NMDA Subunit 2B-Selective Negative Allosteric Modulator Satoprodil (BI 1569912) As Mono- and Adjunctive Therapy in Patients with Major Depressive Disorder: Results from Two Phase 2 Randomized, Controlled Trials

Major depressive disorder (MDD) is a leading cause of disability worldwide, with many patients experiencing inadequate response to standard antidepressants. Dysregulation of N-methyl-D-aspartate (NMDA) receptor activity is implicated in the pathophysiology of MDD. Satoprodil (BI 1569912), an oral NMDA subunit GluN2B-selective negative allosteric modulator, was evaluated for safety and efficacy in MDD in two multicenter, randomized, placebo-controlled Phase II dose-finding trials as an adjunctive or monotherapy. In each trial, patients (18-65 years old) were randomized 2:1:1:2 to placebo or satoprodil (5 mg, 10 mg, or 20 mg) once-daily for 6 weeks, with ongoing antidepressant treatment in the adjunctive trial. Primary endpoint was change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Week 6 (both trials). Safety and tolerability were also assessed. In the adjunctive trial (N = 243; 60.9% female), the adjusted mean (standard error [SE]) change in MADRS total score at Week 6 was: placebo, -12.0 (1.1); satoprodil 5 mg, -7.8 (1.6); satoprodil 10 mg, -11.9 (1.6) and satoprodil 20 mg, -12.3 (1.2). In the monotherapy trial (N = 225; 54.2% female), the adjusted mean (SE) change in MADRS total score at Week 6 was: placebo, -10.3 (1.4); satoprodil 5 mg, -13.6 (2.1); satoprodil 10 mg, -10.6 (2.0) and satoprodil 20 mg, -10.0 (1.4). In patients with MDD, satoprodil (all doses) over 6-weeks was well tolerated but did not reduce depressive symptoms beyond placebo in either trial in a relevant manner. These trials provide the most comprehensive clinical evidence to date on GluN2B-selective modulation in MDD and will inform future research on glutamatergic pathways.