PPH80 is an odorless, tasteless synthetic investigational pherine with a novel, rapid-onset potential mechanism of action (MOA) that is fundamentally differentiated from the MOA of all currently approved treatments for both vasomotor symptoms (hot flashes) due to menopause, premenstrual dysphoric disorder and migraine headaches. PH80, which is administered as a nasal spray at microgram-level doses, engages and activates chemosensory neurons in the nasal cavity, which are connected to neural circuits in the brain that modulate neural circuits in the basal forebrain. associated with vasomotor symptoms (hot flashes) due to menopause, premenstrual dysphoric disorder and migraine.

Acute Management of Vasomotor Symptoms (Hot Flashes) due to Menopause

Approximately 60% to 80% of women entering menopause suffer from hot flashes and associated symptoms lasting up to ten years, according to the Massachusetts General Hospital Center for Women’s Mental Health. Menopausal symptoms are triggered by hormonal fluctuations that develop at the onset of menopause and affect areas of the brain involved in the control of core body temperature. Sudden changes in core body temperature result in hot flashes, sweating, reddening of the face and upper thorax, rapid heartbeat and general feelings of discomfort that can have an impact on the quality of life.

In an exploratory double-blind, placebo-controlled Phase 2A study designed to explore the efficacy, safety, and tolerability of intranasal administration of PH80 for the acute management of vasomotor symptoms (hot flashes) due to menopause conducted at Hospital Angeles, Mexico City Mexico, treatment with PH80 demonstrated statistically significant efficacy versus placebo for the acute treatment of hot flashes. PH80 induced a statistically significant reduction in the daily number of hot flashes compared to placebo at the end of the first week of treatment (p<.001), and the improvement was maintained through each treatment week until the end of the four-week treatment period. PH80 treatment also significantly reduced the severity, disruption in function and sweating related to hot flashes during the treatment period as compared with placebo. PH80 was well-tolerated with no serious adverse events, and the adverse event profiles were comparable between PH80 and placebo.

Vistagen is currently preparing, on its own or with collaborators, to submit an U.S. IND for a Phase 2B clinical study of PH80 as a treatment for vasomotor symptoms (hot flashes) due to menopause. 

Acute Management of the Symptoms of Premenstrual Dysphoric Disorder

Premenstrual dysphoric disorder (PMDD) is a severe, sometimes disabling extension of premenstrual syndrome (PMS). Approximately, 5% to 8% of menarcheal individuals have moderate-to-severe symptoms that can cause significant distress and functional impairment, suggestive of PMDD¹. PMDD symptoms usually begin in the luteal phase (approximately seven to 10 days before a person’s period starts) and continue for the first few days of the period. Like PMS, PMDD can cause bloating, breast tenderness, fatigue, and changes in sleep and eating habits, but distinctively, it can also cause extreme mood shifts that can disrupt daily life and damage relationships. The cause of PMDD is not clearly understood, but it is thought that neurotransmitter systems may trigger PMDD. Brain areas that regulate emotion and behavior are studded with receptors for estrogen, progesterone, and other sex hormones. These hormones affect the functioning of neurotransmitter systems that influence mood and thinking, possibly triggering PMDD.

In an exploratory randomized, double-blind, placebo-controlled Phase 2A clinical study of PH80 designed to explore the efficacy, safety, and tolerability of intranasal administration of PH80 for the acute management of PMDD in subjects with a regular menstrual cycle and at least a one-year history of PMDD, PH80 showed statistically significant improvement versus placebo in symptoms of PMDD, including negative mood and physical and behavioral symptoms.

PH80 demonstrated statistically and clinically significant improvement versus placebo in symptoms of PMDD using the subject-rated Penn Daily Symptom Report (DSR) as early as Day 4 and continuing to Day 6. At Day 6, change from baseline was -12.1 for PH80 (n=29) versus -7.6 for placebo (n=23) (p=0.008), showing significant and clinically meaningful improvement. PH80 also demonstrated statistically and clinically significant improvement versus placebo at Day 6 on the clinician-rated Premenstrual Tension Scale (PMTS) total score where the PH80 change from baseline was -12.0 versus -7.7 for placebo (p=0.006).

Analysis of the data revealed that mood symptoms seemed to be the most sensitive to PH80:

• Depression/feeling sad or blue was reported by 0% of PH80 and 68% of placebo-treated subjects;
• Irritability/persistent anger was reported by <3% of PH80 and 43% of placebo-treated subjects;
• Anxiety/tension/on edge was reported by 0% of PH80 and 35% of placebo-treated subjects; and
• Difficulty concentrating was reported by 0% of PH80 and 18% of placebo-treated subjects.

PH80 was well-tolerated with no serious adverse events (AEs). The most common AE was headache, reported by 17% in the placebo group and 7% in the PH80 group. No other treatment-emergent AE occurred more than once per subject.

Acute Management of Migraine

Migraine headaches are a common and debilitating neurological disorder experienced by approximately 4% to 9% of men and 11% to 25% of women, according to the American Headache Society. A migraine is characterized by unilateral, pulsating headaches of moderate to severe intensity lasting four to 72 hours. Symptoms are aggravated by routine physical activity and are associated with nausea, photophobia and phonophobia. Usually, migraine headaches are preceded by premonitory symptoms (fatigue neck discomfort, gastrointestinal symptoms and mood changes), and these are followed by an aura of sensory and language disturbance.²

PH80 initiates neural impulses in the olfactory bulb transmitted by pathways that rapidly affect the function of multiple structures in the brain, including the amygdala and hypothalamus that have been linked to the pathology of migraine. Due to its mechanism of action and a small proof of concept study, Vistagen believes PH80 may have therapeutic potential to relieve premonitory and aura symptoms of migraines.

_{1. Mishra S, Elliott H, Marwaha R. Premenstrual Dysphoric Disorder. [Updated 2023 Feb 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.}

_{2. Headache, 58: 4-16, 2018. American Headache Society}

_{For more information on partnering with Vistagen, please contact us at bd@vistagen.com.}