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arGentis Ocular

arGentis has licensed the intellectual property (one issued patent, two pending) for three transdermal compounds from the Southern College of Optometry to treat dry eye syndrome (DES). Our lead compound is ARG101 for the treatment of DES in menopausal women caused by waning androgen levels. ARG102 is for the treatment of younger women and men with DES caused primarily by lack of lipid secretion. ARG103, a combination therapy used to treat post-menopausal women. Each therapy uses transdermal delivery of the active pharmaceutical ingredient through application of a cream or gel formulation to the outer upper and lower eyelids, providing a mechanism of action that restores the natural process of tear production.

arGentis DES (Dry Eye Syndrome) Therapies

ARG101 is a testosterone cream or gel formulation used to treat DES in menopausal women. Waning androgen levels in women before, during, and after menopause has been identified as a primary cause of DES in this population. ARG101 is unique in that it is applied to the upper and lower eyelids for transdermal delivery of testosterone directly to the affected glands. Delivering the active pharmaceutical ingredient transdermally allows better access to the glands and enables convenient twice-daily dosing. ARG101 restores aqueous and lipid production thereby restoring the natural process of tear production.

Clinical practice at the Southern College of Optometry (SCO) has documented ARG101 efficacy and safety. Patients using ARG101 achieved a 51% increase in aqueous secretion (p=0.01) and a 68% increase in tear breakup time, a measure of meibomian gland function, versus baseline measurements. There was also a 51% (p=0.01) decrease in symptoms as measured by the Ocular Severity Disease Index (OSDI), a validated measure of DES symptoms. There have been no adverse events and, importantly, no increase in intraocular pressure in patients using the testosterone cream for three years. Results of the use of testosterone in patients at SCO have been presented at the Annual Meeting of the American Association of Optometrists in each year 2002-2006.

ARG102 is a progesterone cream or gel formulation used to treat DES in men and younger women. The cross-reactivity between progesterone and corticosteroid receptors in the ocular region is believed to activate corticosteroid anti-inflammatory activity in the glands and on the ocular surface, restoring normal aqueous and lipid production. ARG102 is also applied to the upper and lower eyelids for transdermal delivery of progesterone directly to the affected glands.

Patient data from clinical practice at SCO has shown that patients using ARG102 had a 34% increase in tear breakup time (p=0.01) and a 20% decrease in symptom severity (p=0.05) after only three weeks of use versus baseline measurements. There were no reported adverse events or increases in intraocular pressure. These results were presented at the 2006 Annual Meeting of the American Association of Optometrists.

ARG103 is a combination of testosterone and progesterone in a cream or gel formulation used to treat previously untreated post-menopausal women. Anecdotal results from SCO have shown promise in treating these women who because of lack of treatment options may have more severe glandular dysfunction.

These treatments share several characteristics which make them unique among current DES therapies and those in development:

• A patient-friendly application with a cream or gel formulation to the outer upper and lower eyelids versus conventional drop application.
• Transdermal delivery of anti-inflammatory hormones directly to the affected glands.
• Restores the natural process of tear production versus tear replacement of conventional therapies.
• Convenient twice-daily dosing versus the frequent applications required by tear replacement therapies.
• No stinging or burning of the skin to which it is applied or of the ocular surface.

The transdermal treatments are believed to act locally at the site of the affected glands. Systemic effects have not been seen. Due to the inefficiency of the current formulation, each will be reformulated for clinical trials and contain less steroid hormone than other transdermal hormone treatments for other indications currently on the market.

Dry Eye Syndrome

Dry eye syndrome (DES), also known as keratoconjuctivitas sicca (KCS), is one of the most common disorders of the eye. It is caused by a lack of tear quantity, or lack tear quality, adequate tear production without the necessary elements to maintain them. Those suffering from DES present with a sense of dryness, grittiness, foreign body sensation, or visual disturbances depending on the severity of the condition. DES is much more complex than originally thought, involving secretions from three separate glands, comprehensively known as the lacrimal system.

