PROGRESS IN PHERINE MEDICATIONS
 

We are exclusively focused on the development of pherines for the treatment of human diseases and disorders.  To date, our technology has allowed us to make discoveries and file patents and patent applications that cover over 1,000 pherines.  Our broad pipeline of products includes four lead compounds:  PH80-PMS for the acute treatment of Premenstrual Syndromes, PH80-HF for the acute management of Hot Flashes and other symptoms of menopause, PH94B for the acute treatment of Social Phobia, PH10 for Depression, PH15 for Cognitive Enhancement, and PH284 for Appetite Stimulation. Pherin holds worldwide marketing rights to these compounds. We are open to discussions of collaborative licensing opportunities with forward-looking and technologically innovative pharmaceutical companies.

Table 1. Overview of Pherin Pharmaceuticals Product Pipeline

Figure 1. Pherin Pharmaceuticals Pipeline

Pherin conducted a Phase 2A clinical study to investigate the dosing regime, product profile and proof of concept, and completed a Phase 2B clinical efficacy and safety study of the compound PH80-PMS. Also, Pherin has undertaken the same steps for a study of the anxiolytic compound PH94B in patients diagnosed with Social Phobia. We expect to complete the second phase (Phase 2B) of the Social Phobia study in 2Q2010.

Premenstrual Syndrome (PMS)

Several epidemiological studies indicate that up to 75% of women of reproductive age (12 to 45 years) experience physical and emotional symptoms of PMS during several days prior to the onset of menses. Approximately 40% of these women are affected severely enough that they seek medical treatment. Only 7% of women of reproductive age are affected by an extremely severe condition called premenstrual dysphoric disorder (PMDD) and require psychiatric assistance. The constellation of symptoms and signs associated with PMS are commonly referred to as premenstrual syndrome, premenstrual distress, or premenstrual tension.

Clinically significant PMS are characterized by negative mood as well as behavioral and physical symptoms that occur consistently for several days to two weeks before the onset of menses. Irritability, mood swings, fatigue, appetite changes and pain are among the most common symptoms of moderate to severe PMS. These symptoms disrupt occupational and social functioning and may be of sufficient severity that professional help is sought. The symptoms subside after menstruation begins. 

Although negative mood may be reported on several days preceding the onset of menses, the symptoms of PMS can be distinguished from chronic psychiatric disorders by the presence of at least one symptom-free week after menstruation begins.  For some women, over-the-counter medications can relieve some of the physical symptoms of PMS, such as headaches and other aches and pains.  Prescription antidepressant medications such as serotonin selective reuptake inhibitors have been used as chronic prophylactic treatment (continuous daily medication) primarily for relief of some of the mood symptoms of PMS such as anxiety and labile moods. These medications often produce undesirable risks, particularly in adolescent women, and side effects such as decreased libido, gastro-intestinal and urinary tract symptoms and increased appetite. PH80 is a new product developed for the treatment of acute symptoms of PMS, using a novel route of administration.

The results of a Phase 2A (double-blind, placebo controlled randomized, crossover) clinical study in 35 women with PMDD found that administration of PH80 six times daily during 15 consecutive days was well tolerated and there were no reports of adverse effects. In the first arm of the study, treatment with PH80 showed dose dependent clinical efficacy to improve mood swings, irritability, depression and poor coordination.

Pherin has completed a Phase 2B clinical study in 60 women with clinically significant PMS under the direction of Dr. Ellen Freeman from the University of Pennsylvania. The statistically significant favorable results of this study are set forth in the Press Release that is attached to this website and include improved dysphoria, irritability, anxiety, depression, social life, eating habits and physical symptoms. At present

Pherin is in contact with the US FDA to request authorization to start Phase 3 clinical trials in the US. Since PH80 has been shown to improve PMS symptoms, it has a clinically proven broad safety and tolerance profile and it could be used on demand during the critical days of PMS, we expect that it could have considerable market potential.

Menopausal Hot Flashes

Hot flashes are the most common symptom of menopause. In the USA approximately 40 million women are at or near menopause with some 45 million beyond menopause. 75% women 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 their use in the USA 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 FDA for treatment of menopausal hot flashes.

Pherin Pharmaceuticals recently conducted a pilot open-label study of PH80-HF controlled with placebo in twenty eligible volunteers age 45-65 years, to compare the effectiveness and tolerability of 1.6 mg PH80-HF intranasal spray or placebo intranasal spray for the acute management of hot flashes. Study medication and placebo were administered 6-times per day for 2 consecutive weeks. The primary outcome measure was a statistically significant improvement in the severity of hot flashes. Secondary endpoints included tolerability and safety.

The results of this exploratory study showed rapid mean onset of action (35 sec) of PH80-HF (1.6 micrograms) after intranasal spray administration. Body temperature, electrodermal activity and muscle tension that were significantly increased from baseline level during the induction of a hot flash, returned to baseline level after intranasal administration of PH80-HF. Placebo did not improve significantly these parameters during the course of a hot flash.

Ph80-HF (1.6 mg) significantly improved the severity or daily hot flashes along the 14-days in-house treatment period. Patients reported significant reduction of the frequency and the intensity of hot flashes and also reported feeling overall better. 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. The effect of PH80-HF was statistically significantly better than the effect of intranasal placebo.

In view of the favorable results of the exploratory clinical study Pherin Pharmaceuticals started Phase 2A proof of principle clinical trials in 60 menopausal women screened for moderate to severe hot flashes. Phase 2A trials are conducted in two qualified clinical sites in Mexico City.

