Merck KGaA’s BTK Inhibitor Fails Phase 3 MS Studies

 Germany’s Merck KGaA on Tuesday announced that its investigational BTK inhibitor evobrutinib did not meet its primary efficacy endpoint in the Phase III evolutionRMS 1 and evolutionRMS 2 trials in relapsing multiple sclerosis.

In evolutionRMS 1, patients treated with evobrutinib saw an annualized relapse rate (ARR) of 0.11, similar to those patients treated with Sanofi’s Aubagio (teriflunomide) tablets. In evolutionRMS 2, ARR following evobrutinib treatment was 0.15 versus 0.14 in counterparts on Aubagio. Both treatment effects fell short of statistical significance, according to Merck KGaA’s announcement.

EvolutionRMS 1 and evolutionRMS 2 are randomized, parallel-group, double-blinded and active-controlled studies, and both fall under Merck KGaA’s Phase III EVOLUTION clinical development program for evobrutinib in relapsing multiple sclerosis (RMS), including relapsing-remitting disease or secondary progressive MS with relapses.

Patients in the program were given 45 mg of evobrutinib two times a day, while Aubagio was administered at a 14-mg once-daily dose. Treatment lasted for at least 24 weeks and could run up to 156 weeks.

Merck KGaA said the ARR rates for Aubagio in EVOLUTION were “lower than reported in other recent Phase III studies.” The company will “complete a full evaluation of the data from the EVOLUTION clinical trials,” working toward a future presentation or publication.

In terms of safety, evobrutinib’s overall profile was consistent with what had been established in its Phase II development program.

Evobrutinib is an orally available and highly selective inhibitor of the BTK enzyme, which plays a key role in the development and activation of B cells. This mechanism of action allows evobrutinib to modulate B cell responses, including their release of antibodies and cytokines, as well as their proliferation. Evobrutinib is also designed to be able to penetrate the central nervous system.

In April 2023, the FDA placed EVOLUTION under partial clinical hold after two patients treated with BTK blocker showed signs of liver injury. The regulatory pause formally froze new enrollment into the program. However, at the time, the company noted that EVOLUTION was fully enrolled and participants had already been treated with evobrutinib for more than 70 days, adding that the clinical hold was unlikely to derail EVOLUTION’s timeline.

Evobrutinib’s Phase III failure on Tuesday demonstrates the difficulties of developing BTK inhibitors. Last week, the FDA placed Roche’s candidate fenebrutinib on partial clinical hold after the pharma detected potential cases of liver injury.

In December 2022, Biogen and InnoCare’s orelabrutinib was put on regulatory pause, also for liver injury. Biogen abandoned the candidate in February 2023.

https://www.biospace.com/article/merck-kgaa-s-btk-inhibitor-fails-phase-iii-multiple-sclerosis-studies/