789-P: Discovery of a Novel, Long-Acting Amylin Receptor Agonist for Body Weight Control

Introduction & Objective: Amylin, a hormone co-secreted with insulin from pancreatic beta-cells, reduces food intake and glucagon levels. Combination of GLP-1 and amylin analogs promotes weight loss and glucose control. However, treatment is complicated by the need to formulate the peptides in different buffers. The objective of this study was to discover a novel amylin analog that could be co-formulated with GLP-1 peptides at neutral pH.

Methods: Peptides were designed and assessed for thermal-stressed stability (pH 7.4 at 40 oC for 20 days), as well as tested in CHO-K1 CRE reporter cells overexpressing the amylin receptor complex (calcitonin receptor and Ramp3) (AMY3) or calcitonin receptor alone (CTR), and evaluated for body weight reduction by single subcutaneous injection in SD rats. Cmpd C was selected and further characterized by once daily injection for 10 days in diet-induced obese (DIO) rat and pharmacokinetic (PK) study in cynomolgus monkey. Cagrilintide (Novo Nordisk), an amylin analog in Phase 3 studies, was used as a comparator.

Results: Among the peptides tested, Cmpd C activated AMY3 and CTR with similar potencies to cagrilintide (EC50 for Cmpd C and cagrilintide, respectively, AMY3: 0.038 nM vs 0.045 nM; CTR: 0.41 nM vs 0.45 nM). In SD rats, Cmpd C decreased body weight by 7.36% compared to 6.28% for cagrilintide over 48 hours. In DIO rats, body weight loss after end of dosing (Day 11) was 8.19% for Cmpd C and 7.55% for cagrilintide. In cynomolgus monkeys, Cmpd C showed comparable PK to cagrilintide. Importantly, Cmpd C showed superior thermal stability to cagrilintide at pH 7.4. While 44.83% of cagrilintide was degraded after 10 days, Cmpd C was reduced by 4.26% after 20 day incubation.

Conclusion: Overall, Cmpd C demonstrated potency and PK comparable to cagrilintide. Moreover, Cmpd C exhibited greater stability at pH 7.4 than cagrilintide, providing the opportunity to co-formulate with GLP-1 analogs. Formulation of GLP-1 and amylin in a single vial will improve ease of use and reduce cost.