Pherin Clinical Development Programs

 

Social Anxiety Disorder (Social Phobia)

The term Social Anxiety Disorder, previously called Social Phobia, describes a collection of disorders that share many similar clinical features and treatment strategies.  Social Anxiety Disorder is the most common anxiety disorder, with a lifetime prevalence of 13-14%; and it is among the most common psychiatric illness, ranking third after depression and substance abuse.  Although both pharmacological and non-pharmacological therapies are considered useful in the treatment of Social Anxiety Disorder, it is estimated that only 30% - 50% of people with Social Anxiety Disorder currently receive professional treatment.  This disorder can significantly impair a person's occupational and social functioning, as well as place high economic demands on society.


Patients with Social Anxiety Disorder experience a marked and persistent fear of most social or performance situations in which they believe embarrassment could occur. Exposure of these patients to social or performance situations almost invariably provokes an immediate anxiety response.  The subjects learn either to avoid these situations or to endure them with dread.  The avoidance, fear or anxious anticipation of these situations interferes significantly with the person's daily routine, having a marked impact on occupational functioning and social life.


Social Anxiety Disorder episodes occur within the context of several different anxiety disorders.  In all instances there is a discrete period of intense fear or discomfort, accompanied by both physical and cognitive symptoms that develop abruptly and reach a peak within minutes.  These symptoms may include heart pounding, sweating, trembling, shortness of breath, nausea, dizziness and the fear of losing control or of dying.  The severity of the episode varies widely, and it may occur daily, weekly or less frequently, depending on the exposure of the patient to the phobic situation.


Pharmaceuticals used to treat Social Anxiety Disorder include beta-blockers, antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, monoamine oxidase inhibitors and benzodiazepines. The use of these medications typically requires a prolonged period of treatment and is associated with a number of undesirable side effects.  Furthermore, these medications must be taken daily, on a prophylactic basis. We believe that a product with a novel mechanism of action, broad safety profile, and very rapid onset of efficacy that is used on an on-demand basis as needed for treatment of Social Anxiety Disorder could have substantial clinical and economic advantages over currently available medications.


Pherin Pharmaceuticals completed favorable randomized, placebo-controlled, double blind, longitudinal Phase 2 clinical trials using PH94B nasal spray in patients diagnosed with Social Anxiety Disorder. The analysis of 91 patients that completed treatment shows that PH94B was efficacious to reduce symptoms in 75.6%, as compared with placebo (37% only). PH94B was significantly superior to placebo to relieve performance anxiety symptoms (t= 3.16; p<.01) and social interaction anxiety (t= 2.67, p< .01) during a public speaking challenge. These effects were achieved within 15 minutes after intranasal administration of 800 nanogram (0.8 thousand of a milligram) of PH94B. There were no adverse events or side effects reported associated with nasal administration of PH94B and the medication was well tolerated by the treated individuals. After completion of the Phase 2B clinical trials, Pherin held a successful End-of-Phase 2-Meeting with the US Food and Drug Administration (US FDA) regarding PH94B. Based upon these favorable results, an updated version of the Phase 3 clinical protocol was submitted to the US FDA to allow Pherin to move into Phase 3 clinical trials.


A Phase 3 pilot feasibility trial using PH94B nasal spray in men and women was successfully completed. Men and women (mean age 40.2 years) who met predetermined criteria for event frequency and severity were randomized to 2-weeks of treatment with PH94B or placebo, used on a PRN basis up to 4-times daily, self-administered 15-minutes before entering a feared situation. Patients carried a diary to rate the severity of their anxiety in a scale from 0 to 100 (SUD scores).


PH94B improved social anxiety symptoms on the primary endpoint (SUD scores) significantly better than placebo (p = 0.006), and the drug superiority over placebo was similar for men and women. PH94B also showed significant superiority to placebo on several secondary endpoints as the Liebowitz Social Anxiety Scale (LSAS), Patient Global Improvement (PGI) and Clinical Global Improvement (CGI). Adverse effects were mild and did not show drug-placebo differences. These findings are important because they support the follow up Phase 3 trials, and because PH94B could be the first systematically studied PRN treatment for Social Anxiety Disorder that could be used either as a monotherapy or as an adjunctive treatment.

