3078-LB: HM17321, a Novel UCN2 Analog, Improves Weight Loss Quality in Combination with Amylin Analogs in DIO Rats

Introduction and Objective: GLP-1 therapies have transformed the treatment landscape for obesity, yet significant unmet medical needs remain, including GI adverse events, variability in patient response, and notably lean mass (LM) loss. Amylin analogs are being developed to address these limitations, but their impact on LM remains unclear. Previously, HM17321 showed body weight (BW) loss while increasing functionally intact muscle mass, and improved weight loss quality (WLQ) in combination with incretin therapies. Here, we evaluated a novel combination potential of HM17321 and amylin analogs. Methods: Combination efficacy of HM17321 and amylin analogs (cagrilintide, petrelintide, and eloralintide) was evaluated in DIO rats. At the end of treatment, body composition was assessed by time domain nuclear magnetic resonance. Results: HM17321 monotherapy resulted in significant fat mass (FM) reduction and LM gain, confirming a favorable body recomposition. Each amylin analog showed significant BW loss, primarily through FM loss (-32.4% to -15.8% vs. day -1; p 0.001 vs. DIO, vehicle). Combination treatment of HM17321 with amylin analogs promoted greater FM reduction (-56.5 % to -45.4 % vs. day -1; p 0.05 ~ 0.001 vs. each mono) without additional food intake inhibition. Importantly, HM17321 combination markedly enhanced LM gain (17.9 % to 22.1 % vs. day -1; p 0.01 ~ 0.001 vs. each mono) compared with each amylin monotherapy (9.2% to 12.9% / DIO, vehicle 6.6% vs. day -1), suggesting WLQ improvement. Similarly, all treatment groups improved blood glucose profile compared to DIO vehicle, and HM17321 combination showed a trend toward further improvement. Conclusion: In DIO rats, combination treatment of HM17321 with amylin analogs enhanced FM reduction while promoting LM gain, leading to marked improvement in WLQ. These findings highlight the unique potential of HM17321 to improve body composition during weight loss and support its development both as a monotherapy and as a combination partner for amylin- or incretin-based therapies. Disclosure Y. Kim: None. S. Lee: None. E. Kim: None. W. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. E. Park: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: None. S. Lee: Employee; Current; Hanmi Pharm. Co., Ltd. S. Bae: None. I. Choi: None.