Vasomotor symptoms (hot flashes) are the most common symptom of menopause, affecting about 75% of menopausal women and about 40% of perimenopausal women. PH80, an investigational neuroactive nasal spray, is hypothesized to be a potential treatment for moderate to severe hot flashes due to menopause given that it rapidly activates olfactory to limbic-hypothalamic neural circuits that control autonomic activity, including body temperature and sweating. The primary objective of this Phase 2A clinical study was to explore the efficacy, safety, and tolerability of intranasal administration of PH80 for the acute management of hot flashes due to menopause.

The study was a randomized, double-blind, placebo-controlled, exploratory Phase 2A clinical study. PH80 nasal spray containing epoxyestrenolone 0.8 μg per 50 μL was self-administered intranasally; two sprays in each nostril (total dose = 3.2 μg) up to four times daily as needed for 4 consecutive weeks. One additional dose was allowed at night if subjects were awakened by hot flashes. During the study period, subjects recorded the number and severity of hot flashes, disruption in function, and sweating related to hot flashes. Patient global impression of change (PGI-C) and clinician global impression of severity (CGI-S) were also assessed.

At baseline, subjects reported a daily mean of 7.7 hot flashes in the PH80 group (n = 18) and 8.0 in the placebo group (n = 18). After 1 week of treatment, the number of hot flashes dropped to 2.8 for PH80 and 6.4 for placebo (P <.001), and after 4 weeks of treatment, the number of hot flashes dropped to 1.5 for PH80 and 5.1 for placebo (P <.001). Treatment with PH80 significantly reduced the severity, disruption in function, and sweating associated with hot flashes during the treatment period as compared with subjects in the placebo group. There was a significant improvement in PGI-C for PH80 vs placebo at endpoint (P = .015) and a strong trend for improvement on CGI-S (P = .053). PH80 was well-tolerated with no serious adverse events (AEs); the AE profiles of PH80 and placebo were comparable. All 36 subjects completed 4 weeks of treatment and with no study discontinuations due to AEs.

The rapid onset, significant reduction in symptoms, and improved function induced by intranasal PH80 in menopausal women with hot flashes compared with placebo, observed as early as the end of week 1 of treatment, provide a strong signal for continued development of PH80 for the acute treatment of hot flashes due to menopause. The safety data further suggest that, if approved, PH80 will provide a substantial safety benefit over all currently available agents.

Vistagen Therapeutics, Inc. Editorial assistance was provided by Peloton Advantage, an OPEN Health company, funded by Vistagen Therapeutics, Inc.

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.

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.

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.

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.

Vistagen Therapeutics