Top-Line Results from Phase 3 PALISADE-2 Trial of Fasedienol (PH94B) Nasal Spray in Social Anxiety Disorder (SAD)

Introduction Fasedienol (PH94B; 3β-androsta-4,16-dien-3-ol) is a synthetic neuroactive nasal spray from the androstane family of pherines. Intranasal fasedienol activates receptors in peripheral nasal chemosensory neurons connected to subsets of neurons in the olfactory bulbs that in turn are neurally connected to neurons in the limbic amygdala involved in the pathophysiology of SAD and potentially other anxiety and mood disorders. Fasedienol is locally metabolized in the olfactory mucosa without systemic uptake or binding to CNS receptors. The objective of the present study was to compare fasedienol vs. placebo during a public speaking challenge in subjects with SAD. Methods This was a multi-center, double-blind, randomized, placebo-controlled study (NCT05011396). After screening (Visit 1), all subjects completed Visit 2 (V2, Baseline, placebo nasal spray administered to all subjects) and participated in a 5-minute public speaking challenge (PSC) during which Subjective Units of Distress Scores (SUDS) were recorded. Subjects with SUDS >= to 70 were invited back a week later for the Visit 3 (V3) treatment visit and randomly allocated to receive either fasedienol (3.2 μg intranasally) or placebo, then undergo a second 5-minute PSC, with SUDS scores recorded. After the V3 PSC, subjects completed a Patient Global Impression of Change (PGI-C) and trained raters completed a Clinical Global Impression of Improvement (CGI-I). CGI-I responders were defined as those assigned scores of 1 (very much improved) or 2 (much improved); PGI-C responders reported scores of 1 (very much less anxious) or 2 (much less anxious). ANCOVA with baseline SUDS as a covariate was used to compare change in mean SUDS from V2 to V3 for the subjects administered fasedienol at V3 vs those who received placebo at V3. Results Fasedienol-treated patients (n=70) demonstrated a statistically significant greater change in mean SUDS score (least-squares (LS) mean = -13.8) compared with placebo (n=71, LS mean = -8.0), for a difference between groups of -5.8 (p=0.015). The proportion of CGI-I responders was higher in the fasedienol group 37.7% vs. placebo 21.4% (p=0.033), as was the proportion of PGI-C responders: fasedienol 40.6% vs. placebo 18.6% (p=0.003). Fasedienol was well-tolerated with no treatment-emergent adverse events above 1.5% occurrence. Conclusion The Phase 3 PALISADE-2 trial results demonstrated that a single dose of fasedienol prior to a stressful PSC produced efficacy on patient-rated SUDS and PGI-C, as well as the clinician-rated CGI-I. The results also confirmed the nasal-amygdala neural circuits as a new portal for administration of pharmaceuticals. The data support continued development of fasedienol as a first-in-class, rapid-onset, well-tolerated treatment option for SAD without addictive properties. Funding Vistagen Therapeutics