Phase III Remibrutinib Data Show Superior Relapse Reduction in Relapsing MS

Data from two identical phase III studies showed that twice daily oral doses of 100 mg of the Bruton’s tyrosine kinase (BTK) inhibitor remibrutinib reduced relapses more than teriflunomide (Aubagio) in patients with relapsing multiple sclerosis (MS).

In REMODEL-1, the annualized relapse rate was 0.073 with remibrutinib versus 0.112 with teriflunomide (rate ratio [RR] 0.648, 95% CI 0.453-0.927, P=0.018), reported by Heinz Wiendl, MD, of the University of Freiburg in Germany, at MSToronto2026, the joint meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

In REMODEL-2, annualized relapse rates were 0.080 versus 0.116 (RR 0.688, 95% CI 0.487-0.972, P=0.034) favoring remibrutinib, Wiendl said. The findings were published simultaneously in The Lancet.

The relapse rate with remibrutinib translated to approximately one relapse in 13 years, Wiendl said.

A key secondary endpoint was the reduction of new and enlarging T2 lesions, he added. “In REMODEL-1 and REMODEL-2, there is a highly significant reduction, 65% and 70%” compared with teriflunomide, Wiendl reported. “Similarly, gadolinium-enhancing lesions were massively reduced in remibrutinib in comparison to teriflunomide, 66% and 66% in both trials, showing a very low occurrence rate.”

At month 12, levels of serum neurofilament light chain (NfL) — a marker of axonal injury — were lower with remibrutinib compared with teriflunomide in both REMODEL-1 (geometric mean ratio 0.91, P=0.0001) and REMODEL-2 (geometric mean ratio 0.93, P=0.0036).

Pooled data from both trials showed that the percentage of patients with 3-month confirmed disability progression was 11.7% with remibrutinib and 14.1% with teriflunomide, indicating a non-significant risk reduction with remibrutinib (HR 0.80, 95% CI 0.61-1.04, P=0.090). The percentage of patients with 6-month confirmed disability progression was 7.7% with remibrutinib and 10.5% with teriflunomide (HR 0.70, 95% CI 0.51-0.98, P=0.038).

A 25-mg formulation of remibrutinib (Rhapsido) twice daily is approved to treat chronic spontaneous urticaria and symptomatic dermographism. In the REMODEL trials, the safety profile of remibrutinib was consistent with its profile in other indications, including no liver concerns. Newly occurring liver enzyme elevations were infrequent, transient, and reversible.

Safety findings from trials of other BTK inhibitors in MS raised questions about drug-induced liver injury. Unlike these studies, “we haven’t seen really a liver signal at all,” Wiendl said. There were no cases meeting criteria for Hy’s Law, a prediction of fatal drug-induced liver injury risk.

The most common adverse events in the REMODEL studies were upper respiratory tract infection (13.1% with remibrutinib vs 13.7% with teriflunomide), nasopharyngitis (9.1% vs 12.3%), diarrhea (8.3% vs 10.9%), and alopecia (5.8% vs 13.5%). Adverse events leading to treatment discontinuation were less frequent with remibrutinib (3.1%) than with teriflunomide (5.8%).

REMODEL-1 and REMODEL-2 evaluated relapsing MS patients ages 18 to 55 with evidence of recent disease activity and an Expanded Disability Status Scale (EDSS) score of 0 to 5.5. EDSS scores can range from 0 to 10, with higher scores indicating worse disability. Participants were randomly assigned to oral remibrutinib 100 mg twice daily or teriflunomide 14 mg once daily.

REMODEL-1 included 1,000 patients and REMODEL-2 included 1,007; half in each trial were assigned to remibrutinib. The mean baseline EDSS score was approximately 2.5 in all groups. The mean age in both studies was 38 to 39 and 67% were women. On average, patients had over 6 years since first MS symptoms and over 4 years since diagnosis.

Bleeding events occurred more frequently with remibrutinib (12.7%) compared with teriflunomide (6.7%). “As a class effect for BTK inhibitors, we are observing bleeding events at a very low percentage, which are usually mild, transient, and only defining at the skin — so, it’s skin manifestations,” Wiendl said.

There were two deaths in the remibrutinib group, he added: carbon monoxide poisoning for which suicide was ruled out, and suicide in a patient with a previous history of psychiatric illness. Both deaths were considered unrelated to the drug.

Remibrutinib is being studied for other immune-mediated conditions, including hidradenitis suppurativa and food allergy. Drugmaker Novartis said it plans to seek regulatory approval for the drug in relapsing MS globally.

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