Eloralintide (LY3841136), a Selective Amylin Mimetic, Lowered Body Weight with Improved Quality of Weight Loss and GI Tolerability in Rats Compared with Cagrilintide

Introduction and Objective: Non-selective amylin analogs have shown clinical weight loss benefits, though clinical incidence of nausea and vomiting are high and may require prolonged dosing titrations. Moreover, preclinical studies in rats suggest lean mass preservation versus GLP-1 receptor agonists. Herein, we evaluated weight loss efficacy, GI tolerability, and lean-mass preservation in rats administered eloralintide compared to the non-selective amylin analog, cagrilintide. Methods: Peptides were made using automated peptide synthesizers and evaluated in amylin and calcitonin receptor functional and binding assays. PK and conditioned taste avoidance studies performed using lean rats. Weight loss studies were carried out in lean and DIO rats using QNMR to determine body composition. Results: Eloralintide is an amylin peptide analog modified with a C20 fatty diacid moiety that binds to amylin receptors while retaining selectivity from calcitonin receptors. Eloralintide demonstrated prolonged plasma half-life and reduced clearance compared to cagrilintide. In lean rats, eloralintide matched the food intake reductions of cagrilintide, resulting in a similar degree on body weight change, without the same degree of conditioned taste avoidance. In DIO rats, eloralintide lowered body weight primarily by loss of fat mass and with more potent effects for weight loss efficacy, food intake lowering, and fat mass reductions compared to cagrilintide, with head-to-head studies demonstrating reduced loss of lean mass in comparison to cagrilintide. Conclusion: Eloralintide demonstrated preclinical improvements in efficacy, GI tolerability, and quality of weight loss compared to the non-selective amylin analog cagrilintide. These findings support clinical investigation of eloralintide as a weight loss therapeutic. Disclosure: D.A. Briere: Employee; Lilly USA LLC. A. Long: Employee; Eli Lilly and Company. D.M. Bullock: None. L. O'Farrell: None. B. Bowen: Employee; Eli Lilly and Company. K. Lansu: Employee; Eli Lilly and Company. T. Coskun: None. J.S. Moyers: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. H. Qu: Employee; Eli Lilly and Company.