2872-LB: Cardioprotective Effects of HM17321, a Novel UCN2 Analog, in Rodent Heart Failure Models and a Translational Nonhuman Primate Model

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Introduction and Objective: Heart failure (HF) is a major global cause of mortality, and its prevalence is increasing with rising obesity rates, particularly in HFpEF. Urocortin-2 (UCN2) exerts beneficial cardiovascular effects, including vasodilation and improved cardiac function in HF. HM17321 is a CRFR2-selective UCN2 analog currently in phase 1 clinical development as an anti-obesity therapy with improved weight loss quality (WLQ). This study evaluated the therapeutic potential of HM17321 in rodent HF models and a translational non-human primate model.Methods: Cardioprotective effects of HM17321 were evaluated in three preclinical models, including an obesity and hypertension driven HFpEF mouse model (HFD/L-NAME), a monocrotaline (MCT)-induced HF rat model, and middle-aged obese rhesus monkeys. HM17321 was administered for 2 to 5 weeks in rodents and for 13 weeks in non-human primates. Cardiac structure and function (echocardiography) and exercise capacity were assessed.Results: In HFpEF mice, HM17321 significantly reduced left ventricular (LV) hypertrophy with decreased LV mass and wall thickness compared to vehicle (LV mass: 132.2 mg vs. 177.6 mg; wall thickness: 0.88 mm vs. 1.05 mm). HM17321 also decreased MV E/E′ ratio and shortened IVRT compared to vehicle, suggesting improved diastolic function (MV E/E′ ratio: 22.8 vs. 28.7; IVRT: 16.2 ms vs. 20.5 ms). In MCT-induced HF rat model, HM17321 markedly improved exercise capacity, arterial oxygen saturation, and myocardial fibrosis. In obese rhesus monkeys, HM17321 significantly reduced systolic and diastolic blood pressure (114/54 mmHg vs. 140/69 mmHg, vehicle) without increasing heart rate.Conclusion: HM17321 improved cardiac function and attenuated pathological cardiac remodeling in rodent HF models and a non-human primate model. These findings suggest that HM17321, developed as an anti-obesity therapy for improved WLQ, may also represent a novel therapeutic option for HF, supported by cardiovascular effects observed in primates.

Disclosure

B. Ye: Employee; Current; Hanmi Pharm. Co., Ltd. W. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. H. Kwon: Employee; Current; Hanmi Pharm. Co., Ltd. Y. Kim: None. S. Lee: None. J. Kim: Employee; Current; Hanmi Pharm. Co., Ltd. J. Kim: None. S. Bae: None. S. Lee: Employee; Current; Hanmi Pharm. Co., Ltd. I. Choi: None.



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