Novel Anti-B-Cell Therapy Looks Promising in MS

October 18, 2018

BERLIN — A new and novel oral drug therapy for multiple sclerosis that targets B-cell activation has shown promising results in its first efficacy study.

Evobrutinib (Merck Serono) is the first of a new class of agents that inhibit the enzyme Bruton's tyrosine kinase (BTK), which is believed to bring about some of the pathologic activity of B cells and macrophages.

"Evobrutinib primarily acts on B cells without depleting them. Rather, it inhibits pathogenic functions of B cells involved in autoimmune diseases like multiple sclerosis," one of the clinicians involved in the current study, Martin Weber, MD, Institute of Neuropathology at University Medical Center Göttingen, Germany, explained to Medscape Medical News.

"It could be thought of as a more benign approach to targeting B cells compared with the current B-cell depleting therapies (the anti-CD20 antibodies like ocrelizumab). The hope is that it will achieve similar benefits without the necessity of depleting all the B cells, and it also has an additional effect on macrophages," he added.

Jerry Wolinsky, MD, University of Texas Health Science Center at Houston, who was also involved in the study, called this "an interesting new approach."

"Because this drug has a dual mechanism on both B cells and macrophages it is probably doing something that the anti-CD20 antibodies, which target B cells alone, can't do, but we won't be able to see evidence of that in this small phase 2 study," he told Medscape Medical News.

However, Wolinksy said the new drug had "some qualities that may make it more attractive" than the anti-CD20 antibodies, even if it just targets B cells. "We can turn it on and off quite quickly. Just stop it for a few days and the B cells are back in action. This could be useful if a patient develops certain complications or an opportunistic infection."

The current phase 2 study was presented here at the 34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018 by Xavier Montalban, MD, professor of medicine at the University of Toronto, Ontario, Canada. 

For the study, 267 patients with relapsing-remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS) with superimposed relapses were randomized to three different doses of evobrutinib (25 mg once daily, 75 mg once daily, or 75 mg twice daily) or placebo or open-label dimethyl fumarate (240 mg twice daily; reference group).

The primary endpoint was the sum of T1 gadolinium enhanced (T1 Gd+) lesions at weeks 12, 16, 20, and 24.

Such lesions were reduced with the two highest doses of evobrutinib — 75 mg once daily and 75 mg twice daily. A dose-response effect was observed, with a greater effect with the 75 mg twice daily dose. A lower dose of 25 mg once daily showed no difference compared with placebo.

Mean Total T1 Gd+ Lesions (Weeks 12 to 24)

Endpoint Placebo Evobrutinib 25 mg
Once Daily
Evobrutinib 75 mg
Once Daily
Evobrutinib 75 mg
Twice Daily
Number of Lesions 3.85 4.06 1.69 1.15
P value vs Placebo .295 .001 .031

The dimethyl fumarate group actually had a higher mean number of T1 Gd+ lesions (4.78) than placebo, but Montalban said this result was driven by one major outlier.

Secondary endpoints suggested substantial reductions in annualized relapse rate and number of T2 lesions with the two higher doses.

Montalban said the treatment was "overall well tolerated" and none of the three doses investigated was associated with serious infections or lymphopenia.

Increases in laboratory measures (alanine aminotransferase, aspartate aminotransferase, lipase) were observed but these were reversible and not associated with any symptoms.

"The results of this study highlight the potential of BTK inhibitors as an oral disease-modifying treatment for relapsing MS," Montalban concluded.

"There are important thresholds of B-cell activation," Weber added. "With BTK inhibition, we believe we are only cutting off the highest level of B-cell activation, which we hope inhibits autoreactivity without inhibiting the ability to fight pathogens."

Wolinksy gave additional examples of situations where it may be useful to be able to bring back B-cell activity quickly.

"There is the awkward question of what to do with a patient who is failing rituximab or ocrelizumab, as it can take many months for the cell populations to come back. With this new drug, the B cells are still there — just inactivated. Once we get beyond the half-life of the drug — a few days — the cells are active again," he said.

"Another possible issue with B-cell depleting therapies is: What do we do about influenza vaccination or other vaccinations that might be necessary?" he added. "With this new drug we could turn the switch off for a few weeks so we can get an antibody response."

Edward Fox, MD, PhD, MS Clinic of Central Texas, who was not involved in the study, said he was pleased with the results. "They certainly justify going to phase 3," he told Medscape Medical News.

He suggested that in theory an oral agent that inactivated B cells such as evobrutinib could be used in combination with cell-depleting agents in an induction/maintenance regimen. "We could have a scenario where the B-cell depleting agents like ocrelizumab or other anti-CD20 antibodies are given first as an induction treatment, and then a BTK inhibitor could be used as a maintenance therapy long-term."

Evobrutinib is also in clinical development as a treatment for rheumatoid arthritis and systemic lupus erythematosus.

The current study was funded by Merck Serono. Montalban, Weber, and Wolinsky have all reported receiving travel funding and/or speaker honoraria from the company.  

34th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2018. Abstract 322. Presented October 12, 2018.

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