gcg-xten an improved glucagon capable of preventing hypoglycemia without increasing baseline blood glucosegcg-xten改进胰高糖素预防低血糖不增加基线血糖的能力.pdfVIP

Gcg-XTEN: An Improved Glucagon Capable of Preventing Hypoglycemia without Increasing Baseline Blood Glucose 1 1 1 1 1 1 Nathan C. Geething , Wayne To , Benjamin J. Spink , Michael D. Scholle , Chia-wei Wang , Yong Yin , Yi 1 1 2 1 1 Yao , Volker Schellenberger , Jeffrey L. Cleland , Willem P. C. Stemmer , Joshua Silverman * 1 Amunix, Inc., Mountain View, California, United States of America, 2 Versartis, Inc., Mountain View, California, United States of America Abstract Objective: While the majority of current diabetes treatments focus on reducing blood glucose levels, hypoglycemia represents a significant risk associated with insulin treatment. Glucagon plays a major regulatory role in controlling hypoglycemia in vivo, but its short half-life and hyperglycemic effects prevent its therapeutic use for non-acute applications. The goal of this study was to identify a modified form of glucagon suitable for prophylactic treatment of hypoglycemia without increasing baseline blood glucose levels. Methodology/Principal Findings: Through application of the XTEN technology, we report the construction of a glucagon fusion protein with an extended exposure profile (Gcg-XTEN). The in vivo half-life of the construct was tuned to support nightly dosing through design and testing in cynomolgus monkeys. Efficacy of the construct was assessed in beagle dogs using an insulin challenge to induce hypoglycemia. Dose ranging of Gcg-XTEN in fasted beagle dogs demonstrated that the compound was biologically active with a pharmacodynamic profile consistent with the design