Efficacy and safety of TS-121, a novel vasopressin V1B receptor antagonist, as adjunctive treatment for patients with major depressive disorder: A randomized, double-blind, placebo-controlled study

Abstract

Vasopressin 1B (V1B) receptor has a pivotal role in the regulation of the hypothalamus-adrenal-pituitary axis, and V1B receptor antagonists have shown efficacy in a number of preclinical models of depression. The efficacy and safety of, TS-121 (active ingredient: THY1773), a novel V1B receptor antagonist, was investigated in patients with major depressive disorder (MDD) who had an inadequate response to current antidepressant therapy. In a randomized, double-blind, placebo-controlled phase 2 study, 51 MDD patients (43 of whom completed the study) were randomly assigned to either TS-121 10 mg, 50 mg or placebo for 6 weeks treatment period. The primary endpoint was change from baseline on the Montgomery-Åsberg Depression Rating Scale (MADRS) score at week 6. The study was conducted from Jul 2017 to Dec 2018. The changes from baseline in MADRS score at week 6 (Least Square Mean [95% Confidence interval] were: TS-121 10 mg (-9.0 [-13.9, -4.1]), TS-121 50 mg (-9.0 [-13.4, -4.5]), and placebo (-6.4 [-10.7, -2.2]). TS-121 groups showed greater numerical reductions in MADRS score change from baseline compared to placebo, though these reductions did not achieve statistical significance. Similar trends of numerically greater improvements in TS-121 groups were observed across secondary endpoints. Higher baseline urinary and hair cortisol levels were associated with a greater separation between TS-121 groups and the placebo group in the primary endpoint. These findings, combined with favorable safety and tolerability, warrant further investigation of TS-121 in an adequately powered study in patients with MDD.

Trial registration: ClinicalTrials.gov NCT03093025.

Keywords: Antidepressant; MDD adjunctive treatment; Major depressive disorder; THY1773; TS-121; V(1B) receptor antagonist.

Conflict of interest statement

Declaration of competing interest Fava M and Nemeroff CB have acted as consultants for Taisho Pharmaceutical R&D Inc. throughout planning and conducting of the trial. Dr. Nemeroff was compensated by Taisho Pharmaceutical R&D Inc. for his work according to the contracts made for the consultation. Dr. Fava's work was compensated by Taisho Pharmaceutical R&D Inc. with payments to Massachusetts General Hospital, as his consultations were made on behalf of Massachusetts General Hospital. In addition, Dr. Fava oversaw the work done by the SAFER independent raters through a contract with Massachusetts General Hospital. For a list of lifetime disclosures of Dr. Fava, please see https://mghcme.org/faculty/faculty-detail/maurizio_fava. Dr. Nemeroff reports following disclosures: Research/Grants: National Institutes of Health (NIH). Consulting (last three years): Xhale, Takeda, Taisho Pharmaceutical R&D Inc.,Signant Health, Sunovion Pharmaceuticals Inc., Janssen Research & Development LLC, Magstim, Inc., Navitor Pharmaceuticals, Inc., TC MSO, Inc., Intra-Cellular Therapies, Inc., EMA Wellness, Gerson Lehrman Group (GLG), Acadia Pharmaceuticals. Stockholder: Xhale, Celgene, Seattle Genetics, Abbvie, OPKO Health, Inc., Antares, BI Gen Holdings, Inc., Corcept Therapeutics Pharmaceuticals Company, TC MSO, Inc., Trends in Pharma Development, LLC, EMA Wellness. Scientific Advisory Boards: American Foundation for Suicide Prevention (AFSP), Brain and Behavior Research Foundation (BBRF), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Signant Health, Laureate Institute for Brain Research (LIBR), Inc. Board of Directors: AFSP, Gratitude America, ADAA, Xhale Smart, Inc. Income sources or equity of $10,000 or more: American Psychiatric Publishing, Xhale, Signant Health, CME Outfitters, Intra-Cellular Therapies, Inc., Magstim, EMA Wellness. Patents: Method and devices for transdermal delivery of lithium (US 6,375,990B1). Method of assessing antidepressant drug therapy via transport inhibition of monoamine neurotransmitters by ex vivo assay (US 7,148,027B2). Compounds, Compositions, Methods of Synthesis, and Methods of Treatment (CRF Receptor Binding Ligand) (US 8,551, 996 B2). Speakers Bureau: None. Kamiya M is an employee of Taisho Pharmaceutical Co. Ltd., and was formerly employed at Taisho Pharmaceutical R&D Inc. at the time this work was done. Sabia HD, Marella J are employees of Taisho Pharmaceutical R&D Inc. Umeuchi H, Iijima M, Chaki S and Nishino I are employees of Taisho Pharmaceutical Co., Ltd.

Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.