Patients with relapsing multiple sclerosis (MS) who received evobrutinib, a Bruton's tyrosine kinase inhibitor (BTK), showed fewer T1 gadolinium-enhancing lesions in the brain, than those who received placebo, according to the results of a double-blind, randomized, phase 2 trial published online May 10 in the New England Journal of Medicine.
Evobrutinib is a dual action-mode oral investigational therapy that regulates the function of B cells and myeloid cells. It inhibits the protein BTK that transmits signals through a variety of receptors in B cells and myeloid cells. Activated B cells and innate immune cells play a role in the pathogenesis of MS, and BTK inhibition may alter these biological pathways.
Evobrutinib has previously been found effective in experimental autoimmune encephalomyelitis, an animal model of brain inflammation.
Currently, BTK inhibitors are being investigated in several types of autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis.
In the current trial, patients who received 75 mg of evobrutinib once daily had significantly fewer gadolinium-enhancing lesions during weeks 12 to 24 than did those who received placebo (mean 1.69 vs 3.85).
The researchers, led by Xavier Montalban, MD, PhD, of Vall d'Hebron University Hospital in Barcelona, and colleagues, reported no significant difference in those who took evobrutinib at 25 mg once daily or the 75-mg twice daily compared with placebo. There were no significant changes in the annualized relapse rates or disability progression at any dose.
To investigate the effects of evobrutinib on patients with RRMS, the researchers enrolled and randomized 267 RRMS patients 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 as reference. All patients were white and had a mean age of 45 years old; 69 percent were women. A total of 261 patients were included in the modified intention-to-treat analysis, which consisted of those who had been randomized to a treatment arm and had had an MRI at baseline and at least once after baseline.
The primary endpoint was the cumulative number of lesions identified by T1-weighted MRI at weeks 12, 16, 20, and 24.
The mean total number of gadolinium-enhancing lesions at weeks 12 to 24 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 mg in the evobrutinib 75 mg twice daily group, and 4.78 in the dimethyl fumarate group.
Secondary outcomes included the 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.
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. As compared with placebo, no significant effect on the annualized relapse rate was found in the evobrutinib groups.
Also, the investigators observed no significant effect from baseline in the EDSS score. Patients had an average EDSS score of around 3.0 to 3.5 at baseline.
The highest rate of serious adverse events occurred in patients treated with evobrutinib 75 mg twice daily (7 percent). Grade 3 or 4 adverse events most common were among patients in the evobrutinib 75 mg once daily group (13 percent), the evobrutinib 75 mg twice daily group (15 percent), and the DMF group (13 percent).
Nasopharyngitis and increases in levels of alanine aminotransferase, aspartate amino-transferase, and lipase were commonly associated with evobrutinib, the researchers reported. Those with elevations in liver aminotransferase values were asymptomatic and the elevations were reversible.
Overall, "longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis," the researchers concluded.
Study limitations included an older MS patient population, longer disease duration, and fewer patients with relapses within two years before baseline, as compared with other MS trials. In addition, only white patients were included in the study, limiting the generalizability of the findings to other patient populations. Lastly, the trial focused on MRI disease activity as an outcome measure.
EMD Serono Research and Development Institute supported the study.
Dr. Montalban and co-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.
Link up for More Information:
Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med 2019; Epub 2019 May 10.