What are commonly known as tears are actually a film comprised of three layers. The outermost lipid (oily) layer is secreted by the meibomian glands. This oily layer coats the middle aqueous (water) layer secreted by the lacrimal glands and retards evaporation. Once thought only to wash away debris, it is now understood that the aqueous layer supplies oxygen and a special mixture of electrolytes to surface eye cells since these cells have no blood supply. The innermost or base layer of the tear film is a mucous layer produced by the conjunctiva goblet cells which attaches the tear film to the corneal surface. The hydrophilic quality of the mucous layer allows the aqueous to spread over the corneal surface. The mucus is secreted by goblet cells on the ocular surface. Each of these layers is critical to producing and maintaining tear film that hydrates, nourishes, and protects the ocular surface from infection. Dysfunction of one or more of these elements may cause DES.

Central to virtually all dry eye disorders is a loss of water from the tear film that increases solutes (osmolarity) on the ocular surface such as sodium and potassium. This loss of water and increase in osmolarity may result from any condition that either decreases tear production or increases tear evaporation; either of which causes the eye surface to dry, become irritated, itchy, or have the sensation of foreign matter. Tear production can decline due to lacrimal gland disease, as a result of anything that decreases the delivery of lacrimal gland fluid to the ocular surface, or even in reaction to decreased corneal sensation. Increased evaporation, meanwhile, commonly comes from meibomian gland dysfunction, which causes a drop in the amount of protective lipid in the tear film. Whatever the initial causes of dry eye, chronic dryness of the ocular surface results in inflammatory reactions and gradual destruction of the lacrimal glands and conjunctival epithelium. Once dry eye disease has developed, inflammation is the key mechanism of ocular surface injury, as both the cause and consequence of cell damage.

In the last decade, it has become well-recognized that sex hormones such as androgens, estrogens, and progesterones help regulate the function of the lacrimal and meibomian glands. An imbalance in these hormones may lead to DES and irritation to the ocular surface. Perceiving the eye to be under attack, the body’s immune system produces T lymphocytes, immune cells that destroy infection. These T cells in turn release proteins known as cytokines, which cause inflammation on the ocular surface. The proper effects of these hormones are critical to glandular secretions which comprise tear film and also determine who is susceptible to DES.

In several population-based studies DES have been found to be much more prevalent in women. The decrease in serum androgens in women as they reach menopause has been shown to increase the incidence of DES. This has been confirmed in Sjogren's syndrome, an autoimmune disease causing the most severe dry eye condition, which occurs almost exclusively in women. Both the aqueous-producing lacrimal glands and the lipid-producing meibomian glands are sensitive to androgens. As women age, androgen production decreases, the functionality of these glands can wane, causing either insufficient aqueous production from the lacrimal glands or a lack of lipid secretion from the meibomian glands, decreasing the evaporation time of tears produced, or both.

(link to PDF with citations)

ARG201 - An Innovative Approach to Treating Systemic Scleroderma

arGentis Pharmaceuticals, Inc. has licensed a treatment for systemic sclerosis (systemic scleroderma - SSc), a life-threatening autoimmune disease that result in widespread accumulation of collagen in the skin, blood vessels and internal organs. A number of autoantigens have been identified in SSc including type I collagen, the most prevalent protein in the body. According to the Scleroderma Foundation, there are approximately 100,000 individuals in the U.S. with systemic disease (Mayes 2003). There appear to be a similar number of patients in Europe.

SSc patients develop confluent areas of hardened skin to varying degrees depending on the type of scleroderma. Persons with limited SSc generally have skin involvement that does not extend above the elbow or above the knee, although in some patients, the face can be affected. Those with diffuse SSc can have widespread skin thickening involving the entire body. Patients also present with Raynaud's Phenomenon, a vasospastic condition causing pallor of the fingers. Moreover, diffuse SSc has a high degree of internal organ involvement with fibrosis of the lungs, kidneys, and gastrointestinal tract. Twenty years ago patients died predominately from extreme hypertension caused by fibrosing blood vessels leading to renal failure. Although renal failure still occurs, with better therapies to manage hypertension, most patients today die from pulmonary hypertension; lung fibrosis leading to respiratory failure; GI tract fibrosis, which impedes the ability to eat and digest food; and fibrosis of the heart, leading to cardiopulmonary failure. Median survival from diagnosis is eleven years in patients with diffuse systemic sclerosis (Mayes 2003).

Although some populations have a higher incidence of SSc, it is a pan-ethnic disease. As with most other autoimmune diseases, scleroderma is more prevalent in women than men by a 3:1 margin. Onset typically occurs in adults 25-45 years old; although older adults and children do get the disease.

