PH94B – Acute Treatment of Social Anxiety Disorder (“SAD”)
Social Anxiety Disorder is defined as an intense and persistent fear of being watched and judged by others, causing subjects to avoid everyday social situations for fear of being scrutinized, judged, humiliated or embarrassed. It is one of the most prevalent mental health conditions in the United States. SAD can interfere with daily routines and job performance and make it difficult for sufferers to maintain social relationships (Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Fifth Ed, 2013, American Psychiatric Association). SAD affects as many as 22 million American adults according to the National Institute of Mental Health (“NIMH”), an estimated 7% of the U.S. population. SAD is generally treated with antidepressants, which have a slow onset of effect (several weeks or months) and known side effects that may make then unattractive to certain individuals, including those with intermittent or episodic SAD.
Current drug treatments for SAD have not been fully successful. Antidepressants like serotonin reuptake inhibitors (“SSRIs”) and serotonin and norepinephrine reuptake inhibitors (“SNRIs”) take weeks or months to work and may initially worsen anxiety. Many patients are reluctant to take long-term daily SSRIs or SNRIs which may have significant side effects for a disorder that may only be situational. Off-label treatments such as Xanax sometimes exhibit side-effects such as addiction, tolerance, sedation and cognitive impairment. Beta-blockers may relieve physical symptoms such as racing heart but have to be taken in advance of a social anxiety event and lower blood pressure.
PH94B is a synthetic neuroactive steroid for which Phase 2 clinical data showed rapid onset of efficacy (10-15 minutes) and an excellent safety profile (Liebowitz et al., American J. of Psychiatry 2014, 171:675–682). Administered as a nasal spray, PH94B is designed to act locally on peripheral nasal chemosensory receptor cells that in turn trigger rapid activation of the limbic amygdala, the major neural structure controlling anxiety. In prior clinical studies in patients diagnosed with social anxiety disorder PH94B demonstrated rapid reduction of social and performance anxiety and there were no reports of addiction, sedation, and other adverse effects. We support VistaGen in its goal to make PH94B the first FDA-approved medication for as needed (“PRN”) and long-term treatment of individuals with SAD.
We have licensed PH94B to VistaGen Therapeutics (“VistaGen”) of South San Francisco, California. Upon any successful Phase 3 clinical trials of PH94B and approval of a New Drug Application (“NDA”) with the United States Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA”), VistaGen will pay to Pherin milestone payments and royalties on sales of PH94B products.
PH10 – Fast-Acting Intranasal Treatment for Major Depressive Disorder (“MDD”)
MDD is the most common psychiatric condition worldwide. According to the 2017 National Survey on Drug Use and Health, in the USA the prevalence of MDD is higher among adult women (8.7%) compared to men (5.3%) and it is highest (13.1%) among individuals aged 18-25 years. Major Depressive Disorder is characterized by episodes of at least two weeks involving changes in affect, depressive mood and changes in cognition and neurovegetative function with inter-episode remissions. (Diagnostic and Statistical Manual of Mental Disorders (DSM-5), Fifth Ed, 2013, American Psychiatric Association).
The most commonly used treatments for MDD are antidepressants and psychotherapy or a combination of the two. Most common antidepressants, including SSRIs, SNRIs, tricyclic antidepressants, ketamine and esketamine, have significant side effects and many have limitations related to the situations and patients in which they can be used. Orally administered antidepressants must be taken four to six weeks before they begin to produce substantial improvement. Injectable antidepressants like ketamine are rapidly acting but need to be administered in a clinical setting and chronic use may develop significant side effects.
PH10 is a synthetic neuroactive steroid that has been formulated in spray form for intranasal administration. PH10 targets nasal chemosensory receptor cells that are neutrally connected to specific areas of the limbic amygdala and in turn activate midbrain areas and the prefrontal cortex resulting in improvement of depression symptoms.
A Phase 2 pilot study in 30 patients diagnosed with MDD demonstrated safety and efficacy of PH10 significantly better than treatment with a placebo. This study also revealed rapid onset of antidepressant effect (accompanied by only minimal side effects) when compared to administration of placebos.
The Company believes that the potential competitive advantage of PH10 includes: (i) the first safe medication for treatment of MDD that can be self-administered intranasally without systemic exposure, (ii) adjunctive therapy that may provide rapid antidepressant effect at the beginning of the treatment (where conventional treatments generally take weeks for the onset of effect), and (iii) possible prevention of relapse following treatment with ketamine, administered either intravenously or intranasally.
We have licensed PH10 to VistaGen Therapeutics (“VistaGen”) of South San Francisco, California. Upon any successful Phase 3 clinical trials of PH10 and approval of a New Drug Application (“NDA”) with the United States Food and Drug Administration (“FDA”) and the European Medicines Agency (“EMA”), VistaGen will pay to Pherin milestone payments and royalties on sales of PH10 products.
