Nelivaptan (BH-200)

Mechanism of action

Selective, orally active, competitive non-peptide antagonist at the arginine-vasopressin V1B receptor (AVPR1B), a Gq-coupled class-A GPCR expressed on anterior-pituitary corticotrophs, where vasopressin acts synergistically with CRH to drive ACTH release and hence the HPA stress axis. Nelivaptan was the first selective nonpeptide V1B antagonist described (Serradeil-Le Gal et al., JPET 2002): competitive nanomolar affinity at animal and human V1B receptors, much lower affinity at rat and human V1A, V2 and oxytocin receptors, no interaction with a large panel of other receptors, enzymes or ion channels, and full antagonism of AVP-induced Ca2+ increase in CHO cells expressing rat or human V1B. IUPHAR/BPS records human pKi 8.4-9.3 at V1B versus 7.0 at V1A, 5.9 at V2 and 6.8-8.8 at the oxytocin receptor. The oxytocin figure is the important caveat: Griffante et al. (Br J Pharmacol 2005) concluded that SSR149415 is better described as a MIXED V1b/oxytocin receptor antagonist at human receptors than as a clean V1b-selective agent. In vivo (rat) it blocked AVP-induced and AVP-potentiated CRH-induced ACTH release, blunted restraint-stress ACTH elevation by about 50%, and was anxiolytic-like in the mouse four-plate test, with a long-lasting oral effect. A 2021 review also notes a suboptimal rat PK profile (extensive first-pass metabolism, brain/plasma ratio 0.03). The clinical hypothesis carried forward by HMNC is that blocking V1B normalises HPA-axis hyperdrive and that the responsive subset can be identified prospectively by a 14-SNP V1b polygenic score built from vasopressin-signalling biology and dexamethasone-CRH-characterised cohorts.

Formulations

Nelivaptan (BH-200) for Major depressive disorder

Phase 2ActiveMajor depressive disorder indication →

Nelivaptan (BH-200), a selective vasopressin V1B receptor antagonist, as 8-week monotherapy for major depressive disorder, paired with a proprietary 14-SNP 'V1b polygenic score' companion diagnostic. The programme has two distinct eras. Sanofi era (2006-2008): four Phase 2 trials of SSR149415 100/250 mg BID — two in MDD (DFI5878 / NCT00358631, 319 patients, US; DFI5879 / NCT00361491, 324 patients, seven countries), one HPA-axis pharmacodynamic study in MDD (PDY5467 / NCT01606384, 100 patients) and one in GAD (DFI5880 / NCT00374166, 325 patients). In DFI5878 the 250 mg dose separated significantly from placebo on HDRS but the trial lacked assay sensitivity because the escitalopram active control also failed to separate; in DFI5879 neither dose separated while the paroxetine control did; GAD was negative. Sanofi halted development in 2008. HMNC era (2021-): HMNC Brain Health in-licensed the compound worldwide on an exclusive basis (announced 2021-09-16) on the thesis that the failures reflected an unselected population rather than a dead mechanism, and ran the Phase 2b OLIVE trial (BH-200-03, EudraCT 2022-002757-26 / CTIS 2024-513104-34-00): 338 outpatients with moderate-to-severe MDD randomised 2:1 to BH-200 250 mg BID or placebo for 8 weeks across eight European countries plus Serbia, enrolling May 2023 to April 2025, with a 4-week follow-up. The prespecified primary endpoint was HAM-D17 change from baseline to Week 8 in genetic Subgroup C — and it was NOT met (delta -1.94, p=0.153, Cohen's d 0.28). The full mITT population (N=331) did separate (delta -2.98, p=0.0003, d 0.44), as did Subgroup A (n=89, delta -4.47, p=0.005, d 0.55, separating from Week 1) and Subgroup B (n=119, delta -2.85, p=0.037, d 0.49) — but these were not the prespecified primary analysis. Safety: most frequent AE headache 8.9%; all three serious adverse events occurred in the placebo arm; ALT or AST above 3x ULN in 5.8% of BH-200 patients, asymptomatic and reversible on or after treatment. A pooled individual-patient-data analysis of DFI5878, DFI5879 and OLIVE (N=610; BH-200 362, placebo 249) presented at ASCP 2026 gave a Week 8 LS-mean difference of -2.47 HAM-D17 points (p=0.000063) with non-significant treatment-by-study heterogeneity and a pooled 5.9% absolute risk of ALT/AST >=3x ULN. HMNC has said it is opening regulatory discussions for Phase 3 and, following the June 2026 Series B first close, is funding Phase 3-readiness activities; no Phase 3 trial is registered and no Phase 3 start date has been guided. The company has also signalled interest in harder-to-treat populations such as TRD on the strength of a post-hoc pre-exposed-MDD subgroup, but no such trial exists yet.

Clinical trials