NN1213 – A Potent, Long-Acting, and Selective Analog of Human Amylin
Kirsten Dahl, Kirsten Raun, Jakob Lerche Hansen, Christian Poulsen, Charlotta Dornonville de la Cour, Trine Ryberg Clausen, Ann Maria Kruse Hansen, Linu M. John, Annette Plesner, Gao Sun, Morten Schlein, Rikke Bjerring Skyggebjerg, Thomas Kruse
Abstract
Amylin, a member of the calcitonin family, acts via amylin receptors in the hindbrain and hypothalamus to suppress appetite. Native ligands of these receptors are peptides with short half-lives. Conjugating fatty acids to these peptides can increase their half-lives. The long-acting human amylin analog, NN1213, was generated from structure-activity efforts optimizing solubility, stability, receptor affinity, and selectivity, as well as in vivo potency and clearance. In both rats and dogs, a single dose of NN1213 reduced appetite in a dose-dependent manner and with a long duration of action. Consistent with the effect on appetite, studies in obese rats demonstrated that daily NN1213 dosing resulted in a dose-dependent reduction in body weight over a 21-day period. Magnetic resonance imaging indicated that this was primarily driven by loss of fat mass. Based on these data, NN1213 could be considered an attractive option for weight management in the clinical setting.