HM17321 significantly reduced left ventricular mass (132.2 mg vs 177.6 mg) in HFpEF mice and reduced blood pressure (114/54 vs 140/69 mmHg) in obese rhesus monkeys compared to vehicle.
Does HM17321 improve cardiac function and structure in preclinical models of heart failure?
HM17321, a novel UCN2 analog, improves cardiac function and attenuates pathological remodeling in preclinical rodent and non-human primate models of heart failure.
Absolute Event Rate: 132.2% vs 177.6%
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.
Ye et al. (2026) studied Heart failure. HM17321 vs. Vehicle was evaluated on Left ventricular mass in HFpEF mice. HM17321 significantly reduced left ventricular mass (132.2 mg vs 177.6 mg) in HFpEF mice and reduced blood pressure (114/54 vs 140/69 mmHg) in obese rhesus monkeys compared to vehicle.