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T26

A PHASE 2 CLINICAL TRIAL EXPLORING EFFICACY AND SAFETY OF THE VASOPRESSIN V1B ANTAGONIST BH-200, A TREATMENT FOR MDD, EVALUATING THE PERFORMANCE OF A GENETIC CLASSIFICATION TOOL TO IDENTIFY A SUBSET OF PATIENTS WITH LARGER IMPROVEMENT

Christine zu Eulenburg — Daniel Gehrlach2, Evangelos Papanastasiou2, Ani Damyanova2, Caren Strote3, Lars Arvastson2, Bertram Müller-Myhsok2, Hans Eriksson2 1HMNC Brain Health; University Medical Center Hamburg-Eppendorf, 2HMNC Brain Health, 3HMNC Brain Health; LMU University Hospital

2026 ASCP Annual Meeting

Background

A disturbance in the hypothalamus-pituitary-adrenals axis (HPAaxis) function has been implicated in a subset of depressed individuals. BH-200 is a selective V1b receptor antagonist, that previously has shown efficacy in a Phase 2 trial in MDD (N=319). A genetic classification tool was used to identify a subset of MDD patients with a robust response to V1b inhibition.

Methods

Using insights in the biology of vasopressin signaling and results from the DexCRH test in depressed individuals, a genetic classification tool was developed. It is based on 14 single-nucleotide polymorphisms (SNPs), and classifies patients into three subgroups, A, B, and C, reflecting different levels of suppression of ACTH release from the pituitary. 338 patients with MDD were randomized (2:1) to treatment with BH-200 (250 mg BID), or placebo for eight weeks, in 8 European countries. The primary efficacy endpoint was change vs. placebo in HAM-D17 total score from baseline to Week 8, in Subgroup C patients.

Results

The estimated mean improvement from baseline to Week 8 in the mITT population (N=331) was larger in the BH-200-treated arm than in the placebo arm (∆ = -2.98, p = 0.0003). In all three BH-200 treated subgroups, clinically relevant improvements were observed, but the magnitudes of the mean effects between the BH-200-treated arm and the placebo arm were different; Group A, n=89, ∆ = -4.47, p = 0.005, Cohen’s d, 0.55; Group B, n=119, ∆ = -2.85, p = 0.037, Cohen’s d, 0.49; and, Group C, n=123, ∆ = -1.94, p = 0.153, Cohen’s d, 0.28. In Group A, all comparisons between BH-200 and placebo Week 1 had a p < 0.05. The findings were supported by results on the MADRS, and on the CGI-S scale. The improvement from baseline was maintained during the 4-week follow-up period. In the full population, 50.0% of the patients in the BH-200 arm and 25.7% of the patients in the placebo arm were responders (≥ 50 % decrease in baseline HAM-D17 score) at Week 8, Odds Ratio (OR) 3.0. In subgroup A, 58.9% of the patients in the BH-200 arm and 25.9% of the patients in the placebo arm were responders by Week 8, respectively, OR 4.2. In the full population, 25.8% of the patients in the BH-200 arm and 16.8% of the patients in the placebo arm reached remission (HAM-D17 score ≤ 7) at Week 8, OR 1.6. In subgroup A, 33.9% of the patients in the BH-200 arm and 11.1% of the patients in the placebo arm achieved remission by Week 8, respectively, OR 3.8. BH-200 was generally safe and well-tolerated. The most frequent adverse event was headache, in 8.9% of the patients in the BH-200 arm. Three serious adverse events in two patients were reported, all in the placebo arm. In the BH-200 arm, 5.8% of the patients had an elevation of AST or ALT concentrations to > 3 times the upper level of normal. The changes were asymptomatic and all reversed while on treatment or after stopping the treatment.

Conclusion

Specific inhibition of V1b signaling appears to be associated with a clinically relevant improvement of depressive symptoms. In an MDD subpopulation characterized by a prespecified genetic tool, the clinical outcome was substantially better than in the full population. The findings suggest that HPA-axis modulators are a viable, novel class of antidepressants. Though efficacy was observed across the population, use in combination with a genetic selection tool appears to enhance the treatment outcome in a subset of MDD patients, showing the promise of precision psychiatry.