PH80 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 vasomotor symptoms (hot flashes) due to menopause and premenstrual dysphoric disorder (PMDD), and other women’s health disorders, as well as migraine headaches. Administered as a nasal spray at microgram-level doses, PH80 activates chemosensory neurons in the nasal cavity connected to neural circuits in the brain that modulate neural circuits in the basal forebrain.
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.1 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 in 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 menopausal hot flashes compared to placebo at the end of the first week of treatment (p<0.001), and the improvement was maintained through each treatment week until the end of the four-week treatment period. 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 a U.S. IND for Phase 2B clinical development of PH80 for the treatment of patients with moderate to severe 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 PMDD2. 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 symptoms 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 four and continuing to day six. At day six, 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.
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1. Massachusetts General Hospital Center for Women’s Mental Health, https://womensmentalhealth.org/posts/the-immense-burden-of-menopausal-symptoms/.
2. Mishra S, Elliott H, Marwaha R. Premenstrual Dysphoric Disorder. [Updated 2023 Feb 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.