A NEW DAWN FOR SOCIAL ANXIETY TREATMENT: CLINICAL ADVANCEMENT OF THE NOVEL V1AR ANTAGONIST, NTX-1472

Background

NTX-1472 is a potent and selective vasopressin 1a receptor (V1aR) antagonist that has been studied in two completed Phase 1 clinical trials. Currently, NTX1472 is in clinical development by Newleos Therapeutics, Inc. for the treatment of Social Anxiety Disorder. The disease includes 2 subtypes, generalized (SAD-g) and performanceonly (SAD-p). SAD-g is characterized by marked fear or anxiety about various social situations. These situations are avoided or endured with intense discomfort, leading to significant impairment and decreased quality of life (Kessler et al., 2005; Stein and Stein, 2008). The SOcial Anxiety Reduction (SOAR) study (NTX-1472-201) is an ongoing, Phase 2, proof-of-concept study that aims to assess the safety, tolerability, and efficacy of NTX1472 compared to placebo (PLC) in adults with SAD-g.

Methods

The first clinical trial of NTX-1472 (Study BP41695) was a 3-part study that assessed the safety, tolerability and pharmacokinetics (PK) of single-and multiple-ascending doses of NTX-1472 (Part 1: single-ascending dose and food effect [n=48], Part 2: multipleascending dose [n=24]; Part 3: midazolam drug-drug-interaction [n=16]). The second clinical trial (Study BP43293) was an open-label, 2-period study to investigate the effect of repeat doses of itraconazole on the PK of a single dose of NTX-1472 (n=16). The SOAR study has a double-blind, placebo (PLC)-controlled, parallel-arm study design. Participants must be between 18 and 65 years of age (inclusive) and have a diagnosis of SAD-g as defined by the Diagnostic and Statistical Manual of Mental Disorders 5th Edition and confirmed by the Structured Clinical Interview for DSM-5 Disorders. Participants are randomized, stratified by sex, to receive either NTX-1472 (single dose level, n=50) or PLC (n=50) daily for 8 weeks. The study duration is 99 days for each participant, including a Screening Period of up to 30 days, a Treatment Period of up to 59 days, and a Follow-up Period of up to 10 days.

Results

NTX-1472 has been administered to a total of 86 healthy participants in 2 completed Phase I studies. NTX-1472 was rapidly absorbed with Tmax achieved at 1-3 hours (h) postdose. Food increased the Cmax of NTX-1472 but had no effect on the AUC, and the half-life was about 5-7 h. NTX-1472 given daily had no effect on the PK of midazolam, a CYP3A4 substrate. Multiple doses of the strong CYP3A4 inhibitor itraconazole increased the AUCinf of NTX-1472 by 2.5-fold. Across both studies, NTX-1472 was well tolerated, as all treatment-emergent adverse events (TEAEs) were non-serious and not dose-limiting. Building on the Phase 1 program, the SOAR study is currently enrolling in 11 sites across the United States, with planned completion in early 2027. The primary endpoint is incidence and severity of TEAEs. Key secondary endpoints include change in the clinician-administered Liebowitz Social Anxiety Scale (LSAS) and the Clinical Global Impression – Severity (CGIS) scale.

Conclusion

In humans, V1aR antagonists have been shown to decrease amygdala activation to threatening social cues (Lee et al., 2013) and to reduce anxiety-potentiated startle, a biomarker associated with treatment response in SAD (Hoge et al., 2024; Lago et al., 2021). These, as well as other, findings support the development of NTX-1472, a novel V1aR antagonist, for the treatment of anxiety disorders. The ongoing Phase 2 study will help determine the therapeutic potential of NTX-1472 in SAD-g.