CLINICAL PROGRAMS

OBESITY - THR-4109

Obesity is a complex multifactorial chronic disorder characterized by the accumulation of adipose tissue. Obesity and overweight are associated with an increased risk of developing co-morbid conditions including hypertension, dyslipidemia, type 2 diabetes, coronary artery disease, stroke, osteoarthritis, sleep apnea, respiratory diseases, and malignancies of the breast, endometrium, prostate and colon. Increased consumption of energy-dense, nutrient-poor foods combined with lower levels of physical activity has led to a worldwide epidemic of obesity. The World Health Organization (WHO) estimates that at least 300 million people worldwide are obese. Obesity is defined by a body mass index (BMI) of ≥ 30 kg/m2. The prevalence of overweight is substantially more common and is defined as a BMI of 25 to 29.9 kg/m2.

The treatment of obesity depends upon the clinical assessment of an affected individual taking into account the presence of co-morbid conditions and patient motivation to lose weight. Dietary, behavioral and lifestyle modifications are generally recommended to facilitate weight loss. In many cases the addition of a pharmacological agent is required to induce weight loss. Six agents are currently approved by the FDA for the treatment of obesity. Although these drugs are generally well tolerated, their efficacy is modest. Because of the rising incidence and health burden of obesity, more effective therapies for weight loss are urgently needed.

THR-4109 is composed of two drugs from different classes that have been approved for other indications. The two drugs have well-understood side-effect profiles and have proven to be safe in clinical use. The clinical use of combination therapy with drugs from the two classes is common in certain patient populations, and appears to be safe and well tolerated. Initial results from a physician-initiated study indicate that the combination therapy may have a significant effect on weight loss. In a small uncontrolled study of nine obese and overweight subjects, the experimental treatment resulted in an average 11% loss of body weight over 7½ months of follow-up.

In August 2007 Theracos initiated a Phase II clinical trial to study the safety and effect of THR-4109 on weight loss in obese subjects over a 24-week treatment period. The multinational trial is a randomized, double-blind, placebo-controlled study with a planned enrollment of 220 subjects at up to 20 investigational sites in Europe.

DIABETES - THR-0921

In 2002, approximately 5-6% of the U.S. population was afflicted with type 2 diabetes. Worldwide over 150 million people have the disease, and this number is projected to reach 300 million by 2025. Type 2 diabetes is a chronic metabolic disorder characterized by increased serum glucose (hyperglycemia) due to impaired insulin action and insufficient insulin secretion to overcome the pathological resistance to insulin. Many type 2 diabetics also have abnormally elevated blood lipid concentrations (dyslipidemia). Currently five classes of oral anti-hyperglycemia drugs are available. These include sulfonylureas, biguanides, glucosidase inhibitors, thiazolidinediones (TZDs), and meglitinides. Often, patients take two or more of these drugs in combination, and even then, their glucose concentrations and blood lipids may be poorly controlled or they may suffer from dangerous adverse effects such as hypoglycemia and agent specific toxicities (e.g. lactic acidosis, hepatic toxicity).

TZD drugs are agonists of the peroxisome proliferator activated receptor-gamma (PPAR-γ). PPARs are ligand-activated nuclear transcription factors that exist in three isoforms: alpha (PPAR-α), gamma (PPAR-γ) and delta (PPAR-δ). PPAR-γ is highly expressed in adipose tissue, whereas PPAR-α is expressed in liver, skeletal tissue and macrophages. Despite their similar mechanisms of action, the TZDs that have been approved for marketing in the United States have distinguishable pharmacological profiles, leading to variations in safety and efficacy. The differences in the actions of the existing TZDs has suggested that new drugs in this class might be developed that have lower liability for the known adverse effects associated with the existing marketed compounds.

THR-0921 is a TZD analog of an earlier drug candidate that had been developed from a natural product source. THR-0921 is a prototype of a new class of unconventional TZDs, which have glucose-lowering activity in vivo that greatly exceeds the activity predicted by in vitro measures of PPAR agonism. In vitro, THR-0921 is a weak PPAR agonist, and is less adipogenic than the marketed TZD rosiglitazone. In rodent models of type 2 diabetes, THR-0921 showed strong antihyperglycemic activity, exhibiting equipotency at blood glucose lowering with marketed TZDs. In vivo studies have demonstrated that THR-0921 also lowers triglyceride levels in diabetic animals. A Phase I/II clinical trial of THR-0921 has been completed and showed that the drug was safe and well tolerated in normal subjects and patients with type 2 diabetes. Based upon the preclinical data and early clinical data obtained to date, Theracos believes that THR-0921 has the potential to offer a significant improvement over earlier TZD compounds with respect to potential side effects.

^top