A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans
Brian Finan, Jonathan D. Douros, Ronald Goldwater, Ann Maria Kruse Hansen, Julie Hjerpsted, Karina Rahr Hjøllund, Martin Kankam, Patrick J. Knerr, Anish Konkar, Stephanie A. Mowery, Timo D. Müller, John Rømer Nielsen, Sune Boris Nygård, Diego Pérez–Tilve, Kirsten Raun, Bin Yang, Matthias H. Tschöp, Richard D. DiMarchi
Abstract
Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic peptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706. • NN1706 is a fatty-acylated single-molecule tri-agonist. • NN1706 has balanced activity at GLP-1R and GIPR and lower potency at GcgR. • NN1706 lowers body weight & improves glycemic control in obese rodents and monkeys. • NN1706 treatment led to 8.2% weight loss from baseline after 10 weeks in adults with overweight/obesity. • Increased heart rate was observed across NN1706 treatment cohorts.