Long-acting Growth Hormone for Treating HIV-Associated Adipose Redistribution Syn

DESCRIPTION (provided by applicant): HIV-associated adipose redistribution syndrome (HARS), a form of lipodystrophy, is a common problem in HIV patients on highly active antiretroviral therapy and occurs as a side-effect of their anti-viral drug therapies. HARS is characterized by an increase in visceral adipose tissue, dyslipidemia, and insulin insensitivity, all of which are believed to increase the patient's risk for developing cardiovascular disease. Recombinant GH is effective at treating HARS, as meas ured by reductions in visceral adipose tissue and improvement in lipid profiles. Recombinant GH products had worldwide sales of 2.4 billion in 2006, primarily from sales of the drug to treat GH deficiency in children and adults. GH has a short circulating half-life and must be administered to patients by daily injection. We created a highly potent, long-acting GH analog, BBT-031 that has a significantly increased circulating half-life and superior efficacy in animal models of growth hormone deficiency comp ared to GH. Based upon animal studies we anticipate that our long- acting GH analog will be effective when administered once per week or less frequently in humans. The improved in vivo characteristics of this novel GH analog will reduce the need for freque nt injections, improve patient quality of life and potentially lead to a more effective therapy for the treatment of HARS. Our long-acting GH analog has the potential to significantly reduce healthcare costs by reducing the amount of drug required by patie nts, by reducing costs associated with patient visits to treatment centers and by reducing healthcare worker time associated with providing treatments. The overall goal of this SBIR proposal is to develop this long-acting GH analog for the treatment of HAR S and other metabolic complications of HIV and HIV therapies such as wasting (cachexia). During Phase I of the SBIR grant, we developed a GLP (Good Laboratory Practices) manufacturing process and supporting assay methods to produce material for GLP pharmac ology and toxicology studies. We performed single injection and repeat injection GLP toxicology studies in rats and a GLP pharmacokinetic study in rats. No toxicities were noted at doses up to 30 times the expected dose to be used in humans, and the pharma cokinetic profile of the protein suggested it will be effective as a once weekly therapy in humans. We also showed that the protein was more potent than GH at stimulating weight gain and bone growth in growth hormone deficient rats, particularly when using a less frequent dosing regimen. During Phase I we also designed clinical protocols for Phase 1 safety and Phase 2 dose ranging efficacy studies in humans. The main goal of the Phase II SBIR proposal is to complete animal toxicology and pharmacology studie s in a second species, which is required by the FDA prior to testing this product in humans. We also will continue to optimize the manufacturing process and analytical assays for the protein and perform experiments to identify a stable liquid formulation f or the protein for use in humans. Successful development of our long-acting GH analog will provide HARS patients with a more convenient and potentially more effective treatment for their disease. This product also has potential for treating HIV-associated wasting (cachexia), for which GH has received approval by the FDA. Although not as significant a problem in U.S. due to wider use of more effective antiviral therapies, HIV-associated wasting still is a major problem in undeveloped countries where patients do not have as good access to HIV medications. PUBLIC HEALTH RELEVANCE HIV-associated adipose redistribution syndrome (HARS) occurs as a side-effect of highly active antiretroviral therapy (HAART) and is believed to afflict approximately 80,000 HIV patien ts in the U.S. HARS is characterized by an accumulation of visceral adipose tissue and alterations in lipid profiles. Recombinant growth hormone (GH), which