FDA puts partial hold on trials of Merck KGaA’s evobrutinib in MS

Use of BTK inhibitor linked to elevated liver enzymes in 2 patients

Patricia Inacio, PhD avatar

by Patricia Inacio, PhD |

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The U.S. Food and Drug Administration (FDA) has placed a partial clinical hold on ongoing trials of evobrutinib, Merck KGaA’s experimental BTK inhibitor for relapsing forms of multiple sclerosis (MS).

The decision was based on two cases of patients in Phase 3 clinical trials of evobrutinib who were found to have elevations in their liver enzymes. Merck KGaA is testing the therapy in the MS clinical trials EVOLUTION RMS1 (NCT04338022) and EVOLUTION RMS2 (NCT04338061).

These abnormal values were indicative of drug-related liver damage, but neither patient developed symptoms nor required medical intervention, Merck KGaA (known as as EMD Serono in the U.S. and Canada), said in a press release. Both patients experienced a normalization in their liver enzymes after discontinuing treatment, the company said.

The hold now precludes the dosing of new patients and also prevents the company from giving the inhibitor to people who have been on treatment for less than 70 days. Still, the decision will have limited impact on the MS trials, as both have completed enrollment and all participants have been on treatment for longer than 70 days.

The company will now examine the available clinical trial data to determine if these patients had any factors that could predispose them to liver damage while on evobrutinib. It also will work closely with the FDA to determine the best path forward for the drug’s clinical program.

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Trials for other BTK inhibitors also have been put on hold

“The Phase III EVOLUTION clinical trial program of evobrutinib has been closely monitored by an Independent Data Monitoring Committee, including hepatologists, since initiation,” Merck KGaA wrote in the release.

“In close collaboration with external experts as well as the Independent Data Monitoring Committee for the trials, Merck is assessing the potential contributory role of predisposing factors to the liver injury,” the company added.

Evobrutinib is an investigational oral MS therapy that blocks the activity of the Bruton’s tyrosine kinase (BTK) protein, which is essential for the function of certain immune cells known to drive autoimmune responses in MS.

It was previously tested in a Phase 2 clinical trial (NCT02975349) involving 267 people with relapsing types of MS.

Participants were randomly assigned to three different doses of evobrutinib (25 mg once daily, 75 mg once daily, or 75 mg twice daily), a placebo, or the approved medication Tecfidera (dimethyl fumarate).

Results showed that nearly 80% of patients given the highest dose of evobrutinib experienced no relapses over the trial’s 48 weeks, a period of nearly one year. The two higher doses also led to significant reductions in the number of lesions with active inflammation compared with the placebo group.

While the findings supported the therapeutic benefits of evobrutinib, the most common side effects were increases in the levels of liver enzymes, indicating possible injury to the liver. As in the cases of the two patients reported in the Phase 3 trials, these side effects were asymptomatic and reversible.

In close collaboration with external experts as well as the Independent Data Monitoring Committee for the trials, Merck is assessing the potential contributory role of predisposing factors to the liver injury.

Such adverse events also have been reported with other BTK inhibitors. Sanofi and Biogen, which are also developing BTK inhibitors for MS, have also seen their trials of tolebrutinib and orelabrutinib placed on partial hold.

Meanwhile, the EVOLUTION clinical program will continue to assess the safety and effectiveness of evobrutinib versus Aubagio (teriflunomide) in more than 2,200 patients with relapsing-remitting MS or active secondary progressive MS.

The trials’ primary goal is to determine the impact of evobrutinib on the rate of relapses after up to three years of treatment. Secondary measures include time to confirmed disability progression, changes in fatigue and physical function, and number of lesions.

Both trials are estimated to conclude in 2026, and top-line data is expected by the end of 2023.

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