BTK Inhibitor Reduces MS Relapse Rates in Two Phase 3 Trials

TORONTO — Remibrutinib, an investigational Bruton tyrosine kinase (BTK) inhibitor developed by Novartis, significantly reduced relapse rates and inflammatory brain lesions compared with teriflunonmide, the current standard of care, in patients with relapsing multiple sclerosis (MS), new findings from two industry-sponsored phase 3 trials showed.The REMODEL-1 and REMODEL-2 trials showed relative reductions in annualized relapse rates (ARRs) of 35% and 31.2%, respectively, although the absolute differences were small. Remibrutinib was also associated with a reduction in new or enlarging brain lesions by approximately 65%-70% compared with teriflunomide.The studies also suggested a potential benefit in delayed disability progression with remibrutinib although the findings were not statistically conclusive. The results also showed fewer liver enzyme elevations with remibrutinib vs teriflunomide.“These findings support remibrutinib as a new safe and highly efficacious oral therapy for relapsing MS,” lead author Heinz Wiendl, MD, professor and chair, Department of Neurology, University of Freiburg, Freiburg, Germany, told Medscape Medical News.The studies were presented on October 23 at the 10th Joint European Committee for Treatment and Research in Multiple Sclerosis-Americas Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS-ACTRIMS) 2026 and simultaneously published online in The Lancet.Two Identical Phase 3 TrialsAn inflammatory and neurodegenerative disease of the central nervous system, MS is characterized by demyelination, axonal injury, and neuronal loss leading to relapses and disability accumulation. The relapsing type accounts for about 85% of MS diagnoses.Inhibitors of the BTK enzyme, a crucial part of the B-cell receptor signaling pathway, have a unique action. Evidence suggests that targeting BTK may help calm overactive immune cells in MS, in addition to stopping abnormal B cells from growing in certain cancers.REMODEL-1 and REMODEL-2 were identical, randomized, double-blind, active comparator-controlled phase 3 trials evaluating the safety and efficacy of remibrutinib vs teriflunomide in adult patients with relapsing MS.Contemporary trials are required to show superiority against standard of care. Researchers chose teriflunomide as a comparator as it is relatively safe and moderately active MS treatment, said Wiendl.The two trials were designed to establish reproducibility, an important consideration for regulatory authorities, he added.A total of 1000 patients were randomly assigned in REMODEL-1 and 1007 in REMODEL-2.Both studies included a double-blind core phase in which participants were randomly assigned to receive either oral remibrutinib 100 mg twice daily or teriflunomide 14 mg once daily, along with matching placebos for up to 30 months.Baseline characteristics were generally balanced between treatment groups within and across the two trials. Approximately two thirds of participants were female, nearly 80% were White, and the mean age was approximately 39 years.Inconclusive Disability FindingsThe primary endpoint was ARR, defined as the number of confirmed MS relapses per patient-year over up to 30 months of follow-up. Investigators assessed Expanded Disability Status Scale (EDSS) scores at screening, baseline, month 3, every 3 months thereafter, and whenever an MS relapse was suspected.Results showed the ARR was significantly lower with remibrutinib than with teriflunomide: 0.073 vs 0.112 (rate ratio [RR], 0.648; 95% CI, 0.453-0.927; P = .018) in REMODEL-1, and 0.080 vs 0.116 (RR, 0.688; 95% CI, 0.487-0.972; P = .034) in REMODEL-2.Researchers collected serum neurofilament light chain (NfL), a marker of neuronal injury, at several points during the trials. At month 12, NfL levels were significantly lower with remibrutinib than with teriflunomide in both studies.A key secondary endpoint was new or enlarging T2 lesions. A subset of patients — 721 in REMODEL-1 and 632 in REMODEL-2 — underwent MRI to assess lesion activity.Results showed that remibrutinib significantly reduced the annualized rate of new or enlarging T2 lesions compared with teriflunomide by 65% in REMODEL-1 (RR, 0.35) and 70.3% in REMODEL-2 (RR, 0.30; P < .0001 for both).The mean number of gadolinium-enhancing T1 lesions per scan was also significantly lower with remibrutinib, with relative reductions of 66.3% in REMODEL-1 and 66.2% in REMODEL-2 (RR, 0.34 and P < .0001 for both).Secondary endpoints in the combined analysis included 3- and 6-month confirmed disability progression (CDP), defined as an increase in EDSS of at least 1.5, 1.0, or 0.5 points in patients with a baseline EDSS of 0, 1.0-5.0, or 5.5 or greater, respectively.The study showed a clinically meaningful delay in disability progression for remibrutinib, with a nonsignificant risk reduction in 3-month CDP and nominally significant risk reduction in 6-month CDP, compared with teriflunomide.A greater proportion of patients on remibrutinib than on teriflunomide achieved no evidence of disease activity defined as the absence of confirmed MS relapses, 6-month CDP, and new or enlarging T2 lesions.Reassuring Liver Safety FindingsAdverse events (AEs) were reported in 79.5% of patients receiving remibrutinib and 81.5% of those receiving teriflunomide. AEs occurring in at least 10% of patients in either treatment group included upper respiratory tract infection, nasopharyngitis, diarrhea, and alopecia.Infections were the most frequently reported AEs occurring at similar rates in both treatment groups. Serious infections were uncommon, and no opportunistic infections were reported.New onset liver enzyme elevations occurred less frequently with remibrutinib than with teriflunomide and were transient and reversible.“That’s pretty remarkable considering other BTK inhibitors all had liver safety problems,” said Wiendl.Five BTK inhibitors are currently under investigation for MS, including remibrutinib. Although these small-molecule therapies all inhibit BTK, they differ in their selectivity and the doses needed to bind to their intended targets, a measure known as target occupancy.Remibrutinib’s potential advantage lies in its high selectivity and ability to achieve substantial target occupancy at low doses, along with a favorable pharmacokinetic profile, Wendel said.Another potential advantage of remibrutinib is that it is already approved for the treatment of chronic spontaneous urticaria, a dermatologic condition.Two additional trials of remibrutinib are underway. One is evaluating the drug in patients with nonrelapsing secondary progressive MS, whereas the other is comparing outcomes in patients who continue anti-CD20 therapy with those who switch to remibrutinib.The findings add to the growing body of evidence supporting BTK inhibition as a potential treatment strategy in MS, although questions remain about its effects on disability progression.A Valuable Research ContributionJaume Sastre-Garriga, MD, PhD, neurologist at the MS Centre of Catalonia in Barcelona, Spain, described the research results as “very useful” and a valuable contribution to the emerging evidence on BTK inhibitors.His main reservation was the lack of a statistically significant reduction in 3-month CDP. However, he noted that they were significant at 6 months.“I think this is a shadow, not a large shadow, but a bit of a shadow, on the very positive findings and encouraging data coming from these two trials,” he said.Sastre-Garriga said he would like more time to assess the new findings in the contest of the growing body of evidence on BTK inhibitors.Unlike with anti-CD20 therapies, which tend to produce similar clinical effects, BTK inhibitors appear to differ in their effects across studies, he noted. These differences may reflect variations in trial design, patient selection, and variation in doses evaluated, complicating comparisons across trials.Nevertheless, Sastre-Garriga described the favorable liver safety findings with remibrutinib as “very good news” particularly given liver safety concerns associated with other investigational BTK inhibitors.The trials were funded by Novartis, which was involved in study design, data collection and analysis, interpretation, and writing of the report. Eight of the authors reported being Novartis employees. Wiendl reported serving as a consulting and on advisory board and receiving speaker honoraria and research funding from multiple companies, including Novartis. Sastre-Garriga reported no relevant disclosures.