Introduction and Objective: MET-233 is an ultra-long acting (ULA) amylin analog being evaluated in clinical trials for the treatment of obesity. We sought preclinical proof of concept that MET-233, designed to be combined with GLP-1R agonist MET-097, is an effective candidate for obesity treatment.Methods: MET-233 emerged from an amylin analog development program focused on potency, durability, and combinability. The pharmacokinetics of MET-233 and cagrilintide were compared after single administration in pigs. Compatibility of MET-233 and MET-097 for coformulation was assessed, and body weight loss efficacy of MET-233 ± MET-097 was compared to CagriSema after chronic administration in rats.Results: In pigs, the half-life of MET-233 was determined to be 125 h and cagrilintide 83 h. Both MET-233 and MET-097 were soluble across a wide pH range. Chronic administration of MET-233, CagriSema, and MET-233 with MET-097 to rats over 28 d reduced body weight by 17.6%, 14.8%, and 31.2%, respectively.Conclusion: The long half-life of MET-233 observed in pigs suggests that infrequent administration in humans may be achievable. Results from chronic administration to rats indicate that MET-233 is highly effective, and additive impact on body weight was observed when coadministered with MET-097. The potency, durability, and combinability of MET-233 and MET-097 highlight the potential of MET-233 as a differentiated treatment option.
J.S. Minnion: Stock/Shareholder; Metsera. Employee; Zihipp. C. Hinds: Employee; Metsera, Zihipp. B. Reglinska: Employee; Metsera, Inc.
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