PG-102, a first-in-class heterodimeric Fc fusion protein, simultaneously targets GLP-1R and GLP-2R. In this study, we assess the efficacy of PG-102 against established comparators - semaglutide, tirzepatide, and retatrutide - in severely hyperglycemic, obese db/db mice. Based on our dose response findings, we chose 30 nmol/kg as the optimal PG-102 dose for maintaining normoglycemia in subsequent comparative studies. Strikingly, at the same dosage and regimen, PG-102 surpassed all comparators in reducing blood glucose and HbA1c levels. It was also worth noting that PG-102 was uniquely capable of achieving and sustaining normoglycemia at the end of the study. Histopathological and immunohistochemical analysis of pancreatic islets revealed that PG-102 treatment led to the largest islet mass with the highest percentage of insulin-positive β-cell area along with the lowest percentage of glucagon-positive α-cell area among the treatment groups. We also observed reduced macrophage infiltration into pancreatic islets and peri-pancreatic adipose tissue. These results demonstrate that PG-102’s superior glycemic control may be due to a combination of better protection of β-cell and reduction in islet inflammation. Collectively, our study provides the rationale for advancing the clinical investigation of PG-102.
S. Kim: Employee; ProGen. Co., Ltd. S. Yang: Employee; Progen. Y. Sung: Advisory Panel; Progen Co., Ltd.
