Multiple Sclerosis Disability Suppression Observed in New Fenebrutinib Phase 2 Data
MRI scans showed that 99% of fenebrutinib-treated patients were free of T1 gadolinium-enhancing lesions, indicating minimal active inflammation.
Levi Garraway, MD, PhD
New data expected to be presented at the 40th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Copenhagen, Denmark, show that treatment with investigational fenebrutinib (Roche) resulted in significant suppression of relapses in patients with relapsing multiple sclerosis (MS), in addition to no change in disability over 48 weeks. Phase 3 trials testing the reversible and non-covalent Bruton’s tyrosine kinase (BTK) inhibitor in both progressive MS and relapsing MS remain ongoing.1
The new data stems from the phase 2 FENopta study (NCT05119569), a randomized, double-blind, placebo-controlled 12-week trial that included an open-label extension (OLE) in which all patients receive fenebrutinib up to 192 weeks. In total, 91 patients entered the OLE and 96 remained in the OLE after 1 year. At 1 year, 96% of fenebrutinib-treated patients were free of relapses, equating to an annualized relapse rate of 0.04. In addition, as mentioned, patients on the investigational drug showed no change in disability over that time, as measured by the Expanded Disability Status Scale (EDSS).
Using MRIs, study investigators observed that 99% of patients were free of T1 gadolinium-enhancing (Gd+) lesions, otherwise known as markers of active inflammation, through fenebrutinib treatment. Comparing the end of the 12-week double-blind period to the 48 weeks of OLE showed a more than 3-fold reduction in the volume of T2 lesions in treated patients (–0.33 cm3 vs –0.11 cm3, respectively).
"After a year of treatment, our BTK inhibitor fenebrutinib was able to suppress nearly all disease activity and disability progression in people with multiple sclerosis,” Levi Garraway, MD, PhD, chief medical officer and head of Global Product Development at Roche, said in a statement.1 "If these results are validated in the ongoing Phase III trials, fenebrutinib could further advance the treatment landscape for people living with multiple sclerosis."
Fenebrutinib’s safety stayed consistent as well, with urinary tract infection (8%), COVID-19 (7%), and pharyngitis (5%) as the only reported adverse events (AEs) occurring in more than 5% of treated patients. There was 1 serious AE in 1 patient in the OLE, identified as an asymptomatic aminotransferase elevation, which was resolved with treatment discontinuation. To date, more than 2700 patients and healthy volunteers have been treated with fenebrutinib across phase 1, 2, and 3 trials of various conditions, including MS and other autoimmune disorders.
At the conclusion of the double-blind portion of FENtopa, previously reported findings revealed that fenebrutinib-treated patients had amelioration in the total of new gadolinium-enhancing T1 brain lesions, the primary end point, compared with placebo (P = .0022). Additional findings showed that a higher proportion of patients treated with the agent were free from any new gadolinium-enhancing T1 brain lesions and new or enlarging T2-weighted brain lesions compared with placebo. The investigational therapy also maintained a safe treatment profile, with findings that were consistent with previous and ongoing trials.2
Fenebrutinib is currently being tested in the phase 3 FENtrepid trial, a double-blind, double-dummy, parallel-group study of patients with primary progressive MS. In the trial, patients are randomly assigned to either daily oral fenebrutinib or placebo or intravenous ocrelizumab (Ocrevus; Genentech), the only approved therapy for progressive MS, for 120 weeks. The study uses change in 12-week confirmed disability progression as the primary outcome, with time to onset of composite 24-week CDP, the percentage change in total brain volume assessed by MRI, and change from baseline in participant-reported physical impacts of MS as secondary end points.3
Earlier this year, at the 2024 American Academy of Neurology (AAN) Annual Meeting, an analysis examined the effects of fenebrutinib on MRI outcomes and the ability of the treatment to enter cerebrospinal fluid. Using data weeks 4, 8 and 12 (combined) of FENopta, fenebrutinib patients had a 69% reduction in total new Gd+ lesions and a 74% reduction in total NET2 lesions vs placebo patients. Furthermore, the mean fenebrutinib CSF concentration in 11 patients with relapsing MS after 12 weeks of continuous fenebrutinib administration was 43.1 ng/mL, which was higher than the mean IC50 (active range) in CD63 (10.0 ng/mL), phospho-BTK (7.5 ng/mL) and CD69 (5.3 ng/mL) whole blood assays.4