The primary endpoint of this study is to measure an effect of PH80-HF statistically significant and different from placebo for the acute management of menopausal hot flashes. The secondary endpoints are a significant improvement of symptoms of menopause other than hot flashes, and the safety and tolerability of PH80-HF administered intranasally to menopausal women for these therapeutic indications.

Social Phobia

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

Patients with social phobia 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.  These patients 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 Phobia 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 ten 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.

The primary pharmacological agents used to treat social phobia are beta-blockers, antidepressants such as selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors and benzodiazepines.  The use of these agents 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 action that is used on an on-demand basis for treatment of social phobias could have substantial clinical and economic advantages over currently available medications.

Pherin Pharmaceuticals conducted a randomized, placebo-controlled, double blind parallel Phase 2A clinical trial to study the efficacy of PH94B, in patients diagnosed with social phobia.  The analysis of 40 patients that completed treatment shows that PH94B is significantly better than placebo to relieve anticipatory anxiety and performance anxiety. The effect is achieved within 5 to 10 minutes after intranasal administration of 800 nanogram (0.8 thousand of a milligram) of PH94B. Based upon the favorable results of the first part of the clinical trials, the company started Phase 2B clinical trials in the United States and Mexico. Completion of this study is planned for 2Q2010.

Depression

Depression is a mood disorder that produces an 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.  Data suggest that nine out of ten people who have depression can be helped by antidepressant medications.  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 may provide therapeutic advantages when used as antidepressant treatments, 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.  Pherin started Phase 1 clinical trials in collaboration with Productos Medix. We believe that we have promising antidepressant lead compounds that we intend to explore after completion of the proof of concept studies using PH80 and PH94B.

Body Weight Management - Appetite Stimulant

Each year millions of people worldwide are affected by serious and sometimes life-threatening psychiatric eating disorders, which include anorexia nervosa, bulimia nervosa and binge eating disorders.  The vast majority of those afflicted with these serious behavioral maladies are adolescent and young adult women, although all age groups, including the elderly and children as young as six, are affected.  In addition, the incidence of eating disorders in men appears to be increasing.  The consequences of these eating disorders can be severe.  For example, one in ten cases of anorexia nervosa leads to death from starvation, cardiac arrest, other medical complications or suicide.

A number of other clinical conditions are also associated with changes in appetite and food intake.  Studies have shown that two-thirds of patients with advanced cancer have had some degree of weight loss, and that more than half are underweight, have loss of appetite or complain of a decrease in energy intake.  Loss of appetite and physical wasting are common symptoms.  AIDS patients experience similar problems.  In addition to their psychological and behavioral consequences, cancer-induced and AIDS-related loss of appetite and weight loss are correlated with decreased life expectancy and also are predictors of increased toxicity following chemotherapy.  In addition, inadequate food intake often resulting from loss of appetite is a frequent condition in seniors and is known to affect both health status and life expectancy.  Appetite loss also is one of the most common, challenging and difficult symptoms associated with acute illness.  Furthermore, many pregnant women experience loss of appetite, with potential adverse health effects, as well.  Few if any clinically acceptable and useful medications currently are available for these various conditions, although there are many clinical reports pointing out the urgency of this need.  

The results of Pherin Pharmaceuticals conducted a double blind, parallel, placebo controlled clinical study in cachectic patients (weight loss of 10% or more) diagnosed with terminal cancer, at the National institute of Cancerology in Mexico City. Results showed that intranasal administration of a total dose of 3.6 mg PH284, a pherine with a novel mechanism of action, a broad safety profile and very rapid onset of effect, increased appetite, energy consumption, and increased mean body weight gain of 600 grams at the end of an eight- days treatment. Qualityof life assessed using the Performance Status Index Scale also improved in patients treated with PH284.  We expect that PH284 could have considerable market potential for the treatment of eating disorders and/or appetite loss.

Cognitive Enhancement

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, 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 presents a major present 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 patients complaining of insomnia due to several different causes score very low while 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 (estrogen, cholinergic agonists) or have been proven to have similar efficacy to placebo.

PH15 is a pherine compound discovered and developed by Pherin scientists that is currently being developed 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. Inn vitro and in vivo toxicology studies revealed that PH15 is well tolerated in laboratory animals in 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.

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

Of particular interest is the significant effect produced by PH15 during a cognitive challenge where the volunteers had to identify stimuli administered in random fashion, a situation that requires more attention. The reaction time after intranasal administration of 1.6 mg PH15 nasal spray was faster and statistically significantly more regular than the reaction time recorded after administration of placebo and 400 mg oral caffeine. Due to the rapid onset of effect of pherine PH15, the low dose needed to obtain significant improvement in cognition 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.

Benign Prostatic Hypertrophy (BPH)

For patients with BPH, reduction of circulating levels of testosterone is believed to be of therapeutic benefit by inhibiting tumor growth and/or controlling various physical symptoms of the disorder.  Although several products currently on the market can successfully reduce testosterone concentrations, the use of all of these compounds is associated with significant side effects. Our pilot clinical studies in adult males indicate that our pherine compound PH45 decreases LH concentration in human male volunteers, followed by significant decrease in circulating testosterone. These effects appear within five hours after intranasal administration of the pherine to the nasal passages. We believe that due to the rapid onset of action, pherine PH45 might have a therapeutic advantage over currently available products that decrease testosterone concentration due to the potential to achieve this effect faster, with an increase in patient comfort and acceptance and reduced side effects that affect the quality of life.