Evobrutinib Reduced Signs of Active Inflammation in Patients With Multiple Sclerosis

Patients with relapsing multiple sclerosis (MS) who received 75 milligrams of evobrutinib once a day had significantly fewer gadolinium-enhancing lesions, which signal active inflammation, than those who received placebo, according to a study in the New England Journal of Medicine.

“Bruton’s tyrosine kinase (BTK), a member of the Tec family of kinases, transmits signals through a variety of receptors in B cells and myeloid cells, so it presents a rational target in multiple sclerosis,” researchers said. The efficacy of evobrutinib, a selective oral BTK inhibitor, was examined as treatment for MS as it, “has been shown to inhibit B-cell activation both in vitro and in vivo.”

Researchers conducted a double-blind, randomized, phase 2 trial from March 2017 through July 2018 at 56 centers in Europe and Russia. To meet inclusion criteria, patients had to be between 18 to 65 years old with relapsing-remitting MS or secondary progressive MS with superimposed relapses and scores lower than 6 on the Expanded Disability Status Scale (EDSS). A total of 267 patients, 87% with relapsing-remitting MS and 13% with secondary progressive MS with superimposed relapses, were included in the study. All patients were white, with a mean age of 42 years, and 69% were women. Participants were assigned to 1 of 5 groups after a 4-week screening period. The groups were:

• Placebo
• Open-label dimethyl fumarate (DMF)
• Evobrutinib 25 milligrams once-daily
• Evobrutinib 75 milligrams once-daily
• Evobrutinib 75 milligrams twice-daily

Beginning at week 12, trial visits were scheduled every 4 weeks after screening to assess magnetic resonance imaging results. Clinical disease activity and relapse assessment were also evaluated at unscheduled visits for new or worsening neurologic symptoms.

The study’s primary endpoint was the cumulative number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imagining at weeks 12, 16, 20, and 24. Secondary endpoints included the annual relapse rate as well as the change from baseline in EDSS scores. In the study, qualified relapses were defined as new, worsening, or recurrent neurologic symptoms, preceded by a stable or improving neurologic status of at least 30 days, that were attributed to MS and lasted for a minimum of 24 hours without fever, infection, or adverse reaction to a prescribed medication.

Researchers found the total mean number of gadolinium-enhancing lesions, ± standard deviation, during weeks 12 through 24 in each group were:

• 3.85±5.44 for those who received placebo
• 4.78±22.05 for those who received DMF
• 4.06±8.02 for those who received 25 milligrams of evobrutinib
• 1.69±4.69 for those who received 75 milligrams of evobrutinib once-daily
• 1.15±3.70 for those who received 75 milligrams of evobrutinib twice-daily group

The baseline adjusted rate ratios for the total number of lesions over time, compared with placebo were:

• 1.45 in the group that received 25 milligrams of evobrutinib
• 0.30 in the group that received 75 milligrams of evobrutinib once-daily
• 0.44 in the group that received 75 milligrams of evobrutinib twice-daily

The unadjusted annual relapse rate at week 24 was:

• 0.37 in the placebo group
• 0.20 in the DMF group
• 0.57 in the evobrutinib 25-milligram group
• 0.13 in the evobrutinib 75-milligram once-daily group
• 0.08 in the evobrutinib 75-milligram twice-daily group

At week 24, the percentage of patients who were relapse-free was:

• 77% in the placebo group
• 89% in the DMF group
• 74% in the evobrutinib 25-milligram group
• 88% in the evobrutinib 75-milligram once-daily group
• 87% in the evobrutinib 75-milligram twice-daily group

The percentages were found to be similar at 48 weeks. Researchers determined that there was no significant effect of trial group on the change from baseline in the EDSS score.

Researchers concluded patients assigned to the group that received 75 milligrams of evobrutinib once-daily had significantly fewer gadolinium-enhancing lesions during weeks 12 through 24 than those who received placebo. They determined that there was no significant difference, compared to placebo, for the group that received 25 milligrams of evobrutinib or the group that received 75 milligrams of evobrutinib twice-daily. They also observed no significant differences in the annual relapse rate or disability progression at any dose.

Researchers suggest that larger and more lengthy trials are required to determine the risks and effects of evobrutinib in patients with MS.

Reference

Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. 2019. doi: 10.1056/NEJMoa1901981.