PH80-HF – Acute Management of Menopausal Hot Flashes
Approximately 80% of women entering menopause suffer from hot flashes and associated symptoms lasting up to ten years. 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 of the person (Freedman R. J Steroid Biochem Mol Biol. 2014 Jul; 142: 115–120; National Institutes of Health, Ann Intern Med. 2005;142(12 Pt 1):1003. Epub 2005).
PH80-HF is a synthetic neuroactive steroid that engages nasal chemosensory receptor cells which in turn modulate neural circuits in the basal forebrain associated with the control of body temperature. Pherin conducted a double blind, placebo-controlled pilot study in 40 women diagnosed with menopausal hot flashes. Results showed clinically significant improvement in the number and severity of hot flashes and other symptoms of menopause in the subjects treated with PH80-HF that was significantly better than treatment with a placebo.
Pherin owns the worldwide patent rights to PH80-HF for the Treatment of Menopausal Hot Flashes and is investigating partnering and licensing opportunities for further development of this pherine compound.
PH80-M – Acute Treatment of Migraine Headaches
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 Journal of Headache and Pain (2010). A migraine is characterized by unilateral, pulsating headaches of moderate to severe intensity lasting 4 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 (Headache, 58: 4-16, 2018. American Headache Society)
PH80-M is a research stage neuroactive steroid in the Company’s pipeline of products formulated for intranasal spray administration. In an early pilot clinical study, PH80-M showed a profile compatible with the relief of the premonitory and aura symptoms of migraines. The Company recently filed a patent application with the United States Patent and Trademark Office and is investigating several research partnerships with academic institutions and non-dilutive funding sources to advance the development of PH80-M.
PH15 – Cognitive Improvement
Cognitive deficits are characterized by progressive loss of memory, cognition, reasoning and emotional stability that can gradually lead to an impact in the quality of life. Alzheimer’s Disease is the most common cause of progressive mental failure (dementia) in the aging population. In the USA, approximately 5.5 million people are affected, and the prevalence worldwide is estimated to be as high as 24 million (Alzheimer’s and Dementia, Elsevier, 2017).
PH15 is an early stage neuroactive steroid pherine in development for the acute treatment of cognitive impairment. Early functional MRI studies in human volunteers at Stanford University revealed that intranasal administration of PH15 induced rapid activation of brain areas related to Cognition (Sobel et al, Brain, 1999). In a double blind, placebo-controlled study in human subjects, intranasal PH15 showed rapid and significant improvement in cognitive performance and reaction time that was better than the effect of a placebo and oral caffeine. The Company is investigating potential research partnerships with academic institutions and nondilutive funding sources to advance this pherine compound to clinical trials in patients diagnosed with cognitive impairment.
PH284 – Acute Management of Feeding Disorders
Feeding disorders are characterized by persistent disturbance of eating behavior that results in the altered consumption and absorption of food that significantly impairs physical health or psychosocial functioning. The loss of appetite may have a psychiatric basis (anorexia nervosa in adolescents and Avoidance Restrictive Food Intake Disorder in children and aging subjects) or it may develop as a consequence of terminal disease, leading to cachexia (cancer, AIDS, other chronic medical conditions) (DSM-5, 2013; Heathling and Aker, .J. Cchexia, Sarcopenia and Muscle, 2014).
Cachexia is a serious but under recognized consequence of many chronic diseases with body mass loss of >10% and a prevalence of 5 to 15 %. In the USA, approximately 0.4% of women suffer from anorexia nervosa (women to men relationship 10:1), a psychiatric condition characterized by the relentless drive for thinness and/or a morbid fear of fatness. The medical consequences of starvation include endocrine dysfunction manifested as amenorrhea in women and loss of sexual potency in men, hypothermia, slower heart rate, hypotension and severely reduced body fat stores. (Wood D and C Knight. Pediatrics and child health 25(9) 428-432, 2015; Attia et al. New England J. of Medicine 360, 500-5006, 2009; Bulik et al. Eating disorders 40(4) 310-320, 2007).
Anorexia nervosa and other psychiatric conditions leading to loss of appetite and body mass are commonly treated with serotonin or with SSRIs or SNRIs. Cachexia is usually treated in the course of medicating the patient for the underlying disorder.
Pherin conducted a pilot double blind, placebo controlled clinical study in 40 patients diagnosed with cachexia due to terminal cancer. The study lasted 12 days and upon completion of a 7-day treatment period with intranasal PH284 or placebo all patients started treatment for their underlying condition. At the end of the 7-day treatment period, PH284-treated patients showed a significant increase in the subjective feeling of hunger (appetite), increased body weight and an improved quality of life, as compared with the placebo-treated group.
The Company is investigating possible research partnerships with universities and non-dilutive funding sources to advance this pherine compound to clinical trials in adolescent and young adult patients diagnosed with anorexia nervosa.