This marks the first time a BTK inhibitor showed a clinical proof-of-concept in relapsing MS.
Fernando Dangond, MD, MBA, the Head of Global Clinical Development in Neurology at EMD Serono
Fernando Dangond, MD, MBA
Evobrutinib, an investigational and highly specific Bruton’s Tyrosine Kinase (BTK) inhibitor intended to treat relapsing multiple sclerosis (MS), met its primary end point in a phase II trial, reducing the number of T1 gadolinium enhancing (T1 Gd+) lesions in comparison to placebo.
The 48-week study assessed a trio of doses of evobrutinib—75-mg once daily, 75-mg twice daily, and 25-mg once daily—in comparison to placebo. Additionally, there was a non-compared, open-label reference arm with 240-mg twice daily dimethyl fumarate. The data were presented at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in Berlin, Germany.
“People are going be very excited because this is an oral treatment and it's the first in class to show that it works in MS,” Fernando Dangond, MD, MBA, the Head of Global Clinical Development in Neurology at EMD Serono (Merck KGaA), told NeurologyLive. “This class of drugs has been investigated in several for immune diseases. MS is an autoimmune disease, this is the first demonstration that this class of drugs actually works in autoimmune diseases.”
Dangond explained that the therapy has a dual mechanism of action that targets both microphages and B cells, which have been implicated in the pathogenesis of MS in recent years.
Ultimately, compared to placebo, T1 Gd+ lesions per scan were significantly reduced with both the 75-mg once-daily dose and the 75-mg twice-daily dose, with lesion rate ratios of 0.30 (P = .0015) and 0.44 (P = .0313), respectively. The 25-mg group did not observe statistical significance for this measure (rate ratio, 1.45; P = .295).
Measured at weeks 12, 16, 20, and 24, the mean total of T1 Gd+ lesions from weeks 12 to 24 was 3.85 (standard deviation [SD], 5.44) with placebo, compared to 4.06 (SD, 8.02), 1.69 (SD, 4.69), and 1.15 (SD, 3.70) in the 25-mg, 75-mg once daily, and 75-mg twice daily groups, respectively.
“We were very surprised at the magnitude of the decrease in the relapse rate for an early study,” Dangond said. “For a phase II study with a limited number of patients, we were not expecting to see such a drastic reduction in relapses accompanied, of course, by the reduction in T1 Gd+ lesions and other measures of disease activity in MS.”
Evobrutinib also resulted in a clinically relevant decrease in annualized relapse rate (ARR). A reduction in ARR was observed with evobrutinib 75-mg once-daily (0.13; P = .09) and 75-mg twice-daily (0.08; P = .06) compared to placebo (0.37), with evidence of a dose-response relationship (trend test P = .01).
"The results of this study highlight the potential of BTK inhibitors as an oral disease-modifying treatment for relapsing MS,” said Xavier Montalban, MD, a professor of medicine and the Department Division Director of Neurology at the University of Toronto, as well as Director of the MS Centre at St. Michael’s Hospital, in a statement. “These findings suggest that the dual mechanism of action of evobrutinib, which impacts pathogenic adaptive and innate immune cells in multiple sclerosis, could translate into clinical efficacy.”
Additionally, a secondary end point explored the total number of T2 lesions as assessed by MRI. From weeks 12 to 24, the mean number of new or enlarging T2 lesions was 5.96 (SD, 6.99), 6.52 (SD, 11.57), 3.41 (SD, 10.75) and 2.19 (SD, 4.72) in the placebo, 25-mg, 75-mg once daily, and 75-mg twice daily groups, respectively. Compared to placebo, new or enlarging T2 lesions per scan were significantly reduced with evobrutinib 75-mg twice-daily (rate ratio, 0.42; P = .019).
Evobrutinib was well tolerated in the trial, with no treatment-associated infections, infestations, or lymphopenia observed. The most common treatment-related adverse events (occurring >5%) included increased alanine transaminase (ALT), aspartate transaminase, and lipase in the 75 mg BID group; these events were reversible and asymptomatic. The percentage of shifts from Grade 0 to Grade 3 or greater in ALT were 1.9%, 5.7%, 2.1%, and 6.1% in the placebo, evobrutinib 25-mg, 75-mg once daily, and 75-mg twice daily groups, respectively.
1. Montalban X. Primary Analysis of a Randomised, Placebo-Controlled, Phase II Study of the Bruton’s Tyrosine Kinase Inhibitor
(M2951) in Patients with Relapsing Multiple Sclerosis. Presented at ECTRIMS 2018; October 12, 2018; Berlin, Germany.
2. Positive Late-Breaking Phase II Data Evaluating Investigational Oral The Therapy,
in RMS [press release]. Darmstadt, Germany; Merck KGaA; Published October 12, 2018. Accessed October 12, 2018.