Safety and Efficacy of the NMDA-2b-Selective Negative Allosteric Modulator BI 1569912: A Phase Ib Randomized Trial in Major Depressive Disorder

Abstract

Selective N-methyl-D-aspartate receptor subunit 2b negative allosteric modulators (NR2B NAMs) are being explored as potential new treatment options for major depressive disorder (MDD). This Phase Ib, randomized, double-blind, placebo-controlled, parallel-group trial was conducted in adults (N = 59) with moderate-to-severe MDD and insufficient response to ongoing antidepressant monotherapy. Participants were randomized (1:1:1) to a novel NR2B NAM, BI 1569912 (5 mg or 20 mg tablet) or placebo. The primary safety endpoint was the number and percentage of participants with drug-related adverse events (AEs) from the start of treatment to Day 15. Dissociation and psychedelic symptoms were assessed by the Clinician-Administered Dissociative States Scale (CADSS) and Bowdle-Visual Analog Scale (B-VAS), respectively. Preliminary efficacy assessments included the maximum decrease from baseline in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score within a 7-day interval (primary) and the change from baseline in MADRS total score at individual time points (exploratory). The proportion of participants with ≥ 1 AE was similar between BI 1569912 and placebo, with no dose-dependent trend. There was no increase in suicidal or dissociative symptoms and no clinically relevant sign of human abuse potential. The maximum decrease from baseline in MADRS within a 7-day interval was similar across groups; however, a single BI 1569912 20-mg dose provided a clinically relevant 3.4- to 4.9-point improvement in MADRS total score vs. placebo at Days 2, 4, and 6, meeting predefined criteria for further development. The favorable safety profile and preliminary efficacy signals support continued development of BI 1569912 for adults with MDD.

Figure 1

Participant disposition. ¹Twenty‐nine of the 56 screen failures occurred after the lead‐in phase; n = 3 failed to meet inclusion criteria 3 (insufficient response to SSRI/SNRI) at Visit 1A. ²“Other” included study put on temporary hold (n = 2), unable to repeat electroencephalogram before close of screening window (n = 1), a clinical condition that would jeopardize participants’ safety during the trial (opinion of the investigator; n = 1).

Figure 2

Frequency of participants categorized by CADSS total score on (a) patient‐reported rating and (b) clinician’s rating. CADSS, Clinician‐Administered Dissociative States Scale.

Figure 3

Mean (SEM) of absolute change from baseline in B‐VAS subscale “feeling high” over time. B‐VAS, Bowdle‐Visual Analog Scale; SEM, standard error of the mean.

Figure 4

Adjusted mean (SE) of absolute change from baseline in MADRS total score over time. Time in parentheses represents duration (in hours) from administration. MADRS, Montgomery‐Åsberg Depression Rating Scale; SE, standard error.