Abstract：
Pegozafermin (also known as BIO89-100) is a glycoPEGylated analog of fibroblast growth factor 21 (FGF21) under development to treat nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia (SHTG). In cell-based assays, pegozafermin had a similar receptor engagement profile as recombinant FGF21, with approximately eightfold higher potency at fibroblast growth factor receptor 1c (FGFR1c). In diabetic monkeys, once-weekly and once-every-2-weeks regimens of subcutaneous pegozafermin provided rapid and robust benefits for an array of metabolic biomarkers, including triglycerides, cholesterol, fasting glucose, glycated hemoglobin, adiponectin, alanine aminotransferase, food intake, and body weight. In a single ascending dose study in healthy volunteers, subcutaneously administered pegozafermin was associated with statistically significant improvements in triglycerides, low- and high-density lipoprotein-cholesterol, and adiponectin, an insulin-sensitizing and anti-inflammatory adipokine. Pharmacokinetic half-lives ranged from 55 to 100 hours over the clinically relevant dose range, consistent with the expected half-life extension by glycoPEGylation. These findings provide evidence that pegozafermin is a promising candidate molecule for the treatment of patients with NASH or SHTG. SIGNIFICANCE STATEMENT: Fibroblast growth factor 21 (FGF21) is a stress-inducible hormone that has important roles in regulating energy balance and glucose and lipid homeostasis. Studies presented here demonstrate that a novel long-acting FGF21 analog, pegozafermin, has similar pharmacologic properties as FGF21 and that repeated, subcutaneous dosing of pegozafermin in diabetic monkeys and healthy humans improves lipid metabolism, glucose metabolism, weight, and liver transaminases. These results support future development of pegozafermin for the treatment of metabolic diseases, including nonalcoholic steatohepatitis and severe hypertriglyceridemia.
摘要：
Pegozafermin（也称为BIO89-100）是正在开发的成纤维细胞生长因子21（FGF21）的糖聚乙二醇化类似物，用于治疗非酒精性脂肪性肝炎（NASH）和严重的高甘油三酯血症（SHTG）。在基于细胞的检测中，pegozafermin具有与天然FGF21相似的受体接合谱，对FGF受体1（FGFR1）的效力高约8倍。在糖尿病猴子中，每周一次和每两周一次的皮下pegozafermin方案对一系列代谢生物标志物提供了快速和强大的益处，包括甘油三酯,胆固醇,空腹血糖,HbA1c,脂联素,ALT,食物摄入量,和体重。在健康志愿者的单次递增剂量研究中，皮下给药pegozafermin与甘油三酯的统计学显着改善相关，LDL和HDL胆固醇，和脂联素，一种胰岛素增敏和抗炎的脂肪因子。在临床相关剂量范围内，药代动力学半衰期为55至100小时，与通过糖聚乙二醇化延长预期的半衰期一致。这些发现提供了证据，证明pegozafermin是治疗NASH或SHTG患者的有希望的候选分子。意义声明成纤维细胞生长因子21（FGF21）是一种应激诱导激素，在调节能量平衡以及葡萄糖和脂质稳态中具有重要作用。这里提出的研究表明，一种新型的长效FGF21类似物，pegozafermin,具有与FGF21相似的药理特性，pegozafermin在糖尿病猴和健康人中皮下给药可改善脂质代谢，葡萄糖代谢，体重和肝转氨酶。这些结果支持pegozafermin用于治疗代谢性疾病的未来发展，包括非酒精性脂肪性肝炎和重度高血糖症。
