For physicians treating patients with multiple sclerosis (MS) and following ever-increasing research in MS, the surprise at the annual European Committee for Treatment and Research in MS (ECTRIMS) Congress was late-breaking data released on the safety and efficacy of evobrutinib (M2951; EMD Serono, Rockland, MA) for treating patients with relapsing MS.1

What Is Evobrutinib?

Evobrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor. At a dose of 75 mg once or twice daily, evobrutinib significantly reduced the number of gadolinium-enhancing brain lesions seen on patients’ MRIs at weeks 12, 16, 20, and 24 compared to patients who were given placebo in a phase 2 study. Because BTK affects both the adaptive and innate immune systems by inhibiting B-cell proliferation and antibody/cytokine release, BTK inhibition has potential not only for treating patients with MS but also for those with other autoimmune diseases.

Study Design

Patients with relapsing forms of MS (both relapsing-remitting and secondary-progressive with relapses) were enrolled in a randomized double-blind phase 2 study of evobrutinib 25 mg daily, 75 mg daily, 75 mg twice a day, matching placebo, or parallel active treatment open-label dimethyl fumarate. Following the first 48 weeks, all subjects were switched over to evobrutinib 75 mg daily. The primary endpoint was cumulative T1 gadolinium-enhancing lesions on brain MRI at weeks 12, 16, 20 and 24. Key secondary endpoints include annualized relapse rate (ARR) at week 24 and safety, and other secondary endpoints include clinical and MRI measures and the safety and efficacy of dimethyl fumarate.

Efficacy Results

Subjects given 75-mg evobrutinib once or twice daily had fewer T1 gadolinium-enhacing lesions on brain MRI compared to those given placebo. Although this phase 2 trial was not powered to demonstrate statistically significant improvement in ARR, there was a trend of reduced ARR from 0.37 (placebo) to 0.13 and 0.08 (75 mg evobrutinib once or twice daily, respectively).

Safety Results

There were no serious adverse events reported in the subjects treated with evobrutinib. Only one subject who received evobrutinib 75 mg twice a day had a grade 2 lymphopenia (between 0.8 and 0.9 x 109/L). Although more subjects treated with evobrutinib had elevations of the liver enzyme alanine aminotransferase (ALT), they were all asymptomatic.

Future Directions

Analyses of data from the first 24 weeks of this phase 2 study, including subgroup analyses (eg, how did the subjects with secondary progressive do vs those with relapsing-remitting MS?) will continue to be released. A phase 3 study protocol to move forward with testing the efficacy and safety of evobrutinib in people with relapsing forms of MS is in development.

1. Montalban X, Arnold DL, Weber MS, et al. Primary analysis of a randomised, placebo-controlled, phase 2 study of the Bruton’s tyrosine kinase inhibitor evobrutinib (M2951) in patients with relapsing multiple sclerosis. Late breaking abstract 322: October 12, 2018. 34th Congress of the European Committee for Treatment and Research in MS: Berlin, Germany.