The introduction of the GLP-1 incretins presents an important therapeutic option for patients with type-II diabetes (T2D). In addition to maintaining effective glycemic control, these agents offer a unique weight-lowering benefit which is particularly desirable in this patient population1 As part of our effort to develop long-acting GLP-1 agonists which combine these benefits with the convenience of once-weekly subcutaneous dosing we utilized an optimized GLP-1 sequence modified at its C-terminus with polyethylene glycol (PEG). To achieve a sufficient half-life we evaluated a series of PEG conjugates of the optimized backbone which differed with respect to size, number of PEGylation sites and utilizing either linear or branched PEG polymer. Pharmacodynamic studies of LY2428757 confirmed potent dose-related insulinotropic activity in stepped glucose infusion studies in the rat. Pharmacokinetic evaluation of the candidate peptide in the cynomalgus monkey indicated a half-life of 2.6 days and a bioavailability of 75 % following subcutaneous administration. 1 Peters, A. The Am. J. Med (2010) 123, S28�S37

Optimization of a long-acting PEGylated GLP-1 agonist LY2428757

244th National Meeting (2012)

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