Amylin analogues are being investigated as potential obesity treatments. Amylin receptors (AMYRs) belong to the calcitonin receptor (CTR) family and consist of heterodimers of the calcitonin receptor and receptor activity modifying proteins (RAMPs). CTR and AMYRs exhibit distinct physiological roles with CTR activation being important for calcium homeostasis, while AMYRs are involved in appetite regulation and body weight. It is however uncertain what the clinical role is of different receptor profiles. In this study we compare three amylin analogues in clinical development (cagrilintide, eloralintide and NN1213) on CTR and AMYRs activation as well as calcium lowering ability in rats to evaluate AMYR selectivity and furthermore address the efficacy on food intake and body weight reduction.
Receptor potency was measured in vitro. Receptor selectivity was further investigated in rats, by measuring Ca2+ plasma levels after a single subcutaneous injection of vehicle, cagrilintide (10 nmol/kg), eloralintide (10 or 30 nmol/kg) or NN1213 (10 or 30 nmol/kg). In addition, the effect of NN1213 (10 nmol/kg, qd, sc.) on body weight and food intake was investigated in diet-induced obese rats during 17 days of dosing. Body weight and Ca2+ levels and food intake were analysed by a mixed effect model or 2-way repeated measure ANOVA, respectively, followed by Dunnett’s multiple comparison test.
In vitro, cagrilintide and eloralintide activated both rat and human AMYRs and CTR whereas NN1213 was more selective for AMYRs. In rats, cagrilintide and eloralintide induced a prolonged decrease in Ca2+ plasma levels in rats while NN1213 did not. Furthermore, NN1213 decreased body weight and food intake in diet-induced obese rats.
Cagrilintide and eloralintide are both AMYR and CTR agonists whereas NN1213 is a selective AMYRs agonist that also decreases body weight in rats.
D. Ipsen: Employee; Novo Nordisk A/S. B. Ballarin-Gonzalez: Employee; Novo Nordisk. Stock/Shareholder; Novo Nordisk. E. Moo: Employee; Nov
