AM833, a Long Acting Amylin Analogue Induces Hypocalcemia in Young Rats via a Calcitonin Receptor Mediated Mechanism

Abstract

\n Amylin is a peptide hormone that is co-secreted with insulin from pancreatic β-cells. It is member of the calcitonin family and activates amylin receptors (AMYRs) in the calcitonin receptor (CTR) family. During recent years, several AMYR agonists have been in clinical development for treatment of diabetes and obesity. In contrast to pramlintide, which is a short acting amylin analogue approved for use in combination with meal-time insulin in patients with diabetes, the more recent development candidates have been dual acting analogues activating both the CTR and the AMYRs. In rodents the CTR plays a significant role in calcium homeostasis, while in humans this has been associated with little long-term effect on the plasma calcium levels (Ganong, 1993; Longo et al., 2011); Rodents are usually chosen as first choice pre-clinical models for in vivo testing and introducing acute and profound hypocalcaemia can lead to general neurological and neuromuscular disturbances, which can be challenging in clinical development programs. AM833 (NNC0174-0833) is a long acting acylated dual acting amylin analogue activating both CTR and AMYRs. When combined with the long acting GLP-1 analogue semaglutide for weight management, both preclinical studies in rat models of obesity and clinical trials in humans with obesity have demonstrated significant weight loss potential. In young rats aged 7–9 weeks, single sc dose of 3–300 nmol/kg AM833 induced a reduction of total and ionized calcium of 40–50% from baseline with lowest level around 12 hours after dosing. A similar response was seen after administration of salmon calcitonin which also activates both CTR and AMYRs. Tachyphylaxis was introduced, with no effect on calcium found after sub chronic daily treatment for 2 weeks. Age played a key role in the sensitivity to calcium lowering with almost no effect found in 11 months old rats. When administering AM1213 (NNC0174-1213), a selective AMYR agonist with little activation of the CTR, no or little calcium lowering of around 10% was seen. These data indicated that the calcium lowering properties are CTR mediated. The induction of hypercalcemia was a rodent specific phenomenon as no calcium lowering outside of normal range was seen in young dogs and rabbits. Clinical data confirmed that CTR induced calcium lowering was not human relevant, but these data showed that understanding physiology and pharmacology in the animal models of investigation as well as human translational relevance is of outmost importance in the progress of an early development program. References: GaNong WF. Calcitonin. In: Review of medical physiology. 16th ed. Appleton & Lange. 1993. Longo DL et al. Calcitonin. In: Harrison’s principles of internal medicine. 18th ed. McGraw-Hill; 2011.