Phase 2 Clinical Trial of MK-1942, a Negative Allosteric Modulator of Metabotropic Glutamate Receptor 2, for Treatment-Resistant Depression

Purpose: To evaluate MK-1942, a negative allosteric modulator of mGluR2, for treatment-resistant depression using chronic and intermittent dosing. Methods: Randomized, double-blind, 4-week study of MK-1942 added to stable antidepressant therapy in adults with treatment-resistant depression (NCT04663321). Participants were randomized 2:1:2 to (1) daily MK-1942 titrated from 5 to 20 mg bid, (2) twice-weekly MK-1942 10 mg, or (3) placebo. The endpoints were Montgomery Asberg Depression Rating Scale (MADRS) scores at week 3 (daily MK-1942) and week 1 (twice-weekly MK-1942). Results: The study was terminated following asymptomatic elevations in liver function tests. At termination, ~70% of the planned enrolment was achieved (MK-1942 daily N=40, MK-1942 twice-weekly N=19, placebo N=40). No significant efficacy differences from placebo were seen for either MK-1942 group. The difference in mean change-from-baseline MADRS score for daily MK-1942 vs placebo directionally favored placebo at Week 3 (3.3 [95% CI: −1.4, 8.0]) and all other time points. The difference between twice-weekly MK-1942 and placebo directionally favored placebo at week 1 (1.9 [95% CI: −2.7, 6.4]) but not at later time points (eg, week 4, −1.5 [95% CI: −8.0, 4.9]). Interestingly, at every time point, the difference between twice-weekly and daily MK-1942 directionally favored the twice-weekly group. Discontinuations due to an adverse event were more common with MK-1942 than placebo (daily=10.0%, twice-weekly=15.8%, placebo=2.5%), and dizziness was the most common adverse event (daily=25.0%, twice-weekly=31.6%, placebo=7.5%). Conclusions: Although interpretation of the findings is limited by the early termination of the trial, MK-1942 was not effective in treatment-resistant depression.