Dr Xavier MontalbanXavier Montalban, MD, PhD
In a phase 2 trial, a once-daily, 75-mg dose of evobrutinib, an oral Bruton’s tyrosine kinase (BTK) inhibitor, has been shown to be associated with significantly fewer gadolinium-enhancing (Gd+) lesions from week 12 to week 24 compared to placebo in adults with relapsing multiple sclerosis (MS).1

Ultimately, there were 3 groups of the study drug assessed—75 mg in once-daily and twice-daily doses, and a 25-mg dose—as well as a placebo group, and an open-label dimethyl fumarate reference group. From weeks 12 to 24, the baseline adjusted rate ratios for the total number of lesions over time compared with placebo were 1.45 (P  = .32), 0.30 (P = .005), and 0.44 (P = .06) in the 25-mg, 75-mg once daily, and 75-mg twice daily groups, respectively.

“These positive Phase II evobrutinib data are a great example of the strength of our pipeline and commitment to developing new, innovative treatments in multiple sclerosis,” said Luciano Rossetti, MD, head of Global Research & Development, Merck KGaA, in a statment.2 “As a leader in autoimmune diseases and MS we are proud of this in-house discovery at Merck KGaA, Darmstadt, Germany. We look forward to continuing to investigate the potential of evobrutinib as we continue to address unmet patient needs in MS care.”

The data were presented at the 2019 American Academy of Neurology (AAN) Annual Meeting in Philadelphia, Pennsylvania, and simultaneously published in the New England Journal of Medicine. Overall, 267 patients were randomized: 54 to the placebo group, 52 to evobrutinib 25-mg, 53 to evobrutinib 75-mg once daily, 54 to evobrutinib 75-mg twice daily, and 54 to the comparator group.

From weeks 12 to 24, the total number of Gd+ lesions, the primary end point, were 3.85 ±5.44 in the placebo group, 4.06 ±8.02 in the evobrutinib 25-mg group, 1.69 ±4.69 in the evobrutinib 75-mg once-daily group, 1.15 ±3.70 in the evobrutinib 75-mg twice-daily group, and 4.78 ±22.05 in the dimethyl fumarate group.

At Week 24, patients randomized to 25-mg, 75-mg once daily, and 75-mg twice-daily evobrutinib experienced a respective total of 13, 3, and 2 relapses. In comparison, the dimethyl fumarate and placebo groups experienced 5 and 9 relapses, respectively.

The unadjusted annualized relapse rate (AAR) was 0.37 in the placebo group (95% CI, 0.17 to 0.70), 0.57 in the evobrutinib 25-mg group (95% CI, 0.30 to 0.97), 0.13 in the evobrutinib 75-mg once-daily group (95% CI, 0.03 to 0.38), 0.08 in the evobrutinib 75-mg twice-daily group (95% CI, 0.01 to 0.30), and 0.20 in the dimethyl fumarate group at week 24. Similar results were seen at Week 48.

"Building on our initial analysis at 24 weeks, these new data further demonstrate the potential role of evobrutinib in relapsing multiple sclerosis, subject to further clinical investigation,” said study author Xavier Montalban, MD, PhD, professor of Medicine, Department Division Director, Neurology, University of Toronto, in a statement.

Additionally, the 24-week secondary outcome of the lesion rate ratio for new or enlarging lesions on T2-weighted MRI was 0.42 (95% CI, 0.20 to 0.87) in the evobrutinib 75-mg twice-daily group, showing a greater response than the other study drug groups.

Montalban, the director of the MS Centre at St. Michael’s Hospital, Canada, and Chairman & Director Neurology-Neuroimmunology Department & Neurorehabilitation Unit, Multiple Sclerosis Centre of Catalonia, Vall d'Hebron University Hospital, Barcelona, Spain, added that the BTK inhibitor is the first of its kind “to demonstrate clinical proof of concept in multiple sclerosis. We are pleased that these 48-week data further support our continued clinical development of evobrutinib and investigation into its efficacy for patients with MS.”

No effect of significance was observed on the change in Expanded Disability Status Scale score from baseline.

As for adverse events (AEs), they occurred in 30 (56%) patients in the placebo group, 28 (54%) patients in the 25-mg group, 35 (66%) patients in the 75-mg QD group, 34 (63%) patients in the 75-mg BID group, and 35 (65%) patients in the reference group. The highest rate of serious AEs occurred in the high-dose twice-daily group (7%). The high-dose twice-daily group also had the highest rate of Grade 3 or 4 AEs, at 15%, followed by the once-daily and dimethyl fumarate groups at 13% each. Elevations in levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase values were observed with evobrutinib, as well as nasopharyngitis.

“Patients with elevations in aminotransferase levels were asymptomatic, the elevations were reversible, and no cases fell within the criteria of Hy’s law for drug-induced liver injury, as defined by the Food and Drug Administration,” Montalban and colleagues wrote.

The investigators concluded that longer and larger studies will be needed in order to determine the effect and risks of evobrutinib in patients with MS.

For more coverage of AAN 2019, click here.
REFERENCES
1. Montalban X, Arnold DL, Weber MS, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med. Published online May 10, 2019. doi: 10.1056/NEJMoa1901981.
2. Positive Phase II Data Further Highlights Clinical Proof of Concept for Evobrutinib, First Oral Bruton´s Tyrosine Kinase (BTK) Inhibitor to Report Positive Phase II Clinical Results in MS [press release]. Darmstadt, Germany: Merkc KGaA; Published May 10, 2019. emdgroup.com/en/news/pp2-data-further-highlights-clinical-proof-of-concept-for-evobrutinib-10-05-2019.html. Accessed May 14, 2019.