¹HMNC Holding GmbH, Clinical Development, Munich, Germany, ²University Medical Center Hamburg-Eppendorf, Department for Medical Biometry and Epidemiology, Hamburg, Germany, ³LMU University Hospital, Department of Medicine I, Munich, Germany

Background: Treatment-resistant depression (TRD), a subtype of major depressive disorder (MDD) defined by suboptimal response to antidepressant treatment, represents a significant unmet medical need. Vasopressin V1b receptor modulation has emerged as a potential mechanism relevant to stress-system dysregulation in MDD. BH-200, a selective V1b receptor antagonist, was evaluated in a Phase 2 randomized, double-blind, placebo-controlled trial (OLIVE, CTIS: 2024-513104-34-00) in adults with MDD, together with a previously developed polygenic stratifier (Ising et al., 2025). To approximate BH-200’s potential in TRD, a post-hoc subgroup analysis was performed in OLIVE for MDD patients who at baseline had not responded to at least one adequate antidepressant in their current depressive episode. This subgroup is referred to as pre-exposed MDD. To test whether V1b-related biology is predictive to treatment response, we applied the polygenetic stratifier retrospectively to the pre-exposed MDD subjects.

Aims & Objectives: This post-hoc analysis aimed to (1) determine whether BH-200 demonstrates antidepressant efficacy versus placebo in pre-exposed MDD participants, and (2) evaluate whether the polygenic stratification is associated with efficacy of BH-200, in the pre-exposed MDD cohort. Secondary objectives included (3) describing the proportion of each stratification group within the pre-exposed MDD cohort, and (4) assessing consistency of findings across HAMD-17 and MADRS outcomes.

Method: Data were derived from the OLIVE trial (mITT N = 331), including a pre-exposed MDD subset defined by non-response to at least one adequate antidepressant (N = 171). The target endpoint for this analysis was HAMD-17 change from baseline at week 8. The LS mean difference versus placebo was -2.98 (p = 0.0003) on HAM-D17 in the full population (Eriksson, 2026). Mixed-model repeated measures were applied. The predefined polygenic stratifier divides individuals into three groups (A, B, and C) designed to capture HPA-axis functioning. These groups serve as strata in the analysis.

Results: A total of 171 pre–exposed MDD participants were included. (1) BH-200 showed greater antidepressant efficacy versus placebo in LS mean change from baseline on HAMD-17 in pre-exposed MDD cohort. A nominally significant treatment difference was observed at week 6 (Δ = -2.00, p = 0.029), while the primary endpoint at week 8 was non-significant. (2) Polygenic stratification showed nominally significant differences to placebo in one (Group A) of three groups across weeks 1 to 6. At week 6, LS mean change over placebo was −3.87 (p = 0.025) in Group A compared with −0.96 and −1.46 in Groups B and C, respectively (p > 0.05). (3) Proportions, 28.7% of participants were classified as Group A, 33.9% as Group B, and 37.4% as Group C. (4) Findings were broadly consistent across HAMD-17 and MADRS outcomes.

Discussion & Conclusions: In one polygenically stratified subgroup of pre-exposed MDD patients, BH-200 demonstrated a clinically meaningful separation versus placebo at multiple time points. This stratification category also showed greater improvement in the overall MDD population earlier. These findings suggest that the combination of polygenic stratification and BH-200 treatment may benefit patients with treatment resistance. Prospective trials using biomarker-based enrichment appear warranted.