(#18) Efficacy and Safety of a Single Administration of the N-methyl-D-aspartate Subunit 2B-Selective Negative Allosteric Modulator, BI 1569912, in People Living with Major Depressive Disorder: A Phase Ib Randomized Controlled Trial

Abstract: Background: BI 1569912 is a selective negative allosteric modulator of NR2B subunit-containing NMDA receptors (NR2B NAM) in development for major depressive disorder (MDD). Methods: A randomized, double-blind, placebo-controlled Phase Ib trial (NCT04937829) of a single oral dose of BI 1569912 (5 mg or 20 mg) vs placebo adjunctive to antidepressants in adults with MDD was conducted. Efficacy was assessed by maximum decrease from baseline in Montgomery-≈sberg Depression Rating Scale (MADRS) total score at any day within a 7-day interval (primary), change from baseline in MADRS at individual timepoints (exploratory), and by Leuven Affect and Pleasure Scale (LAPS) subscales (exploratory). Primary safety endpoint was number/% patients with drug-related adverse events (AEs). Results: Participants (Nf59) were randomized 1:1:1 to receive placebo (n=19), BI 1569912 5 mg (n=20), or 20 mg (n=20). Mean (SD) MADRS total score at baseline was 34.6 (5.8) points. Adjusted mean (SE) maximum decrease from baseline in MADRS within a 7-day interval was similar between groups, at -19.3 (2.3), -16.8 (2.2), and -19.9 (2.2) for placebo, BI 1569912 5 mg, and 20 mg, respectively. A single 20-mg dose provided a clinically relevant 3.4- to 4.9-point improvement in MADRS versus placebo at Days 2, 4, and 6. LAPS results suggested improvement in negative affect with active treatment. Drug-related AEs were reported in the placebo (n=1, 5.3%), BI 1569912 5 mg (n=3, 15.0%), and 20 mg (n=1, 5.0%) groups with no severe/serious AEs. Conclusion: BI 1569912 was well tolerated, and preliminary efficacy signals support continued development. Funding: Boehringer Ingelheim Pharmaceuticals, Inc.Short Description: A Phase Ib randomized, double-blind, placebo-controlled trial evaluating BI 1569912, an oral NR2B-selective negative allosteric modulator, as adjunctive treatment for MDD. Fifty-nine adults with moderate-to-severe MDD and inadequate response to antidepressants received a single dose (5 mg or 20 mg) or placebo. BI 1569912 was well tolerated and although mean maximum MADRS score reductions were similar across groups, clinically meaningful improvements observed with the 20 mg dose at Days 2ñ6 support its further development.Name of Sponsoring Organization(s): Boehringer Ingelheim Pharmaceuticals, Inc.