POOLED INDIVIDUAL PATIENT DATA ANALYSIS OF THREE PHASE 2 TRIALS SUPPORTS VASOPRESSIN V1B RECEPTOR ANTAGONISM (BH-200 250 MG BID) AS AN ANTIDEPRESSANT MECHANISM FOR THE TREATMENT OF MAJOR DEPRESSIVE DISORDER (MDD)

Background

Lack of novel pharmacological mechanisms to address symptoms of MDD, is the main reason behind the unmet medical need in those clinical populations showing suboptimal response to existing treatments. Vasopressin V1b receptor antagonism as a modulator of the HPA stress axis has a therapeutic potential, but clinical evidence across studies has been inconsistent. We conducted a pooled, individual patient data (IPD) analysis across all three randomized, double-blind, placebo-controlled Phase II trials that had a similar design, to estimate overall efficacy and evaluate consistency across studies for BH-200 250 mg BID. Two of the trials demonstrated a separation between patients treated with BH-200 and patients treated with placebo at Week 8, with p < 0.05, while the third trial showed no separation.

Methods

Individual Patient Data (IPD) from three Phase II studies (DFI 5878, DFI 5879, and OLIVE) were pooled in an ITT framework (randomized participants with ≥1 post-baseline assessment). The endpoint was the change from baseline to Week 8 in Hamilton Depression Scale total score (HAMD-17). A mixed model for repeated measures (MMRM) included baseline, visit, treatment, study, visit-by-treatment, visit-by-study, and treatment-by-study, with covariates (sex, age, baseline BMI) and random effects for country and subject-level visit slope/intercept. Primary estimates focused on the overall treatment effect at Week 8 and assessment of heterogeneity via treatment-by-study interaction.

Results

The pooled dataset included N=610 participants (BH-200 n=362; placebo n=249). BH200 demonstrated robust improvement versus placebo with a separation starting in Week 2 and increasing over time until Week 8. The least-squares mean difference (BH-200 – placebo) was −2.47 HAMD-17 points (p=0.000063). Treatment effects were directionally consistent across studies, with non-significant treatment-by-study heterogeneity (treatment-by-study interaction not significant). A follow-up assessment four weeks after the end of treatment demonstrated a sustained treatment effect for BH-200. Liver enzyme elevations (ALT or AST ≥ 3x ULN) were seen, and the pooled absolute risk was 5.9%, varying across studies. Overall adverse event rates appeared comparable between placebo and BH-200, with a generally benign tolerability profile.

Conclusions

In a pooled IPD analysis across three phase 2 trials, BH-200 showed statistically robust and clinically meaningful antidepressant efficacy versus placebo, supporting vasopressin V1b receptor antagonism as a viable antidepressant mechanism in MDD and justifying further evaluation in harder-to-treat populations such as TRD. The benefit/risk ratio remains favorable, with transient and reversible liver enzyme elevations being observed.