Introduction & Objective: Both GLP-1 and amylin are peptide hormones that reduce food intake, delay gastric emptying, and decrease glucagon levels. Combination of GLP-1 and amylin analogs promotes weight loss and glucose control in clinical trials. The objective of this study was to assess the efficacy of GLP-1 analog ecnoglutide (XW003) combined with novel amylin analogs in rodent models.

Methods: Amylin peptides were designed and tested in CHO-K1 CRE reporter cells expressing the amylin receptor complex (human calcitonin receptor and Ramp3) (AMY3) or calcitonin receptor alone (CTR). Combinations of amylin analogs and ecnoglutide were evaluated for body weight reduction in SD rats (single subcutaneous injection) and diet induced obese (DIO) rats (subcutaneously dosed once a day for 21 days). Cagrilintide (Novo Nordisk), an amylin analog in Phase 3 trials, was used as a comparator.

Results: Novel amylin analogs Cmpd A and Cmpd B activated both AMY3 and CTR receptors with similar potencies to cagrilintide. The EC50 values for Cmpd A, Cmpd B, and cagrilintide, respectively in the AMY3 assay were 0.017 nM, 0.028 nM, and 0.041 nM and in the CTR assay were 0.028 nM, 0.046 nM, and 0.042 nM. In SD rats, combination of 3 nmol/kg ecnoglutide and 3 nmol/kg Cmpd A induced synergistic body weight loss at 24 hours post-injection by -7.7%, compared to -1.1% for 3 nmol/kg ecnoglutide and -3.6% for 3 nmol/kg Cmpd A alone. In DIO rats, body weight loss on Day 22 was -19.7% for a combination of 3 nmol/kg ecnoglutide and 3 nmol/kg Cmpd B, compared to -15.4% for 3 nmol/kg ecnoglutide and -1.2% for 3 nmol/kg Cmpd B.

Conclusion: Novel amylin analogs (Cmpd A and Cmpd B) showed similar in vitro activities to cagrilintide. In preclinical animal models, combination of amylin analogs with GLP-1 analog ecnoglutide demonstrated a synergistic effect on body weight reduction.

Disclosure

H. Zou: Employee; Sciwind Biosciences. X. Wu: Employee; Sciwind Biosciences. Y. Li: Employee; Sciwind Biosciences. R. Zhu: Employee; Sciwind Biosciences. R. Wang: Employee; Sciwind Biosciences. S. Hao: Employee; Sciwind Biosciences. Z. Li: Employee; Sciwind Biosciences. Y. Wang: Employee; Sciwind Biosciences. J. Deng: Employee; Sciwind Biosciences. C.L. Jones: Employee; Sciwind Biosciences. M. Fenaux: None.

Funding

Sciwind Biosciences

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