EFFICACY AND SAFETY OF ULOTARONT IN ADULTS WITH GENERALIZED ANXIETY DISORDER: RESULTS FROM A PHASE 2/3 RANDOMIZED PLACEBO-CONTROLLED TRIAL

Introduction

Generalized anxiety disorder (GAD) is a chronic and persistent psychiatric disorder characterized by pervasive, excessive anxiety and worry often accompanied by signs and symptoms such as tension, restlessness, fatigue, and sleep disturbances. As one of the most prevalent anxiety disorders, GAD exerts a notable impact on functioning, quality of life, and health care utilization. Despite its high prevalence and burden, few novel treatments have emerged in recent years, and existing therapies are limited by an undesirable side-effect burden (eg, sexual dysfunction, weight gain) and often a delayed onset of action, highlighting the need for novel therapies. Ulotaront, a trace amineassociated receptor 1 (TAAR1) agonist with 5-hydroxytryptamine 1A (5-HT1A) activity, is under clinical investigation for GAD and other psychiatric conditions owing to its unique mechanism of action and behavioral signature for anxiolytic, antipsychotic, and antidepressant effects.[1] This study evaluated the efficacy and safety of ulotaront in adults with GAD in a Phase 2/3 randomized placebo-controlled trial.

Methods

This Phase 2/3, randomized, double-blind, parallel-group, placebo-controlled, flexible-dose, multicenter study (NCT05729373) enrolled participants (18–65 years) with a diagnosis of GAD in the USA and Europe, with an exploratory cohort in Japan. At screening and baseline, participants were required to have a Hamilton Anxiety Rating Scale (HAM-A) total score ≥20 (including anxious mood and tension scores of ≥2), Montgomery–Åsberg Depression Rating Scale (MADRS) total score ≤22, and Clinical Global Impression – Severity (CGI-S) score ≥4. Treatment resistance and unstable medical conditions were exclusionary. Eligible participants were randomly assigned (1:1) to receive flexibly dosed ulotaront (50–75 mg/day) or placebo over 8 weeks. The primary endpoint was change from baseline in HAM-A total score; the secondary endpoint was change from baseline in CGI-S. Additional endpoints included HAM-A response and remission rates, and safety and tolerability.

Results

A total of 451 adults were randomly assigned to ulotaront (n=227) or placebo (n=224). Mean (range) age was 41.1 (18–65) years; most participants were female (70.3%) and were White (74.3%), Black (14.4%), or Asian (4.4%). Ulotaront demonstrated a significant decrease in least-squares mean change from baseline to Week 8 on the HAM-A total score compared with placebo (−12.9 vs −10.9, P < 0.05), and separation was observed as early as Week 1. A significantly greater decrease in the change from baseline to Week 8 in the CGI-S was also observed for ulotaront versus placebo (P < 0.01). Similarly, a higher HAM-A response rate was observed compared with placebo (54.3% vs 41.7%, P < 0.01). Remission rates were also higher in the ulotaront group compared with placebo (22.9% vs 15.1%, nominal P < 0.05). Most adverse events (AEs) were mild to moderate. Both serious and severe AEs were infrequent. AEs occurring in the ulotaront group at a frequency of ≥5% and > placebo were dizziness, nausea, headache, somnolence, dry mouth, fatigue, vomiting, and constipation. The discontinuation rate due to AEs was low for both the ulotaront (8.4%) and placebo (2.3%) groups.

Conclusion

Ulotaront demonstrated efficacy in improving anxiety symptoms in adults with GAD along with a favorable safety and tolerability profile, supporting its potential as a novel treatment option for GAD.