Activity-balanced GLP-1/GDF15 dual agonist reduces body weight and metabolic disorder in mice and non-human primates.

Abstract

Obesity is a considerable health concern with limited pharmacotherapy options of low efficacy. Here, we develop a GLP-1/GDF15 fusion protein and explore its weight-lowering potential in animals. The molecule, QL1005, is engineered via fusing GLP-1 and GDF15 analogs by a peptide linker and conjugating it to a fatty acid for time-action extension. In vitro, the potency of QL1005 is superior to the GLP-1 analog semaglutide. In obese mice, QL1005 induces reductions in body weight, food intake, insulin, fasting glucose, and triglycerides. Notably, these metabolic effects come as a result of activities emanating from both GLP-1 and GDF15, in an individual pathway-balanced fashion. In a cynomolgus monkey model of obesity, QL1005 reduces body weight, food intake, insulin, and glucose in a dose-dependent manner with limited incidence of GI side effects. Altogether, this long-acting, dual GLP-1/GDF15 molecule demonstrates the promise of poly-pharmaceutical approaches in metabolic drug discovery and development.