Current therapies for SSc include the use of immunosuppressants like cyclophosphamide, mycophenalate mofetil (CellCept® - Roche/Aspreva) and abatacept (Orencia® - Bristol Myers), which has demonstrated only mixed success in SSc patients. Other therapies to treat symptoms include ACE inhibitors for hypertension, proton pump inhibitors to alleviate pain associated with GI tract fibrosis. None of these therapies treat the underlying cause of the disease which stems from ongoing autoimmune reactions. In SSc cases with rapid progression, hematopoietic stem cell transplants have been performed. However, the transplant itself has associated morbidities and some mortality risk. Even if the transplant is initially successful, SSc may return later.

Immune Tolerance

An antigen is something that provokes an immune response. An autoantigen is one that despite being normal tissue provoke the body's immune system. A variety of autoantigens have been identified in SSc patients. One of the most widely distributed autoantigens in SSc is type 1 collagen. In other words, in SSc patients the body is attacking its own type 1 collagen, the most prevalent protein in the body.

ARG201 treats SSc by inducing immune tolerance. Approximately one-third of the body’s immune cells reside in the gut-associated lymphoid tissue (GALT). The GALT is particularly effective in mounting a tolerogenic response to ingested soluble proteins. This process, called oral tolerance (OT), is the specific suppression of cellular and/or humoral immune responses to an antigen by oral administration of the antigen. The mechanisms mediating oral tolerance include active cellular suppression (regulatory T cells), clonal anergy, or clonal deletion. Which mechanism(s) predominate depends on the dose of oral antigen or peptide. After decades of research, Postlethwaite and Kang developed a treatment for systemic scleroderma by orally introducing type I bovine collagen into the gut, inducing tolerance within the immune system.

The prevention or treatment of autoimmune disease by oral tolerance has been demonstrated in a number of animal models, including type II collagen-induced arthritis, experimental autoimmune encephalitis (EAE), experimental autoimmune uveoretinitis and type I diabetes mellitus. Studies in humans have included the oral administration of myelin basic protein to treat multiple sclerosis, bovine retinal antigen for uveitis, and type II native bovine collagen to treat rheumatoid arthritis. These studies, conducted over a decade ago when the mechanisms of tolerance induction were not as well understood, had mixed results due to being inadequately controlled with regard to dose and concomitant use by trial participants of NSAIDs or moderate-dose corticosteroids, which are now known to interfere with tolerance induction.

ARG201 uses precise, low dose of highly purified native type 1 bovine collagen prepared by a proprietary purification method to induce oral immune tolerance in SSc patients' immune system to type 1 collagen. Low dose OT is mediated by induction of antigen specific regulatory T lymphocytes that secrete immunoregulatory cytokines such as IL-4, IL-10 and transforming growth factor (TGF)-β.

ARG201 for the Treatment of Systemic Scleroderma

The Investigational New Drug (IND) application was filed with the FDA in 1995 and began a Phase I clinical trial in patients with systemic sclerosis. Seventeen patients were treated for 12 months. The trial demonstrated that oral administration of BCI to SSc patients induced significant reductions in interferon y and interleukin-10 indicating T cell immunity to type I collagen was decreased by this treatment. Moreover, modified Rodnan Skin Scores (MRSS), a measure of skin thickness at 17 points on the body, improved by 23% (p<0.005). The M-Health Assessment Questionnaire, a patient self assessment of the difficulty of performing daily activities improved by 27% (p<0.05).

Based on the Phase I findings, researchers received a $5 million NIH grant to conduct a 168-patient Phase II trial. The trial was conducted at thirteen major rheumatology centers in the U.S., which included UTHSC. Other medical centers participating in the trial included Johns Hopkins, UCLA, Boston University, Georgetown University, Beth Israel Medical Center (NY), University of Alabama-Birmingham, Medical University of South Carolina, Wayne State University, University of Maryland, University of Connecticut, University of Texas, Benaroya Research Institute-Virginia Mason (Seattle).

