PFI:BIC Bioengineering Glucagon-like Peptide 1 Analogs and a Formulation for Oral Delivery to Treat Diabetes

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This PFI:BIC project from Tufts University will investigate newly discovered orally active analogs of the peptide hormone, glucagon-like peptide-1(GLP-1), to see whether it is possible to adapt them for use in the treatment of type 2 diabetes (T2D). GLP-1 reduces blood glucose after eating by interactions with its receptor (GLP-1R) that signal increased insulin secretion, reduced glucagon secretion, slowed gastric emptying and increased satiety. GLP-1R agonists provide, arguably, the most effective therapeutic approach for achieving recommended blood-glucose targets in the management of T2D. However, the currently available GLP-1R agonists, exenatide and liraglutide, suffer the drawback, especially for chronic medication, of requiring injection. The goal is to develop a solid-dose formulation of a GLP-1 analog that combines convenience of oral administration with the therapeutic advantages. The digestion of peptide hormones via oral delivery is challenged by gastrointestinal (GI) proteases and the absorption barrier of the GI tract. In addition, the active lifetime of GLP-1 is greatly shortened by proteolytic degradation as a result of dipeptidyl peptidase-4 (DPP4) and neutral endopeptidase (NEP) in the blood and tissues. The early-stage technology-oriented research of this project starts with the discovery by Dr. Bachovchin and co-workers of how to make GLP-1 more resistant to destruction by GI proteases, DPP4, and NEP. A combination of peptide chemistry and formulation in enteric-coated tablets will be used to achieve the oral bioavailability and glucose-lowering potency required for clinical use. The methods are also applicable to other peptide hormones of possible therapeutic interest. In this vein, the Bachovchin team has modified the appetite-suppressing peptide oxyntomodulin to provide resistance to DPP4 and NEP without disruption of the receptor-agonist activity required for homeostatic function. The broader impacts of this project lie in its contribution to the solution of a large, costly public health problem. More than half of T2D patients fail to achieve recommended targets for glycemic control, leading to high rates of medical complications. The problem will grow as the number of diabetics rises to an estimated 300 million in 2025. The American Diabetes Association-European Association for the Study of Diabetes consensus recognizes GLP-1 analogs as potentially the most effective treatment; but market penetration suggests only a minority of patients currently receive their benefit. Avoidance of injections reduces prescription of exenatide and liraglutide. Development of a GLP-1 analog in convenient oral formulation would overcome this hurdle and in combination with lifestyle changes might help to slow or prevent disease progression in the increasing numbers of juvenile patients and prediabetics, who, because they are asymptomatic, are less likely to accept long-term injections. For Unigene Laboratories, Inc., the advances anticipated in the course of this project will further validate the versatility of the Peptelligence (TM) platform for solid-dose formulation of peptide-based drugs for oral delivery, and in turn increase its marketability as a service. For Arisaph and Unigene, given success, a drug candidate will result that could be clinically developed and eventually commercialized by research and development conducted in partnership.Partners at the inception of the project are 1) Lead Institution: Tufts University School of Medicine (Department of Biochemistry); and 2) Primary Small Business Partners: Unigene Laboratories Inc.(Boonton, NJ) and Arisaph Pharmaceuticals (Boston, MA).