Our Clinical and Preclinical Development Programs
We use our technologies to pursue opportunities in markets where products can be developed based on an understanding of mitochondrial function. We have internal as well as collaborative research programs underway in a number of chronic and acute diseases, including neurological and related disorders and metabolic and other diseases associated with mitochondrial dysfunction. The stages of research for these programs range from target identification to human clinical studies, and we are constantly evaluating potential new leads and targets in our various research programs. Our clinical and preclinical studies are outlined below.
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Product Pipeline
Major Neurological Disorders
We are investigating the role of mitochondria in major neurological disorders with a focus on neurodegeneration, including Alzheimer's disease, Parkinson's disease and stroke. We believe the increasing average age of the population will lead to increased demand for new therapies that treat these diseases.
Alzheimer's Disease. We have a license agreement with Wyeth related to the development of estrogens for Alzheimer's disease and certain other dementias. Wyeth is funding a Phase III clinical trial evaluating the use of estrogens to delay the onset and slow the progression of dementia in post-menopausal women. This double-blind, placebo-controlled trial is part of the Women's Health Initiative being conducted under the auspices of the NIH. The enrollment of more than 7,500 women for this six-year trial was completed in 1998. In addition, we have been working with Pfizer since 1998 on neurodegenerative disease research. Both with Pfizer and internally, we apply our mitochondrial research expertise to identify targets related to mitochondrial function and neurodegenerative disease that can be used in screens to discover potential drug candidates for therapeutic intervention. We have identified multiple targets and compound series that address neurodegenerative disease.
The most common form of dementia, Alzheimer's disease, is a progressive neurodegenerative disease causing memory loss, language deterioration, cognitive impairment and eventually death. According to articles in the European Journal of Clinical Investigation, approximately 20 million people worldwide have been diagnosed with Alzheimer's disease. The Pharmaceutical Research and Manufacturers of America, or PhRMA, notes that Alzheimer's Disease afflicts approximately 10% of people over age 65 and nearly 50% of people over 85. While there are few drugs on the
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market today for this disease and their effectiveness is limited, worldwide sales of prescription drugs to treat Alzheimer's disease were $670 million in 2000 according to Med Ad News.
The majority of Alzheimer's disease patients exhibit mitochondrial defects, including metabolic changes and reduced activity of cytochrome oxidase, which is complex IV of the mitochondrial electron transport chain, an essential component in the cell's energy production process. Researchers have succeeded in linking the brain cell damage and death that are hallmarks of Alzheimer's disease to these mitochondrial defects. Published reports have shown that the complex IV defect in Alzheimer's patients is transferred into engineered cell lines. These reports provide evidence that the observed defects may result from alterations in mitochondrial DNA. In addition, evidence from a number of studies indicates that estrogens affect mitochondrial function and that estrogen-based hormone replacement therapy delays the onset of Alzheimer's disease in post-menopausal women. Recent published studies with Alzheimer's disease animal models also show that estrogens significantly reduce the accumulation of brain amyloid plaques, a hallmark of the disease.
Parkinson's Disease. We have successfully completed a Phase I trial for Parkinson's disease with an estrogen we have designated MITO-4509. This compound is a component of marketed hormone replacement products, but it has minimal feminizing activity. Our future trials will assess the ability of this compound to moderate the symptoms and progression of Parkinson's disease.
Parkinson's disease causes tremor, rigidity and diminished quality of life. It is an age-related, neurodegenerative disorder that, according to PhRMA, affects an estimated 1.5 million patients in the United States today and approximately 1% of people over age 60. Worldwide sales of prescription drugs to treat Parkinson's disease totaled $607 million in 2000 according to Med Ad News. However, the effectiveness of these drugs is limited by side-effects, loss of efficacy over time and little impact on disease progression.
Published reports suggest that Parkinson's disease is associated with mitochondrial dysfunction. Several studies have shown that patients with Parkinson's disease have a defect in complex I of the mitochondrial electron transport chain, which is a key component of energy production. In addition, a Parkinson's disease-like syndrome can be induced in humans and in animals by mitochondrial toxins that impair the function of complex I. Cells from Parkinson's disease subjects exhibit selective defects in the activity of complex I. The transfer of this defect into engineered cell lines suggests that the metabolic defect of Parkinson's disease has a mitochondrial genetic origin. It has also been shown that the inhibition of complex I is associated with abnormal aggregation of alpha-synuclein and other cellular proteins that are pathological hallmarks of Parkinson's disease.
Stroke. We have developed a late-stage preclinical product called NeuroStat that we believe will protect the brain tissue of stroke victims by improving mitochondrial stability. The active ingredient of NeuroStat appears to have a high margin of safety and rapidly achieves high drug blood levels after a single subcutaneous injection. This should allow paramedics to administer NeuroStat at the initial point of care soon after a stroke when at-risk brain cells may still be saved from dying. Our proprietary approach may also yield drug candidates and targets for congestive heart failure and heart attacks, where mitochondrial failure causes a series of events similar to what happens with a stroke.
Stroke is caused by a sudden loss of blood supply to the brain, resulting in cell death, paralysis and other complications. According to the American Stroke Association, each year more than 600,000 Americans suffer a stroke and approximately 160,000 die from its consequences.
