Phase 3 studies of BTK inhibitor evobrutinib fail to meet main goal

The Phase 3 EVOLUTION clinical trials have failed to demonstrate that evobrutinib is more effective than the approved medication Aubagio (teriflunomide) at preventing disease flares in people with relapsing types of multiple sclerosis (MS).

The findings, which were shared by the drug’s developer Merck KGaA (known as EMD Serono in North America), mean that both trials failed to meet their primary goal. The company now will continue to evaluate the trials’ full data, which will be presented and published later.

“While we are very disappointed with the results, we continue to advance our strategy in healthcare with a focus on progressing our marketed portfolio and internal pipeline, complemented by external innovation, with the aim of bringing more medicines to patients, faster,” Danny Bar-Zohar, MD, said in a press release. Bar-Zohar is global head of research and development and chief medical officer for the healthcare business sector at Merck KGaA.

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“I would like to sincerely thank all patients participating in the trials, their caregivers and our network of dedicated clinical investigators,” Bar-Zohar added.

Evobrutinib is an oral therapy designed to block the activity of a protein called Bruton’s tyrosine kinase or BTK, which plays a central role in the inflammatory activation of certain immune cells including B-cells and microglia. By inhibiting BTK, the therapy aims to reduce the inflammation in the brain and spinal cord that drives MS.

“With evobrutinib, our aim was to address the significant unmet need of smoldering MS in addition to strong relapse control for people living with this condition,” Bar-Zohar said.

Merck sponsored a pair of Phase 3 clinical trials, called EVOLUTION RMS1 (NCT04338022) and EVOLUTION RMS2 (NCT04338061). They tested  evobrutinib, at a 45 mg dose twice daily, against Aubagio in more than 2,200 people with relapsing-remitting MS or active secondary progressive MS.

The trials hoped to show that patients given evobrutinib would have fewer relapses (flares when symptoms worsen suddenly) than those given the older medication over about two years of treatment.

Comparable relapse rates

However, results now showed that annual relapse rates for both therapies were comparable. In one trial, the average annual relapse rate was 0.15 relapses per year for evobrutinib, and 0.14 for Aubagio. In the other study the annual rate was 0.11 relapses per year for both medications.

According to Merck, the relapse rates seen with Aubagio in this study are somewhat lower than rates seen with the drug in other clinical trials. The company said that the safety of evobrutinib in the Phase 3 trials was consistent with prior studies, but did not provide specifics.

Long-term data from a previous Phase 2 trial (NCT02975349), which enrolled 267 people with relapsing MS, showed an annual relapse rate of 0.12 relapses per year among patients given a 75 mg twice-daily dose of evobrutinib for four years.

Earlier this year, the U.S. Food and Drug Administration (FDA) put a partial hold on clinical testing of evobrutinib after two patients showed signs of possible liver damage. The move prevented dosing of additional patients in the trials — though at that point both studies had already finished recruitment. Similar holds related to liver damage also have been put on clinical programs for other experimental BTK inhibitors.