 

Depression

Depression is a mood disorder characterized by extreme and persistent disruption of a person’s usual emotional state, affecting physical health as well as how the sufferer feels, thinks and behaves toward others.  Depression is a physical disorder resulting from an imbalance of important chemicals within the brain.  Because of its disabling effects and the possibility of suicide, major depression requires treatment.  Depression in some form affects 20% of all women, 10% of all men and 5% to 10% of all adolescents worldwide.  It is the most common psychiatric illness in the United States, afflicting an estimated 17.6 million people each year.  The common time of onset of depression is early middle age, and depression is particularly common among the elderly.  It is estimated that untreated depression costs American employers as much as $43.0 billion per year through sick days, lost productivity, employee turnover and medical bills.


The most commonly used treatments for depression are antidepressant medications, psychotherapy or a combination of the two.   The major types of antidepressants currently available commercially include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors and so-called new-generation antidepressants.  All of these medications have significant side effects, and many have limitations related to the situations and patients in which they can be used.  In most cases antidepressant medications must be taken for four to six weeks before they begin to produce substantial improvement in a depressed person’s mood.  Furthermore, finding the right antidepressant at exactly the right dosage for a given individual usually involves a substantial period of trial and adjustment.  In many cases, the use of adjunct medication has been found helpful in curbing the symptoms of depression during the period before antidepressant medication achieves its therapeutic efficacy.  PH10, a representative of a family of our proprietary pherine compounds, is being investigated to provide therapeutic advantages when used as antidepressant treatment, particularly as an adjunct medication during the early stages of the antidepressant treatment period, because of the pherine’s potential to have a very rapid onset of effect and very low incidence of side effects.  Using PH10 nasal spray, Pherin completed an initial pilot study, outside the U.S., in humans with favorable results.


Subsequently, an exploratory Phase 2A randomized study was conducted in 30 patients diagnosed with major depression, to compare the efficacy and safety of 400 and 800 nanogram PH10 and placebo administered intranasally in spray form. Patients self-administered PH10 nasal spray up to 4 times daily during 9 consecutive weeks and were evaluated in the clinic at the end of each treatment week, using validated psychometric instruments.
The preliminary analysis of the results shows significant dose dependent effect of PH10 nasal spray on Hamilton Depression scores, which is different from the effect of treatment with placebo. The clinical efficacy of 800 nanogram PH10 nasal spray on Hamilton Depression scores was greater than that of 400-nanogram PH10, increased progressively starting on the first day of treatment and continued along the 98-week treatment period. The rapid onset of effect of PH10 nasal spray reported in the present study is very promising and may help mitigate the symptoms of depression with a much faster onset of efficacy, and safer than conventional antidepressants.

 

Menopausal Hot Flashes

Hot flashes are the most common symptom of menopause. In the U.S. approximately 40 million women are at or near menopause and some 45 million are beyond menopause. Up to 80% of women may experience hot flashes during the perimenopause transition or after menopause. Hot flashes are a significant quality of life and workplace issue because substantial numbers of women experience symptoms that are debilitating. Women that experience hot flashes are more likely to seek medical care than those who do not.


Current available therapies to treat hot flashes include hormonal replacement therapy (estrogen with or without progesterone, or a synthetic progestin), gabapentin, SSRIs, clonidine and herbal products. These therapies have well known side effects (hormonal therapies, SSRIs, gabapentin, clonidine) or have been proven ineffective to treat menopausal hot flashes (herbal products). Although estrogens have shown relief of hot flashes, use in the U.S. became sharply curtailed after 2002 with concerns about breast cancer and cardiovascular events associated with chronic treatment. At present, there is no other alternative prescription medication approved by the US Food and Drug Administration for treatment of menopausal hot flashes.


Pherin Pharmaceuticals conducted a Phase 2 exploratory randomized study in forty eligible volunteers age 45-65 years, to compare the effectiveness and tolerability of 1.6 microgram PH80-HF nasal spray for the acute management of daily menopausal hot flashes. Study medication or placebo was administered 6-times daily for 2 consecutive weeks. The primary outcome measures were the significant improvement in the severity, number of hot flashes, and the following objective parameters: body temperature, electrodermal activity and skeletal muscle tension. Secondary endpoints included tolerability and safety of Salubrin-HF nasal spray.


The results of this study showed rapid onset of action of PH80 (35-65 sec) after intranasal spray administration of 1.6 microgram. Physiologic parameters that were increased during the occurrence of hot flashes improved significantly better than placebo after administration of Salubrin-HF: body temperature (p<.02), electrodermal activity (p<.01) and muscle tension (p<.04). 

PH80-HF (1.6 microgram) improved the severity (p<.02) and the number (p<.07) of daily hot flashes along the 14-days in-house treatment period. Intranasal administration of PH80-HF was safe and there were no reports of local (nasal) or systemic side effects and/or severe adverse effects during the treatment period and during the follow-up period.

