A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans
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.
Authors
- Jonathan D. Douros (ORCID: https://orcid.org/0000-0003-2299-6163)
- Diego Pérez–Tilve (ORCID: https://orcid.org/0000-0002-0351-4133)
- Martin Kankam
- Ann Maria Kruse Hansen
- John Rømer Nielsen
- Patrick J. Knerr
- Ronald Goldwater
- Stephanie A. Mowery
- Timo D. Müller (ORCID: https://orcid.org/0000-0002-0624-9339)
- Sune Boris Nygård
- Kirsten Raun (ORCID: https://orcid.org/0000-0001-7605-8215)
- Richard D. DiMarchi (ORCID: https://orcid.org/0000-0003-0220-4085)
- Karina Rahr Hjøllund
- Julie Hjerpsted (ORCID: https://orcid.org/0000-0002-6938-786X)
- Anish Konkar
- Bin Yang (ORCID: https://orcid.org/0000-0002-6604-5565)
- Brian Finan
- Matthias H. Tschöp
Institutions
- Roche (Switzerland) (CH)
- Eli Lilly (United States) (US)
- Novo Nordisk (Denmark) (DK)
- Indiana Biosciences Research Institute (US)
- Helmholtz Zentrum München (DE)
- Novo Nordisk (United States) (US)
- Indiana University Bloomington (US)
- PAREXEL International (United States) (US)
- Altasciences Clinical Research Vince & Associates (US)
- Deutsches Diabetes-Zentrum e.V. (DE)
- German Center for Diabetes Research (DE)
- Heinrich Heine University Düsseldorf (DE)
- Ludwig-Maximilians-Universität München (DE)
- University of Cincinnati Medical Center (US)
Publication Details
- Journal
- Molecular Metabolism
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1016/j.molmet.2025.102129
- Citations
- 11
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 10.06