Roger S. McIntyre, Gerard Sanacora*, David P. Walling, Elan A. Cohen, Shishuka Malhotra, Holger Rosenbrock, Manuela Schmitz, Andreas Scholz, Sigurd D. Suessmuth, Franco De Crescenzo Yale University, New Haven, CT, USA, New Haven, Connecticut, United States

Background: Although non-selective N-methyl-D-aspartate (NMDA) receptor antagonists, such as ketamine and esketamine, have shown efficacy in treating major depressive disorder (MDD) they are associated with multiple side effects, including dissociation and psychomimetic effects. Selective negative allosteric modulators of the NR2B-containing subunit of the NMDA receptor (NR2B NAMs) may offer efficacy without the side effects of non-selective NMDA receptor antagonists. BI 1569912 is an oral NR2B NAM currently in development for MDD.

Methods: In this Phase IB multicenter trial (NCT04937829) in the US, adults with moderate-to-severe MDD, and insufficient response to ongoing antidepressant monotherapy (selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors), were randomized 1:1:1 to receive a single dose of oral BI 1569912 5 mg, 20 mg, or placebo during a 1-week inpatient stay. This was followed by a 1-week outpatient period and an end of study visit on Day 15. Efficacy was evaluated by maximum decrease from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) score at any day within a 7-day interval (primary), and by change from baseline (CFB) in MADRS total score on Days 1, 2, 4, 6, 8, 11, and 15 (exploratory). A MADRS response was defined as a CFB score reduction of ≥50%, and a remission was defined as a MADRS score ≤10, at individual time points, assessed on Days 1, 2, 4, 6, 8, 11, and 15 (exploratory). Proof of clinical principle for BI 1569912 was defined as an improvement in MADRS total score of ≥3 points at any time point and ≥2 points at a neighboring time point, at any day within a 7-day interval, versus placebo. Efficacy was also assessed by CFB in Leuven Affect and Pleasure Scale (LAPS) subscales on Days 1, 2, 4, 6, 8, 11, and 15 (exploratory). MADRS response and remission data were analyzed using a logistic regression model, with baseline total score and treatment as fixed effects.

Safety was assessed from start of treatment to last visit (Day 15) and included: monitoring adverse events (AEs), including severe and serious AEs, drug-related AEs (DRAEs) (primary), and AEs of special interest (AESI); Clinician Administered Dissociative States Scale (CADSS) scores at baseline and Days 1 and 15; and assessment of psychedelic effects (indicative of potential for drug abuse and dissociation over time) on the Bowdle-Visual Analog Scale (B-VAS; at baseline, Days 1, 2, and 15).

Results: Participants (N = 59) were randomized and treated as follows: placebo (n = 19), BI 1569912 5 mg (n = 20), and 20 mg (n = 20). Demographic and baseline characteristics were generally balanced between groups. Median age (range) was 54.0 (18–65) years, 54.2% of participants were female, and mean (standard deviation) MADRS total score at baseline was 34.6 (5.8) points.

The adjusted mean (standard error) 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. The 3.4–4.9 point improvement in MADRS total score on Days 2, 4, and 6 after treatment with BI 1569912 20 mg, versus placebo, supported proof of clinical principle. A higher proportion of participants treated with BI 1569912 20 mg achieved MADRS response at Days 2, 4, and 6 (50.0%, 45.0%, and 50.0%) compared with placebo (21.1%, 10.5%, and 21.1%). MADRS remission on Days 2, 4, and 6 was also achieved by a higher proportion of participants treated with BI 1569912 20 mg (20.0%, 35.0%, and 40.0%) than placebo (10.5%, 10.5%, and 21.1%). Logistic regression analysis also showed that, on Days 2, 4, and 6, the predicted odds of achieving a response for participants receiving BI 1569912 20 mg were higher than the odds for participants receiving placebo, with odds ratios (95% confidence interval [CI]) of 3.58 (0.83, 15.48), 6.70 (1.16, 38.53), and 3.58 (0.86, 14.94). In addition, the predicted odds of achieving remission for participants receiving BI 1569912 20 mg were higher than the odds for participants receiving placebo, with odds ratios (95% CI) of 1.78 (0.27, 11.85), 4.22 (0.71, 25.09), and 2.27 (0.51, 10.02) at Days 2, 4, and 6, respectively. Results on the LAPS showed participant-centered dimensions of depression improved in all treatment arms, including placebo.

The proportion of participants with ≥1 AE, from start of treatment to Day 15, was 31.6%, 35.0%, and 15% for the placebo, BI 1569912 5 mg, and 20 mg groups, respectively. The most common AEs in those receiving BI 1569912 were constipation (n = 2), increased blood pressure (n = 2), and headache (n = 2). DRAEs were reported in 1 participant in the placebo group, 3 in the BI 1569912 5 mg group, and 1 in the 20 mg group. In BI 1569912-treated participants, DRAEs included constipation (n = 2), and flatulence, increased blood pressure, decreased appetite, dizziness, and dry skin (n = 1 for all). No severe or serious AEs, or AESI were reported. In participants treated with BI 1569912, no clinically relevant dissociation per CADSS scores was observed, and no signs or symptoms of human abuse potential were indicated from B-VAS assessment.

Conclusions: BI 1569912, an oral NR2B NAM in development for the treatment of MDD, was well tolerated with no dissociation and no clinically relevant signs of human abuse potential. Efficacy assessments showed that proof of clinical principle was met, and study findings support the progression to a Phase II trial of BI 1569912 (NCT06280235) in adults with MDD.

Funding: Boehringer Ingelheim (1447-0003).

Keywords: MDD, NR2B NAM, BI 1569912

Disclosure Abbvie, Atai, Biogen, Bristol-Myers Squibb, Clexio, Denovo Biopharma, Daiichi Sankyo, Janssen, Neurocrine, Perception Neuroscience, Sage Pharmaceuticals, Seelos Pharmaceuticals, Usona Institute, XW Labs: Consultant (Self). Biohaven Pharmaceuticals, Boehringer Ingelheim International, EMA Wellness, Embark, Freedom Biosciences, Gilgamesh, Merck, Novartis, Relmada Therapeutics, Tetricus, Transcend Therapeutics: Advisory Board (Self). Biohaven Pharmaceuticals: Founder (Self). Janssen, Merck: Contracted Research (Self). Relmada Therapeutics, Biohaven Pharmaceuticals: Stock / Equity - Publicly Traded Company (Self). Freedom Biosciences, Tetricus: Stock / Equity - Privately Held Company (Self)