PRODUCT PIPELINE

We are exclusively focused on the development of vomeropherins 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 vomeropherins.  Our broad pipeline of products includes four lead compounds:  PH80 for the treatment of PMS, PH94B for the acute treatment of social phobia, PH15 for improving cognitive performance (alertness), 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’s Product Pipeline

Pherin conducted a Phase 2A clinical study to investigate the dosing regime and product profile for the proof of concept. The company has also completed a Phase 2B clinical efficacy study of the PMS compound PH80 in association with Laboratorios Silanes (which has an option for a marketing license limited to Mexico). Also, Pherin has undertaken steps for a study of the anxiolytic compound PH94B in woman diagnosed with Social Anxiety disorder (Social Phobia). We expect to begin completion in the United States and Mexico of the second phase (Phase 2B) of the Social Phobia study as soon as we receive additional supply of GMP material.

Premenstrual Syndrome (PMS)

Several epidemiological studies indicate that up to 80% 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 60% 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 is 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 menstruation, 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, other aches and pains, uterine cramping and water retention.  Prescription antidepressant medications such as Prozac and other 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 and side effects such as decreased libido or GI and urinary tract symptoms. PH80 is a new product developed for the treatment of acute symptoms of PMS, using a novel route of administration with an excellent safety and tolerance profile.

The results of a phase 2 (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 clinical efficacy to reduce PMS symptoms. Since it has been shown to relieve 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 PH80 could have considerable market potential.

Pherin has completed a Phase 2 clinical study in collaboration with Laboratorios Silanes, 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.

Social Anxiety Disorder (Social Phobia)

The term Social Phobia describes a collection of disorders that share many similar clinical features and treatment strategies.  Anxiety disorders are among the most common forms of psychiatric illness, ranking third after depression and substance abuse.  Although both pharmacological and nonpharmacological therapies are considered useful in their treatment, it is estimated that only 30 - 50% of people with 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 anxiety disorder (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 anxiety disorders 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 has been conducting a randomized, placebo-controlled, double blind parallel clinical trial to study the efficacy of PH94B, in patients diagnosed with social phobia.  Interim 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. The company plans shortly to begin the completion of Phase 2B clinical trials in the United States and Mexico of an additional 50 patients based upon based upon the results of the first part of the clinical trials.

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 the elderly 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 a recent double blind, parallel, placebo controlled clinical study in cachectic patients (weight loss of 10% or more) diagnosed with terminal cancer, conducted at the National institute of Cancerology in Mexico City, showed that intranasal administration of PH284, a vomeropherin 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 after eight days of treatment. Also in the patients treated with PH284, there was improvement in the quality of life assessed using the Performance Status Index Scale.  We expect that PH284 should have considerable market potential for the treatment of eating disorders and/or appetite loss.

Alertness – Increase of Cognitive Performance

A large number of healthy individuals (seniors, women that reached menopause, subjects complaining of general tiredness and stress) complain annually of decreased performance or decreased alertness. A number of clinical conditions are also associated with general tiredness and decreased cognitive performance. Several studies have shown that patients complaining of insomnia due to several different causes score very low while challenged with cognitive performance situations.

The results of a double blind, randomized, placebo-controlled comparative clinical study performed by Pherin using quantitative tests for assessment of cognitive performance show that in comparison to the effects of placebo and 400 milligram caffeine administered orally, the reaction times to visual stimuli presented synchronously and also in random fashion are significantly faster and more regular after intranasal administration of 1.6 microgram vomeropherin PH15.

Of particular interest is the significant effect produced by PH15 during a challenge administered in random fashion, a situation that requires more attention by the subject. Here, the reaction times after intranasal administration of PH15 were rapid and significantly more regular than the reaction times recorded after administration of placebo and/or caffeine.

Also, the analysis of the mean values of the estimation of the stimulus-intervals by the subjects participating in the study did not show significant differences throughout all the study series. This shows that the study procedures and/or the method of administration of the study substances and placebo did not induce, by themselves, learning of the time- intervals by the subject. Therefore, the effects obtained in the study can be attributed to PH15. Due to the rapid onset of action of the effect of this vomeropherin, the low dose needed to obtain significant effects and the absence of side or adverse effects expect reported in the study, we expect that PH15 will have considerable market potential for the treatment of alertness deficiency.

ADDITIONAL AREAS OF INTEREST

Depression

Depression is a mood disorder that produces an extreme, 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 disease 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.  PH10A, a representative of a family of our proprietary vomeropherin 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 vomeropherins’ potential to have a very rapid onset of effect and very low incidence of side effects. 

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.

Benign Prostatic Hypertrophy (BPH) and Prostate Cancer

For patients with BPH or prostate cancer, 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 one of our vomeropherin compounds decreases LH concentration of human male volunteers, which leads to a subsequent decrease in circulating testosterone. This effect appears within five hours after intranasal administration of the vomeropherin to the nasal passages. We believe that due to the rapid onset of action, this vomeropherin might have a therapeutic advantage over currently available products that decrease testosterone concentrations due to the potential for vomeropherins to achieve this effect faster, with an increase in patient comfort and acceptance and reduced side effects that affect the quality of life.

In addition, currently available hormonal therapies for treatment of prostate cancer over stimulate GnRH receptors located in the pituitary gland, a small gland located below the brain.  Overstimulation of pituitary GnRH receptors leads to increased production of luteinizing hormone (LH).  The increased levels of LH then cause a surge of testosterone from the testes in males.  The temporary surge in hormone levels may result in a worsening, or flare, of the disease for which the patient takes the therapy.  Only after several weeks following administration of these hormonal therapies does the desired reduction of hormonal levels occur.  Accordingly, current hormonal therapies, such as Lupron Depot, that TAP Pharmaceutical Inc. markets, and Zoladex, that AstraZeneca Pharmaceuticals markets, have precautionary labeling about the hormone-induced flare.  The FDA mandates this precautionary labeling, and the drug labels and packaging for these currently available drugs must prominently include the precautionary labeling to protect patients and avoid the use of drugs in cancer patients who are at risk for developing a disease flare.

Based on an initial profile of the pulsatory release of LH and testosterone in male human volunteers, we believe that further clinical studies may disclose that our proprietary compound will have a considerably less adverse effcts on libido than the two leading products now being used to treat BPH.

Additional Endocrine System Programs

The hypothalamic area of the brain plays a major role in controlling the release of several hormones, including luteinizing hormone releasing hormone (LHRH).  The hypothalamus shares a special blood circulatory pathway with the pituitary gland, which is a target organ within the brain for LHRH.  When LHRH stimulates the pituitary, it releases LH into the systemic circulation.  The ovaries in women are target organs for LH, and they are stimulated by LH, among other hormones, to produce the sex hormone, progesterone in women.  This hormonal system is kept in balance by a feedback loop to the hypothalamus.

Our early pilot studies in human volunteers indicate that delivery of certain vomeropherins to the VNO can change the concentrations of certain pituitary hormones.  Vomeropherins that influence hormone concentrations could have therapeutic advantage in contraception and other situations that are influenced significantly by neuroendocrine function.  Successful development of a contraceptive vomeropherin could have advantages over other hormonal contraceptives because intranasal delivery eliminates the need for systemic circulation and would potentially allow for the lowest dose contraceptive agent on the market with significantly reduced side effects.