenebrutinib experienced an increase in liver enzyme levels, which can indicate liver damage, but all cases were reversible and did not cause any symptoms of liver damage.
The ongoing FENhance 1 and 2 studies are now testing fenebrutinib against the approved MS therapy Aubagio (teriflunomide), with the goal of testing if fenebrutinib is better at reducing relapse rates after two years. A separate study called FENtrepid (NCT04544449) is comparing fenebrutinib with the approved therapy Ocrevus (ocrelizumab) in primary progressive MS.
Fenebrutinib is not the only BTK inhibitor being developed for MS. Sanofi’s tolebrutinib and EMD Serono’s evobrutinib are BTK inhibitors that have been tested in MS trials. Each of these medications is slightly different in terms of how it interacts with BTK at the molecular level, but all three essentially aim to block the activity of this enzyme.
In an editorial published alongside the study, Laura Airas, PhD, a professor at the University of Turku in Finland, put the results of the FENopta study in context with findings from other BTK inhibitors.
Airas noted that both tolebrutinib and evobrutinib showed effects on lesions similar to fenebrutinib in Phase 2 testing. But neither tolebrutinib nor evobrutinib proved significantly better than Aubagio at reducing relapse rates in people with relapsing forms of MS, according to Airas.
Airas said that the overall data from FENopta are promising and “provide renewed optimism for BTK inhibition as a relevant treatment strategy in people with relapsing-remitting multiple sclerosis.”
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