Latest Data on Evobrutinib, New MS Therapy Targeting B Cells

May 13, 2019

Further data from the phase 2 trial of evobrutinib (Merck Serono), a novel multiple sclerosis (MS) drug targeting B cells, has been reported showing a significant reduction in enhancing MRI lesions with one of the doses tested.

Preliminary results from the study were presented and reported by Medscape Medical News at last year's European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) meeting. Final results were presented at last week's American Academy of Neurology (AAN) 2019 Annual Meeting and simultaneously published online May 10 in The New England Journal of Medicine.

"Evobrutinib at a dose of 75 mg once daily, but not at doses of 75 mg twice daily or 25 mg once daily, reduced the total number of enhancing MRI lesions, as compared with placebo, at weeks 12 through 24," report the authors, led by Xavier Montalban, MD, Vall d'Hebron University Hospital, Barcelona, Spain, and St Michael's Hospital, University of Toronto, Canada, in the NEJM paper.

"Treatment with evobrutinib at any dose had no effect on the annualized relapse rate or disability progression and was associated with elevations in liver aminotransferase levels," they note, adding that "the adoption of hepatic risk-mitigation strategies and stopping rules in future clinical trials may be appropriate."

"Longer and larger trials are required to determine the effect and risks of evobrutinib in patients with multiple sclerosis," they conclude.

Commenting on the study results for Medscape Medical News, Jeff Cohen, MD, Cleveland Clinic, who was not involved in the study, said the fact that evobrutinib is an oral medication and has a novel mechanism of action makes it of interest.

"The drug deserves further study but, based on these results, it does not appear as efficacious as other, currently available medications," Cohen added.

Montalban and colleagues explain that evobrutinib is a selective, oral inhibitor of Bruton's tyrosine kinase (BTK) that blocks B-cell activation and cytokine release, which are involved in the immunopathological features of multiple sclerosis.

The drug has previously been described as inhibiting pathogenic functions of B cells without killing them, and therefore may represent a more benign approach compared with the current B-cell depleting therapies including the anti-CD20 antibodies like ocrelizumab.

The current study included 267 patients with relapsing-remitting MS (87%) or secondary progressive MS with superimposed relapses (13%), and a score of no more than 6 on the Expanded Disability Status Scale (EDSS).

They were randomized to one of five groups: placebo, evobrutinib (25 mg once daily, 75 mg once daily, or 75 mg twice daily), or dimethyl fumarate (DMF) as a reference.

The mean number of gadolinium-enhancing lesions at baseline was 1.54, and the mean EDSS score at baseline was 3.3. The patients' disease characteristics at baseline were similar across the trial groups.

The primary endpoint was the total (cumulative) number of gadolinium-enhancing lesions identified on T1-weighted magnetic resonance imaging at weeks 12, 16, 20, and 24.

Results showed a significant reduction versus placebo on this endpoint with the evobrutinib 75 mg once daily dose, but not with the other two doses.

Cumulative Gadolinium-Enhancing Lesions at 12, 16, 20, and 24 Weeks

Group

Cumulative Number of Gadolinium -Enhancing Lesions (Mean)

Rate Ratio (95% Confidence Interval)

Adjusted P Value vs Placebo

Placebo

3.85

N/A

N/A

Evobrutinib 25 mg Daily

4.06

1.45 (0.72 - 2.91)

.32

Evobrutinib 75 mg Daily

1.69

0.30 (0.14 - 0.63)

.005

Evobrutinib 75 mg Twice Daily

1.15

0.44 (0.21 - 0.93)

.06

DMF

4.78

N/A

N/A

 

Key secondary end points included the annualized relapse rate and change from baseline in the score on the EDSS.

There was no significant difference in unadjusted annualized relapse rate at week 24.

Annualized Relapse Rate at Week 24

Group

Unadjusted Annualized Relapse Rate at Week 24

Rate Ratio (95% Confidence Interval)

Placebo

0.37

N/A

Evobrutinib 25 mg Daily

0.57

1.66 (0.67 - 4.09)

Evobrutinib 75 mg Daily

0.13

0.31 (0.08 - 1.20)

Evobrutinib 75 mg Twice Daily

0.08

0.23 (0.05 - 1.09)

DMF

0.20

N/A

 

There was no significant change from baseline in the EDSS score in any of the groups.

Hepatic Enzyme Elevations

The most commonly observed adverse events of any grade that were associated with evobrutinib were nasopharyngitis and increases in levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lipase. Patients with elevations in aminotransferase levels were asymptomatic, and the elevations were reversible.

Discontinuation owing to an adverse event was seen in 11% of the evobrutinib 75 mg once-daily group and 13% of the 75 mg twice-daily group. Most of the discontinuations were due to protocol-mandated withdrawals for elevations in levels of ALT, AST, and lipase.

The authors point out that limitations of the study include that the population was older, the disease duration was longer, and fewer patients had had relapses within 2 years before baseline compared with other trials in MS.

"These observations may have been related to the inclusion of patients with secondary progressive multiple sclerosis with superimposed relapses and a relatively high baseline EDSS score at trial entry," they say.

The study was funded by EMD Serono. Montalban reports nonfinancial support from Merck Serono, during the conduct of the study; personal fees and nonfinancial support from Biogen, Novartis, Sanofi-Genzyme, Teva Pharmaceuticals, Roche, Celgene, Actelion, Excemed, and Merck Serono, outside the submitted work.

N Eng J Med. Published online May 10. Abstract

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