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PhRMA also estimates that approximately 67% of all strokes occur in people over age 65. Worldwide sales of prescription stroke therapies totaled $447 million in 2000 according to Med Ad News. However, there are very few marketed drugs for the treatment of stroke, and they are designed to re-establish blood flow to the affected region, not to preserve the viability of at-risk brain cells. As a result, their effectiveness is limited.
When blood supply to the brain is compromised in a stroke, a catastrophic drop in mitochondrial ATP production occurs. This leads to cellular and metabolic imbalances, including altered intracellular calcium levels, that precipitate the breakdown and death of brain cells. Brain cells surrounding this area will also die unless salvaged by prompt therapeutic intervention to restore mitochondrial activity.
Metabolic Diseases
We are engaged in research on the role of mitochondria in major metabolic disorders with a focus on obesity and diabetes. We are conducting preclinical studies on the contribution of mitochondrial dysfunction to these diseases and developing new targets and drug candidates for therapeutic intervention.
Obesity. We have identified novel compounds, such as MITO-3108, that are currently in preclinical development for the treatment of obesity. We have overcome certain toxicity problems previously known to occur with this class of compounds, which appear to lower the body-weight set point in multiple species. We believe these compounds represent therapeutic advances because they reduce body weight by modulating the body's own regulatory system, rather than by altering caloric utilization.
Obesity represents a significant health problem in the United States as a risk factor for the development of a number of major diseases, including diabetes, heart disease, hypertension, osteoarthritis, cancer and a variety of psychological disorders. According to articles on the Medscape website, more than 60% of U.S. adults were overweight or obese in 1999. Worldwide sales of prescription therapies for obesity totaled $736 million in 2000 according to Med Ad News. The few therapies available are limited in their effectiveness and have other drawbacks, including safety issues and side effects.
Physiological studies and genetic mouse models indicate that most species actively regulate body weight around a set point that is both genetically and environmentally determined. We believe this may be accomplished, in part, by regulating the number and efficiency of mitochondria. We are studying factors responsible for the regulation of mitochondrial mass, with the aim of developing agents capable of controlling mitochondrial replication.
Diabetes. We have developed novel compounds for the treatment of type II diabetes, including MITO-4183, that we have advanced to preclinical animal studies. These compounds block a mitochondrial ion channel that regulates insulin secretion. We have also identified peptides that target a mitochondrial enzyme complex and increase insulin secretion. Both of our approaches represent potential therapeutic advances over marketed diabetes drugs, because our compounds should affect insulin secretion only when glucose levels are elevated, which mimics normal functioning of the body's regulatory systems after a meal.
Diabetes results from the body's inability to adequately secrete insulin and process glucose. Approximately 90% of diabetic patients suffer from type II diabetes, or non-insulin dependent diabetes mellitus, which can result in blindness, stroke, kidney failure, amputation, nerve damage and often premature death. PhRMA estimates that more than 18% of the U.S. population age 65
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and older, or approximately 6 million people, has diabetes. Worldwide sales of prescription type II diabetes therapies totaled $4.2 billion in 2000 according to Med Ad News. Among other drawbacks, the administration of currently available diabetes therapeutics can be inconvenient, requiring frequent injections and dosing at every meal.
Our research suggests that mitochondrial dysfunction plays a role in a significant percentage of patients with diabetes. For example, diabetes frequently occurs in association with diseases caused by mutations or deletions in mitochondrial DNA. These mutations reduce energy production while increasing cellular stress. Moreover, we believe that the presumed role of apoptotic processes in the death of pancreatic beta-cells and the major involvement of mitochondria in essentially all forms of cell death strengthen the mitochondrial connection in diabetes. We have demonstrated in preclinical studies that glucose-stimulated insulin secretion, which normally occurs after a meal to regulate blood sugar levels, is tightly controlled by mitochondrial ATP production, and not by ATP from other cellular sources. We have also shown that metabolic defects observed in many patients can be traced to a decline in mitochondrial function.
Other Diseases
We continue to use our integrated drug discovery capabilities to evaluate new disease indications and to identify likely therapeutic targets. We are engaged in the preclinical research and development of drugs to treat other degenerative conditions and diseases associated with mitochondrial dysfunction, including osteoarthritis, glaucoma, Friedreich's ataxia and cancer.
Osteoarthritis. We have identified novel and potent compounds, such as MITO-4042, for the treatment of osteoarthritis. This compound improves mitochondrial function in cartilage and chondrocytes, the cells that cushion joints. Our compounds have the potential to be disease-modifying, rather than simply treating secondary aspects of the disease, such as pain. Osteoarthritis is a leading cause of physical disability in the United States.
Glaucoma. Several of our mitochondrial compounds, including MITO-4565, have shown an ability to block cell death pathways in retinal cells, and are being studied in preclinical models of glaucoma and other eye diseases. Glaucoma is a common ophthalmic disease associated with increased pressure within the eye, and according to the Glaucoma Research Foundation, affects more than 3 million Americans, causing blindness in more than 120,000 people.
Friedreich's Ataxia. We have filed an orphan drug application with the FDA related to AlphaTaxin as a treatment for Friedreich's ataxia. Friedreich's ataxia is characterized by clumsy or awkward movements and heart degeneration. Friedreich's ataxia is caused by a mutation in a nuclear gene that codes for a mitochondrial protein and is the most common inherited ataxia.
Cancer. We have identified potential anti-cancer drugs and targets that we are currently researching. Our cancer program is based on considerable published evidence that mitochondrial energy production and mitochondrial cell death pathways are altered in cancer cells. |
