Diabetic foot ulcers constitute a significant, growing global healthcare concern and exact an enormous toll in terms of health, economic and social costs for patients, their families, and society. Along with pain and morbidity, diabetic foot ulcers account for as much as 20% of total expenditures on diabetes in North America and Europe. The progress of wound healing is impaired in chronic, recurring wounds such as diabetic foot ulcers, and there is an urgent, unmet medical need for approaches to enhance the progress and speed of healing.

The World Health Organization (WHO) estimates that at least 171 million people worldwide have diabetes and that number is expected to double by 2030. The unprecedented increase in diabetes is attributed to aging populations and the increasing prevalence of obesity, unhealthy diets and sedentary lifestyles. In the U.S. alone, in excess of 20 million people, or an estimated 7% of the population, suffer from diabetes.

According to the Centers for Disease Control and Prevention (CDC), in 2005, there were 20.8 million people with diabetes and 1.5 million new cases of diabetes were diagnosed in persons aged 20 years or older. In 1980, diabetes was the seventh leading cause of death in the United States, claiming nearly 35,000 lives. By 2004, it rose to sixth leading cause of death. Diabetes was the underlying cause of nearly 73,000 deaths in 2004 and was mentioned on the death certificates of more than twice as many additional deaths. In 2005, more than 7% of the non-institutionalized adult population reported that they suffered from diabetes.

Current DFU treatment regimens include: aggressive control of infection; thorough debridement and preparation of the ulcer bed; maintenance of a moist healing environment; and off-loading mechanical stress and pressure from the affected site. Yet, because a significant portion of diabetic foot ulcers fail to heal in spite of good care, additional therapeutic approaches have been vigorously pursued. For many larger ulcers, treatment in wound-care centers often includes use of bioactive skin substitutes, delivery of autologous platelet concentrates, or application of a platelet-derived growth factors. Current therapeutic alternatives approved by the FDA for diabetic foot ulcers have not gained wide acceptance because they have demonstrated only limited benefit over standard care.

In a defined foot ulcer population, TP508 treatment more than doubled the incidence of complete healing (p < 0.05), increased mean closure rate ~ 80% (p < 0.05), and decreased the median time to 100% closure by ~ 40% compared to placebo (p < 0.05). In heel ulcers within this population, TP508 treatment resulted in mean closure rates 165% higher than placebo (p < 0.02) and complete healing in 86% (6/7) of ulcers compared to 0% (0/5) of placebo ulcers (p < 0.03). Local wound reactions and adverse events (AEs) were equivalent between groups, with no reported drug-related changes in laboratory tests or serious AEs. These results, published in January/February 2007 issue of Wound Repair and Regeneration, indicate the potential safety and efficacy of TP508 for treatment of diabetic foot ulcers.

The Company is currently exploring partnering opportunities for future clinical trials of TP508 in DFU. These may include dose-ranging safety and efficacy studies.

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There are approximately 700,000 distal radius fractures per year in the United States, representing one sixth of all long bone fractures seen in emergency rooms. Distal radius fractures comprise the highest fracture incidence worldwide, and the frequency increases exponentially with the aging population. The increased incidence of osteoporotic fractures is believed to result from reduction in bone density. There is a clear medical need for agents that could accelerate the healing of all fractures, and reduce costs associated with the disability they cause.

OrthoLogic conducted a double-blind, randomized, placebo-controlled, Phase 3 clinical trial evaluating the efficacy and safety of a single percutaneous injection of Chrysalin at 10 µg on the rate of healing in distal radius fractures. Five hundred three adult subjects with unstable and/or displaced intra- or extra-articular fractures of the distal radius were enrolled at 27 active centers in the U.S. The primary efficacy endpoint of time to immobilization removal was not met in this study; however, statistically significant acceleration of healing – a secondary endpoint - was demonstrated based on radiographic evidence. Based on a post-hoc analyses of a pre-specified subgroup, the osteopenic female population showed significance in the primary endpoint (immobilization removal) as well as multiple secondary (radiographic) endpoints.

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Impaired nitric oxide (NO) production reduces the responsiveness of endothelial cells to angiogenic factors and causes loss of endothelial function in ischemic and inflamed blood vessels, contributing to a number of chronic diseases. We hypothesize that TP508 may produce angiogenic and other tissue repair effects by activating or upregulating endothelial nitric oxide synthase (eNOS) in endothelial cells, and if so, that it may have potential therapeutic value in treating diseases involving endothelial dysfunction. In 2007, we plan to continue pre-clinical testing the effect of TP508 on vascular endothelial dysfunction.

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