One of three tested doses of evobrutinib, an investigational selective oral Bruton’s tyrosine kinase (BTK) inhibitor, showed significantly fewer gadolinium-enhancing lesions among relapsing multiple sclerosis (MS) patients, a phase II trial reported.
Relapsing MS patients who received 75 mg of evobrutinib once daily had significantly fewer gadolinium-enhancing lesions during weeks 12 through 24 than patients who received placebo, reported Xavier Montalban, MD, PhD, of Vall d’Hebron University Hospital in Barcelona, and colleagues.
Neither the 25-mg once-daily nor the 75-mg twice-daily dose of evobrutinib showed a significant difference compared with placebo, and there were no significant changes in annualized relapse rates or disability progression at any dose, they reported in the New England Journal of Medicine.
BTK transmits signals through a variety of receptors in B cells and myeloid cells. “We know that B cells and innate immune cells play a role in the pathogenesis of multiple sclerosis,” Montalban said in a presentation of the study at the 2019 American Academy of Neurology annual meeting. “Evobrutinib is a BTK inhibitor and therefore has a dual mode of action, not only impacting on B cells but also on myeloid cells,” he added.
BTK inhibitors also are being investigated in several types of autoimmune disease, including systemic lupus erythematosus and rheumatoid arthritis.
In this double-blind, placebo-controlled trial, Montalban and colleagues enrolled 267 relapsing MS patients, randomizing them into five treatment groups: placebo, 25 mg once daily evobrutinib, 75 mg once daily evobrutinib, 75 mg twice daily evobrutinib, or open-label dimethyl fumarate (Tecfidera) as reference. The average age of patients was about 42 and most were female. A total of 261 patients were included in the modified intention-to-treat analysis.
The primary endpoint was the cumulative number of lesions identified by T1-weighted MRI at weeks 12, 16, 20, and 24. Secondary endpoints were annualized relapse rate and change from baseline in the Expanded Disability Status Scale (EDSS), a measurement of disability on a 0 (no disability) to 10 (death due to MS) scale in 0.5-unit increments. Study participants had an average EDSS score of around 3.0 to 3.5 at baseline.
During weeks 12 through 24, the mean total number of gadolinium-enhancing lesions was 3.85 in the placebo group, 4.06 in the evobrutinib 25-mg group, 1.69 in the evobrutinib 75-mg once-daily group, 1.15 in the evobrutinib 75-mg twice-daily group, and 4.78 in the dimethyl fumarate group. Both doses of evobrutinib 75-mg showed a rapid reduction in the mean number of gadolinium-enhancing lesions; that trend was stable over the 48 weeks of the study, Montalban said.
Compared with placebo, the baseline adjusted rate ratios for the total number of lesions over time were 1.45 in the evobrutinib 25-mg group (P=0.32), 0.30 in the evobrutinib 75-mg once-daily group (P=0.005), and 0.44 in the evobrutinib 75-mg twice-daily group (P=0.06).
At week 24, the unadjusted annualized relapse rate was 0.37 in the placebo group, 0.57 in the evobrutinib 25-mg group, 0.13 in the evobrutinib 75-mg once-daily group, 0.08 in the evobrutinib 75-mg twice-daily group, and 0.20 in the dimethyl fumarate group.
Most treatment-emergent adverse events were mild or moderate. “We observed grade 3 or 4 adverse events in less than 15% of patients in any arm,” Montalban said. About 11% of patients in the evobrutinib 75-mg once-daily group and 13% in the evobrutinib 75-mg twice-daily group withdrew due to adverse events.
Events most frequently associated with evobrutinib were nasopharyngitis and increases in levels of alanine aminotransferase (ALT), aspartate amino-transferase (AST), and lipase. Patients with elevations in liver aminotransferase values were asymptomatic and the elevations were reversible.
“This is an encouraging study because it opens a brand new direction of treatment for relapsing MS,” said Robert Fox, MD, of the Cleveland Clinic, who was not involved with the study.
“Additionally, this novel class of treatment appears to have a very favorable safety profile,” Fox told MedPage Today. “Further evaluation in a phase III trial will be important to ensure that these benefits on MRI translate into a clinical benefit to our patients.”
“Evobrutinib could wind up having a niche, which could be important for patients with multiple sclerosis,” noted study co-author Jerry Wolinsky, MD, of the University of Texas Health Science Center in Houston. “While its mechanism of actions is targeted in large part at B cells, it’s also a mechanism in which myeloid precursor cells should be targeted as well.”
On the surface, this means the drug could have different effects than the anti-CD20 monoclonal antibodies now approved for relapsing and progressive MS, he added. “All of those are limited to cells that express CD20. Evobrutinib could have different effects which might be broadly based in the immune system,” Wolinsky told MedPage Today. “Until we actually see the results of a phase III study, it’s speculative in terms of whether that would be better.”
The study was funded by EMD Serono.
The authors disclosed relevant relationships with Merck Serono, Biogen, Novartis, Sanofi-Genzyme, Teva Pharmaceuticals, Roche, Celgene, Actelion, EXCEMED, the Multiple Sclerosis International Federation, and the National Multiple Sclerosis Society.