236-OR: Molecular and Biological Properties of Insulin Icodec, a New Insulin Analog Designed to Give a Long Half-Life Suitable for Once-Weekly Dosing

Abstract

Insulin icodec is a novel insulin analog with a terminal elimination half-life of ∼196 hours currently in clinical development, designed to be able to cover a full week’s basal insulin requirements with a single subcutaneous injection. To attain such a long half-life, the insulin molecule was modified to achieve an albumin-bound circulating depot of icodec which acts just as human insulin (HI) but is more slowly cleared.Addition of a C20 fatty diacid containing side chain at B29K via a hydrophilic linker imparts strong but reversible albumin binding (10x that of insulin detemir). Three amino acid substitutions (A14E, B16H and B25H) ensure reduced enzymatic degradation of icodec and contribute to attenuating insulin receptor (IR) binding and clearance, further prolonging the half-life. In vitro studies demonstrated that icodec is a specific and full agonist of the human IR, and that it displays the same dose-dependent mode of action as HI, exemplified by its ability to phosphorylate the IR and stimulate intracellular signaling pathways (phospho-AKT and -ERK). Functional assays have demonstrated that icodec elicits the same pattern of metabolic effects as HI, including glucose uptake and lipogenesis in fat cells, and stimulation of glycogen synthesis in liver cells. The affinity of icodec for the IGF-1 receptor was found to be proportionately lower than its binding to the IR. The in vitro mitogenic effect of icodec in primary human mammary cells (HMEC), as well as in mammary and colon carcinoma cells (MCF-7 and COLO 205) was found to be low relative to that of HI. In conclusion, icodec is a new insulin analog designed to achieve a slowly cleared, albumin-bound circulating depot which results in a long half-life suited for once weekly injections, covering the basal insulin requirements for a full week. *Insulin icodec (proposed INN). Disclosure E. Nishimura: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. T. Kjeldsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. F. Hubalek: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. T. Glendorf: Employee; Spouse/Partner; Novo Nordisk A/S. Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. C.E. Stidsen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. B.F. Hansen: Stock/Shareholder; Self; Novo Nordisk A/S. T.A. Pedersen: Employee; Self; Novo Nordisk A/S. A. Luetzen: Employee; Self; Novo Nordisk A/S. Stock/Shareholder; Self; Novo Nordisk A/S. L. Pridal: None. P. Madsen: Employee; Self; Novo Nordisk A/S.