The 168-patient, double-blind, placebo-controlled Phase II trial had two prospectively defined subgroups of diffuse systemic sclerosis patients:

• Early phase patients (patients diagnosed < 3years)
• Late phase patients (patients diagnosed > 3 years)
• Placebo

The primary endpoint of the trial change in modified Rodnan Skin Scores at 12 months with follow up at 15 months

ARG201 has completed a multicenter, 168-patient Phase II clinical trial with very promising results. Although the primary endpoint of the trial was a change in modified-Rodnan Skin Scores (MRSS) in the overall treated patients versus placebo; two subpopulations, Early Phase patients (EP - diagnosed for ≤ 3 years) and Late Phase patients (LP - diagnosed from 3 to 10 years) were prospectively defined due to differences in immunologic function of the two groups. This was indeed borne out in the trial. Changes in modified-Rodnan Skin Scores (MRSS), an FDA mandated endpoint, between placebo versus treated groups, were not statistically significant for the overall population or either subgroup at 12 months. However, at 15 month follow up changes in MRSS were highly statistically significantly lower (p=0.006) based on available data in the treated Late Phase group and approaching statistical significance (p=0.0656) on an intent-to-treat basis. In the trial, 65% of Late Phase patients experienced at least a 25% improvement in skin scores versus only 30% of patient in the group (p=0.01). Importantly, a statistically significant upregulation of IL-10, a marker for tolerance induction and an antifibrotic cytokine, was seen in the peripheral blood mononuclear cells (PBMCs) of the treated LP patients at 12 months, demonstrating that oral immune tolerance had been induced. This confirmed results from the Phase I trial demonstrating that oral tolerance is induced 6 - 9 months after initiation of therapy. Thus, there is a strong signal from both clinical and immunologic data that oral tolerance had been induced in the LP patients. Combined with a discovered single nucleotide polymorphism (SNP), which can distinguish patients who cannot respond to ARG201 therapy from those who can, the clinical and immunologic response in a large prospectively defined subgroup enables a more efficient design of confirmatory pivotal trials.

ARG201 Development Plan

ARG201 has been granted Orphan Drug Designation in the U.S. and the EU. Orphan status provides arGentis with seven years' and ten years' market exclusivity in the U.S. and EU, respectively.

We plan to begin clinical trials in 2010. The clinical trial(s) will focus exclusively on patients with Late Phase SSc that are SNP negative. Current plans are to conduct trials with approximately 125 patients each. As mandated by FDA, the primary endpoint for the trials will be to achieve improvement in MRSS. Patients will be treated for 18 months. Twelve major rheumatology centers in the U.S. have already agreed to participate in trials. We will seek at least an equal number of sites in the EU as well as sites in South Korea, which has a large pool of patients with Late Phase SSc.

ARG301 - Altered Peptide Ligand Therapeutic For Rheumatoid Arthritis

arGentis is collaborating with the University of Tennessee Health Science Center (UTHSC) and the Veterans Affairs Medical Center of Memphis (VAMC) to initiate the first human clinical evaluation of an oral altered peptide ligand (APL), ARG301, in a Phase I study of Rheumatoid Arthritis patients. ARG301 is a synthetic peptide, which in animal studies appears to down regulate autoimmunity to Type II collagen (CII), a known autoantigen in RA. Investigators at the UTHSC and Memphis VAMC developed the therapy and have received a Clinical Merit Review Grant from the Department of Veterans Affairs to conduct the trial.

Rheumatoid Arthritis (RA) is an autoimmune disease that causes chronic inflammation of the joints and is the most common form of inflammatory arthritis. RA most often affects the smaller joints, such as those of the hands and/or feet, wrists, elbows, knees, and/or ankles. The cause of RA is not known but usually develops between 30 and 50 years of age. Although there is no cure for RA, the disease can be controlled in most people. Early, aggressive therapy to stop or slow down inflammation in the joints can prevent or reduce symptoms, joint destruction and deformity.

RA has a significant impact on both individual lives and society, including:

• According to the Centers for Disease Control and Prevention (CDC), arthritis and other rheumatic conditions are the leading cause of disability in the U.S.,
• 3 million RA sufferers in the U.S.,
• 2.2 million are women,
• U.S. incidence expected to increase to 5.8 million in the U.S. by 2013,
• According to Johns Hopkins, disability is higher among patients with rheumatoid arthritis, with 60 percent being unable to work 10 years after disease onset,
• People with rheumatoid arthritis have an increased risk of mortality or death rate compared to the general population, living 10-15 years less than healthy counterparts.

