Based on the plethora of positive results demonstrated in numerous disease and injury models, and the absence of hematopoietic and thrombogenic activities characteristic of EPO, Warren Pharmaceuticals' TPCs may have the potential to alter medical practice in important disease areas such as:

Brain/Central Nervous System
Eye
Heart
Peripheral Nervous System
Kidney

Organ/System	Disease	US Prevalence
BRAIN / CENTRAL NERVOUS SYSTEM	Stroke Alzheimer's Disease Multiple Sclerosis Spinal Cord Injury (incidence)	600,000 4,000,000 300,000 11,000
EYE	Diabetic Retinopathy/Acute Macular Edema Age-related Macular Degeneration (AMD)	1,000,000 1,700,000
HEART	Chronic Heart Failure Myocardial Infarction (prevalence)	4,800,000 1,100,000
PERIPHERAL NERVOUS SYSTEM	Diabetic Neuropathy	1,000,000
KIDNEY	Transplant (per year) Acute Renal Failure Diabetic Nephropathy	11,000 160,000 2,000,000

Warren Pharmaceuticals has developed a library of TPCs that are tissue-protective, cross blood-tissue barriers, but are not erythropoietic or thrombogenic.

Anticipated Safety Profile.
Pre-clinical studies have shown TPCs to be well tolerated. No treatment related side-effects have so far been observed. In particular, no side-effects typical of EPO treatment (hypertension, thromboembolic events) have occurred


Potential Disease Areas for Treatment

THE BRAIN/CENTRAL NERVOUS SYSTEM

Stroke.
The third leading cause of death in industrialized countries, stroke is caused either by blockage (ischemic stroke) or rupture (hemorrhagic stroke) of a blood vessel supplying the brain. The destruction of irreplaceable tissue that follows can cause a catastrophic loss of functional capability. Ischemic stroke is by far the most common (88%) and can also occur when the blood pressure becomes too low (hypotension), reducing blood flow to the brain.

Characteristic of both types of stroke is the devastation of brain tissue surrounding the primary lesion, resulting in profound motor and cognitive losses, and the slow and often only partial recovery that characterize most stroke patients. It is precisely this area surrounding the lesion that Warren Pharmaceuticals' expects to be amenable to TPC therapy.

Spinal Cord Injury.
There are approximately 200,000 people in the U.S. with spinal cord injury and approximately 11,000 new U.S. cases each year. Of these, 38.5% are caused by vehicle crashes, closely followed by violence, falls and recreational sporting activities. Although it is unlikely that TPCs will have an impact on patients who have had spinal cord injuries in the past, preclinical studies show that TPCs delivered close to the time of the injury results in significant improvement in functional outcome.

In disease models, TPCs have been shown to reduce the extent of apoptotic damage in brain tissue surrounding the primary stroke site (the vessel lesion), as well as recruit stem cells into the central nervous system. Importantly, though being large molecules, TPCs readily pass across the blood-brain barrier, providing therapy in an otherwise difficult to access bodily compartment.

Multiple Sclerosis.
MS is a chronic, progressively debilitating disease characterized pathogenically by demyelinization of nerve sheaths in the central nervous system causing adverse effects on nerve conduction, and symptomatically by pain, deadening fatigue, and problems with sight, mobility and coordination. With the recent understanding that the destruction of myelin-producing cells in this disease is mediated by an inflammatory response, TPCs may offer a therapeutic role in controlling the disease.

Preclinical studies in models of acute and chronic disease have demonstrated effectiveness of TPCs in improving the clinical score, consisting of assessment of motor and sensory nerve function.

THE EYE

Age-related macular degeneration.
AMD is the leading cause of blindness in individuals over the age of 50. In this debilitating disease, the central area of the retina, the macula, undergoes progressive degeneration leading to loss of vision, and in some cases, blindness. There are two major forms of AMD, a rapidly progressing, neovascular form (wet) and a slower acting, non-neovascular form (dry).

Proliferative diabetic retinopathy.
PDR, the leading cause of blindness in Americans, is caused by diabetes-related retinal ischemia (lack of blood supply). It is characterized by neovascularization - abnormal new blood vessel growth - in and around the retina. PDR can lead to retinal bleeding, retinal detachment, and ultimately to permanently impaired or lost vision. With time, leakage from the abnormal vessels can result in fluid build up called retinal edema. If the edema occurs in the area of the macula (central vision spot), the condition is called macular edema. Acute macular edema is a critical condition as it affects visual acuity and may lead rapidly to permanent vision damage.

