Small Molecule · TS-121
Brezivaptan (TS-121 / ANC-501)
Orally active, selective small-molecule vasopressin V1B (AVPR1B) receptor antagonist developed as an adjunctive (add-on) treatment for major depressive disorder in patients with an inadequate response to standard antidepressants, with a precision-medicine hypothesis that efficacy concentrates in patients with HPA-axis hyperactivity (elevated baseline cortisol). Originated at Taisho Pharmaceutical (where the active moiety was labeled THY-1773); Taisho's Phase 2 RCT (NCT03093025) was terminated by sponsor decision after results did not reach statistical significance. The compound was subsequently in-licensed from Taisho by Aditum Bio's newco Ancora Bio (doing business as EmbarkNeuro) in 2021 and re-tested as ANC-501 in a small cortisol-enriched open-label Phase 2 (NCT05439603, completed 2023). No further controlled development has been publicly disclosed; EmbarkNeuro's corporate web presence is now defunct, so the program is treated as discontinued/dormant. INN: brezivaptan ( -vaptan vasopressin-antagonist stem).
Also known as: TS-121, ANC-501, THY-1773, TS121, ANC501, THY1773, brezivaptan, 1370444-22-6, 2-[3-(3-chlorophenyl)-1-{4-[2-(morpholin-4-yl)ethyl]phenyl}-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]-N-(propan-2-yl)acetamide
- Modality
- Small molecule
- Chemical class
- triazolone, acetamide, morpholine
- Chemistry
- Achiral
- Mechanism
- V1B receptor antagonist
- Highest phase
- Discontinued
- Lead indication
- Major depressive disorder
- Developer
- Taisho Pharmaceutical Co., Ltd.
- Trials
- 2 tracked · 30 sites
Mechanism of action
Brezivaptan is an orally active, selective antagonist of the arginine-vasopressin V1B receptor (AVPR1B, gene AVPR1B), a Gq-coupled GPCR expressed in the anterior pituitary where it mediates vasopressin-driven, CRH-synergistic ACTH release and thereby drives the hypothalamic-pituitary-adrenal (HPA) stress axis. V1B antagonism is hypothesized to normalize HPA-axis hyperactivity that is observed in a subset of depressed patients, predicting greater antidepressant benefit in patients with elevated cortisol. Brezivaptan binds and occupies pituitary V1B receptors (PET receptor-occupancy of ~55% and ~75% at the tested clinical doses), but no cleanly citable in-vitro binding affinity (Ki/IC50) at the human V1B receptor was found in IUPHAR/ChEMBL or a primary paper, so affinity is left null.
| Target | Action | Affinity |
|---|---|---|
| V1B receptorprimaryAVPR1B | Antagonist | —ⓘ |
Formulations
| Formulation | Route | Regimen | Pharmacokinetics |
|---|---|---|---|
| Brezivaptan oral (Phase 2 MDD) 10 mg and 50 mg (doses evaluated in the Phase 2 adjunctive MDD study, 6-week treatment period) | Oral | — | — |
Development timeline
- metEmbarkNeuro open-label Phase 2 (NCT05439603, n=15) completed: mean MADRS reduction ~17.5 pts at 8 wk (single-arm, no placebo).
- Asset relaunched: Ancora Bio (d/b/a EmbarkNeuro), formed by Aditum Bio, in-licensed the compound from Taisho and dosed the first patient in a new open-label, single-arm, cortisol-enriched Phase 2 trial of ANC-501 (50 mg/day x 8 weeks) for MDD (NCT05439603).↗
- missedTaisho Phase 2 (NCT03093025) missed primary: MADRS 10mg/50mg -9.0 vs placebo -6.4, no significant separation; trial terminated (sponsor decision).↗
- Taisho's Phase 2 trial (NCT03093025) reached primary completion and was TERMINATED ('Sponsor decision', per ClinicalTrials.gov). Published results (Kamiya et al., J Psychiatr Res 2020) showed the primary MADRS endpoint did not reach statistical significance (TS-121 10 mg -9.0, 50 mg -9.0, placebo -6.4); greater drug-placebo separation in patients with higher baseline cortisol. Development at Taisho did not continue.↗
- Taisho initiated a multicenter, randomized, double-blind, placebo-controlled Phase 2 study (NCT03093025) of TS-121 (10 mg, 50 mg) vs placebo as adjunctive treatment for MDD with inadequate antidepressant response.