Preclinical Results

Research in animal models suggests APLs (Altered Peptide Ligands) are effective in preventing and ameliorating tissue-specific autoimmune diseases. Trials of APLs administered intravenously or subcutaneously in human autoimmune disease have had mixed results. None of these trials, however, incorporated a pre-selection step to test the ability in vitro of the APL, to down regulate Th1 response by patient’s peripheral blood mononuclear cells (PBMC) stimulated by a disease-specific autoantigen such as CII in RA patients.

In preclinical testing, mice susceptible to Collagen Induced Arthritis (CIA) bear a transgene for the human RA MHC susceptibility genes, DR1 or DR4. These mice appear to be resistant to CIA after oral administration of ARG301. Although the precise mechanism by which the specific peptide comprising ARG301 exerts its effect is not yet clear, the interaction of the APL/MHC complex with the TCR appears to play a key role in influencing the differentiation of naive T cells into effector cells.

Based on the experience in animals, oral administration of APLs to preselected “in vitro” responders should provide a nontoxic and highly defined therapy for humans with tissue-specific autoimmune diseases such as RA.

Phase I Clinical Trial

42 RA patients are being enrolled a Phase I Trial at the Memphis Veterans Affairs Medical Center which will evaluate multiple ascending doses of ARG301 to be administered orally. The primary objectives of the trial will be to determine if one or more of the three doses of ARG301 given to Rheumatoid Arthritis patients will generate functional T regulatory cells and decrease immune reactivity to CII. The study will have 3 ARG301 treatment arms, each with 10 patients and a placebo arm of 12 patients. Patients will be enrolled who have demonstrated T cell immunity to CII and have an in vitro response to ARG301 at the screening visit. Patients will be randomized to one of the 4 arms, and each of the 3 ARG301 and placebo treatments will be given for 16 weeks.

About ARG301

The altered peptide ligand ARG301 is an oligopeptide derived from human CII sequence with substituted amino acids that binds to the MHC class II and interacts with the T cell receptor. ARG301 acts to change the cytokine profile from Th1 to Th2. Preclinically, DR1 or DR4 transgenic mice treated with oral or parenterally administered ARG301 were protected from arthritis induced by CII immunization. Short term toxicity studies using 100x the maximal human dose of ARG301 on a weight basis in mice did not cause any detectable toxicity. ARG301 is anticipated to have an exceptionally good safety profile in the clinic. To further prove concept, ARG301 will eventually be evaluated in broader clinical trial of Rheumatoid Arthritis patients.

Collagen Pipeline

arGentis Collagen Labs ("aCL") will be set up to produce several highly purified collagens that may be used for multiple applications in the fields of wound care, medicine delivery, dermal filling and pharma research. The higher purity allows for specialized collagens to exhibit premium qualities for medical devices or high quality gels for tissue culture applications. aCL collagens also have low cross-linking to ensure a more homogenous product deliverable. aCL's dedicated cGMP facility offers custom collagen solutions® to produce client specific mixtures for Extra Cellular Matrix-like growth properties.

aCL will produce various types of purified collagen using licensed technology. Currently the product line being considered consists of the following deliverables:

1. veriCol™ - utilizes highly purified Bovine derived Type I collagen and will be the active pharmaceutical ingredient in ARG201 a treatment for systemic scleroderma being developed by arGentis Autoimmune, LLC ("AI").
2. novaCol™ - also a highly purified Bovine derived Type I collagen, but purified using a propriety process specifically designed to produce a unique form of collagen with optimized characteristics which on-going research indicates is very appropriate for uses in medical devices.
3. primaCol™ - is very similar to novaCol™, but has been through an additional process specifically designed to enrich the product for a form of various, purified Types of collagen that can also be utilized for high quality gels for tissue culture and other research grade or pharma applications. Though significantly more costly to produce, primaCol™ and the various signature Types of collagen will provide biomedical research scientists with custom collagen solutions® that have rarely been available to the research community at large. primaCol's™ target customers are the medical device industry's top scientists who may wish to optimize their collagen-based products.

For ordering information please contact us at 901.818.3262 or by e-mail.

We actively seek other therapies that enable arGentis to effectively manage the clinical and regulatory risk of drug development.

Therapies being considered:

• Have demonstrated proof of concept with substantial human safety and efficacy data;
• Streamlined clinical development times;
• A straightforward clinical path;
• Meet an unmet medical need;
• Are attractive to potential partners.