It is well established that apoptosis and inflammation play a crucial role in the pathogenesis of retinal diseases including diabetic retinopathy and macular degeneration. Therefore, TPCs which have anti-apoptotic and anti-inflammatory effects are candidates for offering a beneficial effect in these conditions.

Preclinical data from disease models demonstrate that TPCs protect retinal neurons and glial cells from hypoxia (insufficient oxygen) and neovascularization.

Importantly, Warren Pharmaceuticals' TPCs readily cross the blood-retina barrier, and therefore can be administered parenterally (intravenously, intramuscularly, or subcutaneously) rather than requiring injections into the eye. This may give Warren compounds a clinical advantage over other compounds currently in development.

THE HEART

Myocardial Infarction.
Heart attack, the single largest killer of Americans both male and female, occurs when coronary vessels which supply the heart muscle with blood, oxygen and nutrients, become acutely obstructed. This blockage causes death of heart muscle in the area supplied by that particular vessel.

Congestive Heart Failure.
In CHF, the heart is damaged and overworked, and therefore unable to pump enough blood to meet the demands of the body. At present, the outlook for CHF sufferers is extremely poor- - 20%-40% of patients die within one year of diagnosis, a survival rate lower than for many forms of cancer.

TPCs have been shown to significantly protect the myocardium during acute coronary ischemia and to prevent impairment of cardiac function in chronic heart failure models in animals.

PERIPHERAL NERVOUS SYSTEM

Peripheral neuropathy.
Diverse causes of damage to the peripheral nerves can lead to common symptoms such as weakness, numbness, paresthesia (abnormal sensations such as burning, tickling, pricking or tingling) and pain in the arms, hands, legs and/or feet. Causes include diseases of the nerves or as the result of systemic illnesses, such as diabetes, uremia, AIDS, or nutritional deficiencies, mechanical pressure such as compression or entrapment, direct trauma, penetrating injuries, contusions, fracture or dislocated bones, and vascular or collagen disorders such as atherosclerosis, systemic lupus erythematosus, scleroderma, sarcoidosis, rheumatoid arthritis, and polyarteritis nodosa. One common example of entrapment neuropathy is carpal tunnel syndrome, which has become more common because of the increasing use of computers.

Diabetic neuropathy.
Among the causes described above, diabetes is an important causative factor in peripheral neuropathy. In addition to all of the symptoms mentioned above, those prevalent in diabetic neuropathy include erectile dysfunction, problems with urination, and gastrointestinal disturbances. Numbness in limbs especially the feet can result in inattention to minor wounds that can lead to infections and, because of other metabolic problems in diabetes, poor wound healing.

TPCs have been shown in models of peripheral nerve damage to improve nerve sensitivity scores, as well as prevent the natural loss of nerve fibers in the skin in a diabetic model. Among its mechanisms of preventing apoptosis and promoting blood flow, TPCs may operate through several mechanisms to improve the course of the disease in various neuropathies.

THE KIDNEYS

Acute Renal Failure.
Acute renal failure is sudden loss of the ability of the kidneys to excrete wastes, concentrate urine, and conserve electrolytes, usually caused by exposure to ischemia or toxins. There are approximately 160,000 cases of ARF in the US per year.

Pre-clinical studies have shown that Warren Pharmacuticals' TPC-2 is effective in protecting renal tissue in models of ischemic ARF.

Diabetic Nephropathy.
Diabetic nephropathy is a kidney disease that occurs as a result of long-term diabetes. It is a leading cause of kidney failure in the US and in Europe. Research on the pathogenesis of the disease in experimental diabetes models has identified one of the mechanisms involved in destruction of the kidney to be tubular epithelial cell apoptosis, possibly induced by oxidative damage known to be increased in the diabetic kidney.

By virtue of the protective effect demonstrated by TPCs on cells induced to undergo apoptosis, TPCs are likely candidates for therapeutic intervention into the progression of this disease that ultimately results in the patient requiring dialysis or a kidney transplant.

Renal (and other organ) Transplantation.
Akin to the adverse effects on heart or brain tissue during oxygen starvation (ischemia) from blood vessel occlusion that leads to heart attack or stroke, organs for transplant likewise are subject to prolonged lack of perfusion creating conditions that induce apoptosis and deterioration of the quality of the organ and prognosis for normal function in the recipient. While advances in organ preservation techniques have markedly improved the viability of organs for transplant, ischemia-reperfusion damage still accounts for an unacceptably high failure rate of transplanted organs, especially kidneys.

Preclinical studies have demonstrated marked improvement in the quality of transplanted organs when the donor, organs or recipient, are exposed to TPCs.

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