Efficacy and safety of GW117 tablets in major depressive disorder: a randomised, double-blind, placebo-controlled, phase 2 dose-finding study.

Background: GW117 (N-(2-(6-chloro-7-deuteromethoxy-naphthalen-1-yl) ethyl) acetamide) is a dual-acting agent (MT1/MT2 agonist, 5-HT2C antagonist) with prior evidence of antidepressant efficacy and favourable safety. Aims: To preliminarily evaluate the efficacy and safety of GW117 in major depressive disorder (MDD) and to explore the optimal dosing. Methods: A total of 280 eligible patients aged 18-65 years with MDD were randomly assigned (1:1:1:1) to 8 weeks of double-blind treatment with fixed doses of GW117 tablets (20, 40, 60 mg/day) or placebo. The primary endpoint was the change from baseline to Week 8 in the total score of the Hamilton Rating Scale for Depression-17 item (HAMD-17). Key secondary endpoints included changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score over the same period. Results: In the full analysis set (n=276), GW117 showed numerically greater reductions versus placebo in the HAMD-17 and MADRS total scores, as well as higher response rates at Week 8. However, these differences did not reach statistical significance, potentially due to a high placebo response and other contributing factors. In a post hoc analysis of an optimal subgroup (baseline HAMD-17 >24 or insomnia factor >4), GW117 showed efficacy in improving multidimensional symptoms, including insomnia. The 20 mg dose demonstrated a significant 3.66-point greater reduction in MADRS (p=0.026) and a 23.16% higher response rate (p=0.013) compared with placebo. GW117 was well-tolerated, with no cases of alanine aminotransferase or aspartate aminotransferase exceeding 3× the upper limit of normal and no concerning safety signals reported. Conclusions: This exploratory study found that GW117 demonstrated encouraging antidepressant efficacy and a favourable safety profile in patients with MDD. Although differences versus placebo did not reach statistical significance in the overall population, GW117 20 mg monotherapy showed significant improvements in multidimensional depressive symptoms, including insomnia, in the optimal response subgroup. No hepatotoxicity was reported, supporting its promising therapeutic potential for further clinical development. Trial registration number: NCT06796868. Date of retrospective registration: 23 April 2025.