CR059, a Once-Monthly circRNA-Encoded GLP-1 Analogue, Demonstrates Durable Glycemic Control in T2D Rhesus Monkeys

Introduction and Objective: CR059 is a circular RNA-encoded GLP-1 receptor agonist delivered via lipid nanoparticles (LNP), designed to enable sustained expression and long-acting metabolic control with once-monthly subcutaneous dosing. This study evaluated the glucose-lowering efficacy of CR059 in type 2 diabetic (T2D) monkeys. Methods: Four spontaneously T2D rhesus monkeys received CR059 at 20 μg/kg or 60 μg/kg via subcutaneous injection on Day 1 and Day 32. Fasting plasma glucose (FPG), HbA1c, and fructosamine (FRA) were measured over an 88-day observation period. Safety assessments included clinical observations, serum biochemistry, body weight and food intake. Results: Baseline FPG averaged 6.71±0.15 mmol/L (60 μg/kg) and 6.25±0.62 mmol/L (20 μg/kg). After the first dose, FPG decreased to 4.66±0.16 and 4.68±0.16 mmol/L by Day 2. In the 60 μg/kg group, FPG reached the cutoff of 5.5 mmol/L (~human 6.9) by Day 6-8 and remained near or below this level for ~1 month. In the 20 μg/kg group, FPG declined more gradually and was 5.36±0.30 mmol/L by Day 29, showing sustained glucose-lowering before the second injection. The second dose further reduced FPG to 4.58±0.33 and 4.45±0.39 mmol/L on Day 33, with mean FPG maintained near or below the cutoff through Day 60. HbA1c decreased progressively. In the 20 μg/kg group, mean HbA1c dropped from 4.87±0.14% at baseline to 4.48±0.04% (Day 29) and 4.22±0.16% (Day 60). In the 60 μg/kg group, mean HbA1c decreased from 4.89±0.08% to 4.67±0.04% (Day 29) and 4.37±0.04% (Day 60). FRA decreased in parallel, supporting durable glycemic control. CR059 was generally well tolerated during the 88-day observation period. Body weight showed a modest overall decline. ALT and AST levels remained within normal ranges. Conclusion: CR059 demonstrates durable, once-monthly glucose-lowering activity in T2D monkeys. Its circRNA-LNP platform supports extended half-life and sustained metabolic control, highlighting its potential as a breakthrough long-acting GLP-1 therapy. Disclosure: Y. Pei: None. M. Xu: None.