For patients with primary progressive multiple sclerosis (PPMS), fenebrutinib, an investigational Bruton’s tyrosine kinase (BTK) inhibitor, is no worse at slowing disability progression than the only approved medication for the disease, according to data from the phase 3 FENtrepid trial presented at the ACTRIMS Forum.
Through at least 120 weeks of treatment, 58.8% of patients treated with fenebrutinib and 66.1% of those treated with ocrelizumab met a composite endpoint incorporating measures of functional disability, walking speed, and upper limb function, establishing the noninferiority of the novel agent. Separation between the groups occurred as early as 24 weeks.
Overall rates of adverse events (AEs) were similar in the two arms of the trial, although fenebrutinib came with more fatal events (1.4% vs 0.2%) and more AEs leading to withdrawal (14.1% vs 5.1%).
“Most of those were withdrawals based on protocol-mandated discontinuation because of liver enzyme bumps,” Amit Bar-Or, MD, chief of the MS division at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia, said while presenting the findings.
Fenebrutinib, a central nervous system-penetrant, reversible, highly selective BTK inhibitor, has been shown to provide near-complete suppression of disease activity in patients with relapsing MS, according to phase 2 and top-line phase 3 results, and the hope has been that BTK inhibition may impact both relapsing and progressive biology underlying MS.
In the FENtrepid trial, 985 patients (mean age 48.9 years; 49.5% women) with PPMS were randomized to oral fenebrutinib 200 mg BID plus ocrelizumab-matching placebo or IV ocrelizumab 600 mg every 24 weeks plus fenebrutinib-matching placebo.
“This, I think for many of us, was a pretty brave, bold trial to embark on with a head-to-head [comparison] to the only approved therapy in primary progressive MS,” Bar-Or said.
The primary endpoint was 12-week composite confirmed disability progression, consisting of a worsening on the Expanded Disability Status Scale (EDSS), Timed 25-foot Walk Test, or 9-Hole Peg Test. There was a 12% relative difference favoring fenebrutinib overall (HR 0.88; 95% CI 0.75-1.03), with consistent results across subgroups.
Most patients (63%) progressed based on the walking test, 24% on the EDSS, and 13% on the 9-hole peg test. The risk reduction with fenebrutinib versus ocrelizumab was greatest for the 9-hole peg test (HR 0.74), a measure of upper limb function.
Seven patients in the fenebrutinib group and one in the ocrelizumab group died during the study, although all deaths were deemed unrelated to study drug and there were no discernible patterns in the timing or cause of the events, Bar-Or said.
Transient and reversible asymptomatic hepatic transaminase elevations were more common with fenebrutinib, with these events typically occurring in the first 20 weeks; all resolved. Bruising was also more frequent with the novel agent versus ocrelizumab (8.8% vs 4.9%).
Considering these efficacy and safety results, and if the beneficial impact of fenebrutinib is borne out in remaining trials in relapsing MS, “then one might consider the prospect of it having a broad indication” across the spectrum of MS, Bar-Or said, adding that “there’s no particular reason to think that anybody who has a correct diagnosis of PPMS would not be a candidate.”
He said that because of elevations in liver enzymes with fenebrutinib, routine liver testing “is certainly going to be something that we’re going to want to do in terms of risk mitigation.”
Todd Neale has no conflicts of interest.
Collage by Joe Lee