 

Cognitive Improvement

Cognitive deficits are characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that can gradually lead to profound mental deterioration. In an example of such disorders, Alzheimer’s Disease (AD) is a common cause of progressive mental failure (dementia) in aged humans. Such disorders have been observed in varied races and ethnic groups worldwide and present a major current and future public health problem. These disorders are currently estimated to affect about two to three million individuals in the United States alone. A large number of healthy individuals (seniors, menopausal women, individuals suffering of general tiredness and stress) also complain annually of decreased performance or cognition. Several studies have shown that individuals complaining of insomnia due to several different causes score very low when challenged with cognitive performance situations. In the US.. alone, these conditions address a market estimated to be $2 billion annually.


Current therapies to treat cognitive deficiency include estrogen, cholinergic agonists and OTC products. These therapies have well known side effects or have been proven to have similar efficacy to placebo.


PH15 is in early stage development for the treatment of cognitive impairment. In vitro and in vivo pharmacological studies revealed that PH15 binds to GPC-peripheral receptors in the nasal passages in a dose dependent manner. In vitro and in vivo toxicology studies showed that PH15 is well tolerated in laboratory animals at concentrations 100-fold higher than the dose proposed to use in clinical studies. FMRI studies in human volunteers performed at the Institute of Neuroscience of Stanford University, California, revealed that intranasal administration of PH15 activates human brain areas related to the anterior gyrus cingulate (hippocampus, hypothalamus, limbic system, anterior thalamus, frontal and temporal cortex) in a dose dependent manner and this effect is significantly better that the effect of placebo-control.


Pherin Pharmaceuticals conducted a double blind, randomized, placebo-controlled pilot study in sleep deprived healthy volunteers (N=10) to compare the effects of its proprietary pherine PH15 nasal spray, placebo and orally administered caffeine, using quantitative computer simulation tests for assessment of cognitive performance and reaction time. The results show that intranasal administration of 1.6 microgram PH15 nasal spray improved cognition. This was revealed by a faster reaction time to identify synchronous and randomly presented visual stimuli in volunteers treated with PH15 nasal spray. This effect was statistically significantly better than the effect of placebo, and also than that of 400 milligram of caffeine administered orally.


Of particular interest is the significant effect produced by PH15 nasal spray during a cognitive challenge when the volunteers had to identify stimuli administered in random fashion, a situation that requires increased attention. The reaction time after intranasal administration of 1.6 mg PH15 was faster and statistically significantly more regular than the reaction time after administration of placebo or 400 mg oral caffeine. Due to the rapid onset of effect of PH15 nasal spray, the low dose needed to obtain significant improvement and the absence of side or adverse effects reported in the study, we expect that PH15 nasal spray will have considerable market potential for cognitive enhancement.

 

References

American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.).

Freeman EW, Monti-Bloch L. 2007.Evaluation of a unique new intranasal aerosol in the treatment of clinically significant premenstrual syndrome. NCDEU/ASCP Annual Meeting (New Clinical Drug Evaluation Unit/American Soiciety of Clinical Psychopharmacology) Boca Raton, Florida, 2007.

Liebowitz MR, Hanover R, Draine A, Lemming R, Careri J, Monti L. 2016. Effect of as-needed use of intranasal PH94B on social and performance anxiety in individuals with social anxiety disorder. Depress Anxiety, 33(12):1081-1089. doi: 10.1002/da.22546. Epub 2016 Aug 25. PMID: 27561175.

Liebowitz M, Nicolini H, Hanover R, Monti L. 2013. PH10 May Be a New Rapidly Acting Intranasally Administered Antidepressant. Abstracts of Poster Presentations: CNS Summit 2013: November 14–17, 2013 Boca Raton, Florida. Innovations in Clinical Neuroscience, 10(11-12 Suppl B), 1–18.

Liebowitz MR, Salman E, Nicolini H, Rosenthal N, Hanover R, Monti L. 2014. Effect of an acute intranasal aerosol dose of PH94B on social and performance anxiety in women with social anxiety disorder. Am J Psychiatry, 171(6):675-82. doi: 10.1176/appi.ajp. PMID: 12101342.

Liebowitz M, Salmán E, Rosenthal N, Nicolini H, Monti L. 2011. Evaluation of a Unique Nanogram‐Dose Intranasal Aerosol for the Acute Management of the Symptoms of Social Anxiety Disorder. Abstracts of Poster Presentations: NCDEU, Boca Raton, Florida. doi: 10.13140/RG.2.1.2972.8081.