Efficacy and Safety of NR2B NAM BI 1569912 After Single Oral Administration in Patients with Major Depressive Disorder
Introduction: Non-selective N-methyl-D-aspartate (NMDA) receptor antagonists (e.g. ketamine/esketamine) have demonstrated efficacy in the treatment of MDD; however, these agents are associated with frequent and distressing/unacceptable adverse events (e.g. dissociation).
Objectives: To investigate whether NMDA receptor subunit 2b selective negative allosteric modulators (NR2B NAMs) offer efficacy without the side-effect burden of non-selective NMDA receptor antagonists. BI 1569912, an oral NR2B NAM in development for MDD, did not produce dissociation or any serious adverse events in Phase I studies.
Methods: Here, we report data from a randomized, double-blind, placebo-controlled Phase Ib trial (NCT04937829) of a single dose of BI 1569912 (5 mg and 20 mg) versus placebo as an adjunct to antidepressants in adults with moderate-to-severe MDD and insufficient response to ongoing antidepressant monotherapy. Efficacy was assessed by evaluating change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at individual time points (exploratory). Drug-related adverse events were recorded.
Results: Median age (range) of treated patients (Nf59) was 54.0 (18–65) years; 54.2% (n=32) were female; the mean (SD) baseline MADRS total score was 34.6 (5.8) points. A single BI 1569912 20 mg administration provided 3.4- to 4.9-point improvements in MADRS total score versus placebo at Days 2, 4 and 6.
Conclusions: A single dose of adjunctive BI 1569912 produced a rapid antidepressant effect with early separation from placebo on MADRS total score, and was well-tolerated with no dissociation supporting progression into Phase II (NCT06280235). NR2B NAMs represent potential antidepressant treatments that may offer rapid, well-tolerated efficacy.
Funding: Boehringer Ingelheim
