SAT149 In Vitro Characterization Of A Novel Long-acting Glucagon Analog (HM15136) And Its Potential Effect In Animal Models Of Chronic Hypoglycemic Diseases

Abstract

Abstract Disclosure: J. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. Y. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. B. Ye: Employee; Self; Hanmi Pharm. Co., Ltd. W. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. J. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. S. Bae: Employee; Self; Hanmi Pharm. Co., Ltd. D. Kim: Employee; Self; Hanmi Pharm. Co., Ltd. S. Lee: Employee; Self; Hanmi Pharm. Co., Ltd. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd. Glucagon plays an essential role in glucose homeostasis, and has been used to treat acute hypoglycemia in diabetic patients. However, due to poor solubility and stability at physiological pH as well as short duration of action, its utility was hampered when managing chronic hypoglycemic diseases. One such example is congenital hyperinsulinism (CHI). CHI is a rare genetic disorder characterized by unregulated insulin secretion which leads to severe hypoglycemia especially during fasting condition. Another example is post-bariatric hypoglycemia (PBH) which can also lead to postprandial neuroglycopenia. Despite this life-threatening condition, no drugs are approved for CHI and/or PBH, and available glucagon therapies are very inefficient and inconvenient due to abovementioned limitations. Thus, to provide more optimal therapy for these chronic hypoglycemic diseases, a novel long-acting glucagon analog (HM15136) was developed. Here, we evaluated HM15136’s 1) solubility and stability at physiologic pH, 2) in vitro properties, and 3) potential therapeutic effect in animal models of CHI or PBH. First, we demonstrated improved solubility of HM15136 (≥150 vs. 0.03 mg/mL) at pH 7.0 and stability at day 20, compared to those of native glucagon. Next, in vitro cAMP assay was performed in CHO cells expressing human glucagon receptor (hGCGR), and HM15136 selectively activated hGCGR as a full agonist (EC50 = 0.024 vs. 0.003 nM; relative activity = ca.12.7%). In line with this, HM15136 promoted glycogenolysis and gluconeogenesis in rat primary hepatocytes in a dose dependent manner (relative potency = ca.20%), confirming glucose producing nature of HM15136. To investigate in vivo therapeutic effect on CHI and PBH, chronic hypoglycemia rats induced by SC infusion of insulin (CHI rats) and postprandial hypoglycemia rats induced by vertical sleeve gastrectomy (VSG rats) were established, respectively. Notably, HM15136 treatment significantly restored FBG by 37.3 ∼ 69.7% (p<0.05 ∼ 0.001) in CHI rats. Consistently, HM15136 treatment significantly prevented a massive BG reduction during MMTT in VSG rats (ΔBG between 0 and 45 min = +21 vs. -30 mg/dL, p<0.001). Furthermore, weekly dosing potential and BG elevation effect of HM15136 were also demonstrated in healthy human subjects (1). Based on these results, HM15136 could be a potential therapeutic option for chronic hypoglycemic diseases including CHI and PBH. Phase 2 clinical study in CHI subjects is on-going to assess the clinical relevance of these findings. Reference: (1) Diabetes Obes Metab. 2022 Mar; 23(3):411-20 Presentation: Saturday, June 17, 2023