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WEST PALM BEACH, Fla. -- The investigational oral Bruton's tyrosine kinase (BTK) inhibitor evobrutinib failed to distinguish itself from teriflunomide (Aubagio) in two phase III trials of relapsing multiple sclerosis (MS) patients.

Annualized relapse rates (ARRs) were similar between the agents in both the and studies, reported Xavier Montalban, MD, PhD, of Vall d'Hebron Hospital in Barcelona, during a late-breaker oral presentation at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) forum.

In the first study, the ARR was 0.15 with evobrutinib and 0.14 with teriflunomide. In the second study, the ARR was 0.11 with both drugs.

Furthermore, there were few differences in secondary endpoints in the studies, each of which enrolled more than 1,100 patients and were similarly designed, Montalban noted.

"Evobrutinib did not demonstrate superior efficacy versus teriflunomide on the primary or secondary endpoints," he said, noting that the adverse events were generally well-balanced between the groups, although there were more cases of asymptomatic liver enzyme increases among the patients on evobrutinib. In 2023, the FDA placed a on the phase III trials due to laboratory values that suggested drug-induced liver injury.

In a phase II study, evobrutinib 75 mg showed significantly fewer gadolinium-enhancing lesions in relapsing MS.

The disappointing results of the phase III trials triggered questions from the ACTRIMS audience as to whether the studies should have been designed as noninferiority trials, rather than superiority trials. Montalban suggested that a noninferiority trial would have shown that evobrutinib was as efficacious as teriflunomide, just more toxic.

Natasha Hameed, MD, of Northwell Health Long Island Jewish Hospital in New Hyde Park, New York, told 番茄社区app, "we were all disappointed by these results," noting that because evobrutinib showed the ability to cross the blood-brain barrier, many had hoped it would provide better outcomes.

"There still may be some subgroups that do benefit, which is why the researchers are looking further at these patients," she said.

In the studies, 2,290 MS patients, most of whom had relapsing-remitting disease, across 52 countries were randomly assigned to receive evobrutinib 45 mg twice a day and placebo once daily or teriflunomide 14 mg once daily plus placebo twice a day from July 2020 to November 2023.

The primary endpoint was ARR determined after up to 156 weeks on the study. Key secondary endpoints were the numbers of new gadolinium-enhancing lesions, new or enlarging T2 lesions, and serum neurofilament light (NfL) concentrations at 12 weeks. The curves overlapped in these categories showing no statistical advantage for either drug, Montalban said.

In evolutionRMS 1, the researchers assigned 560 patients to evobrutinib; mean age was 37, 67.3% were women, 75.9% were from Eastern Europe, and 65.4% were naive to treatment. The teriflunomide group of 564 patients had a mean age of 38, 66.3% were women, 75.5% were from Eastern Europe, and 62.4% were naive to treatment. Both groups had a mean Expanded Disability Status Scale (EDSS) score of 2.7.

In evolutionRMS 2, 1,166 patients were randomized 1:1 to evobrutinib or teriflunomide. Mean age in the evobrutinib group was 36, 70.8% were women, and 76.2% were from Eastern Europe. Mean EDSS was 2.8, and 59.7% were treatment-naive. For the teriflunomide group, mean age was 37, 63.5% were women, and 76.3% were from Eastern Europe; mean EDSS was 2.7, and 66% were naive to treatment.

In the pooled analysis, 85.6% of patients on evobrutinib reported adverse events compared with 87.2% of patients on teriflunomide. Serious adverse events were observed in 7.5% and 5.6%, respectively. Twelve percent of patients on evobrutinib had treatment-emergent adverse events that led to discontinuation of the drug versus 10.6% of teriflunomide patients.

Montalban said the research team is scrutinizing their data and additional analyses will be published in the future.

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