Brezivaptan (TS-121 / ANC-501) for Major depressive disorder
DiscontinuedDiscontinuedMajor depressive disorder indication →
Adjunctive Phase 2 program of brezivaptan (vasopressin V1B antagonist) for major depressive disorder with inadequate response to antidepressants, built on a precision-medicine hypothesis (greater benefit in patients with HPA-axis hyperactivity / elevated cortisol). Taisho's randomized, double-blind, placebo-controlled Phase 2 (NCT03093025; TS-121 10 mg vs 50 mg vs placebo, 6 weeks, n=51) was TERMINATED by sponsor decision; the primary MADRS endpoint did NOT reach statistical significance (10 mg and 50 mg both -9.0 vs placebo -6.4), though higher baseline urinary/hair cortisol was associated with greater drug-placebo separation (Kamiya et al., J Psychiatr Res 2020). The asset was in-licensed from Taisho by Aditum Bio's newco Ancora Bio (d/b/a EmbarkNeuro) in 2021 and re-tested as ANC-501 in a small open-label, single-arm, cortisol-enriched Phase 2 (NCT05439603, n=15, 50 mg/day x 8 weeks), completed October 2023 (mean MADRS reduction ~17.5 points; no placebo control). No subsequent controlled or later-stage development has been publicly disclosed, and EmbarkNeuro's corporate web presence is defunct; the program is therefore recorded as discontinued/dormant.
Readouts
- 2023-10-18ReportedTopline datametNCT05439603
EmbarkNeuro open-label Phase 2 (NCT05439603, n=15) completed: mean MADRS reduction ~17.5 pts at 8 wk (single-arm, no placebo).
- 2020-06-01ReportedFull resultsmissedNCT03093025
Taisho Phase 2 (NCT03093025) missed primary: MADRS 10mg/50mg -9.0 vs placebo -6.4, no significant separation; trial terminated (sponsor decision). ↗
Clinical trials
NCT05439603Phase 2Completedn=15
A Phase 2 Study of ANC-501 in the Treatment of Adults With Major Depressive Disorder
metprimaryChange from baseline in MADRS total score at Day 56 (8 weeks), open-label single-arm (ANC-501 50 mg/day adjunctive) — mean MADRS reduction 17.5 points (SD 10.09) from baseline to Day 56, efficacy population N=13
Open-label, single-arm, cortisol-enriched Phase 2 (no placebo control). Mean within-group MADRS reduction of ~17.5 points at 8 weeks in the efficacy population. Interpret cautiously: there was no comparator arm, so this is an uncontrolled within-arm change rather than a demonstration of efficacy over placebo. No controlled follow-up has been disclosed.
NCT03093025Phase 2Discontinuedn=51
A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Patients With Major Depressive Disorder With an Inadequate Response to Current Antidepressant Treatment
terminatedprimaryChange from baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score at week 6 — LS mean MADRS change: TS-121 10 mg -9.0, TS-121 50 mg -9.0, placebo -6.4 (no statistically significant separation from placebo)
Trial terminated by sponsor decision. Primary MADRS endpoint did not reach statistical significance; both TS-121 doses produced numerically greater improvement than placebo but the difference was not significant. Higher baseline urinary and hair cortisol levels were associated with greater drug-placebo separation, consistent with the V1B/HPA-axis-hyperactivity hypothesis; safety/tolerability were favorable.
Identifiers
- ChEMBL CHEMBL5314910
- PubChem CID 56952080
- FDA UNII 575OB1CKN0
Sources
- A Study to Evaluate the Safety and Efficacy of TS-121 as an Adjunctive Treatment for Major Depressive Disorder — ClinicalTrials.gov
- ANC-501 in the Treatment of Adults With Major Depressive Disorder (NCT05439603), Ancora Bio d/b/a EmbarkNeuro — Completed — ClinicalTrials.gov
- Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder — Journal of Psychiatric Research (Elsevier) / PubMed
- EmbarkNeuro Announces Initiation of Phase 2 Trial of ANC-501, a First-In-Class V1b Receptor Antagonist for the Personalized Treatment of Depression (21 Nov 2022) — EmbarkNeuro / PR Newswire
- V1B receptor (AVPR1B), GtoPdb object 367 — vasopressin and oxytocin receptor family — IUPHAR/BPS Guide to Pharmacology