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 B. Hjerpsted; Karina Rahr Hjøllund; Martin K. Kankam; Patrick J. Knerr; Anish Konkar; Stephanie A. Mowery; Timo D. Müller; John Rømer Nielsen; Sune Boris Nygård; Diego Perez-Tilve; Kirsten Raun; Bin Yang; Matthias H. Tschöp; Richard D. DiMarchi

doi:10.1016/j.molmet.2025.102129

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 B. Hjerpsted
, Karina Rahr Hjøllund
, Martin K. Kankam
, Patrick J. Knerr
, Anish Konkar
, Stephanie A. Mowery
, Timo D. Müller
, John Rømer Nielsen
, Sune Boris Nygård
, Diego Perez-Tilve
, Kirsten Raun
, Bin Yang
, Matthias H. Tschöp
, Richard D. DiMarchi

Medicine and Health

Novo Nordisk Research Center
Novo Nordisk Research Center Boston
Klinikum Westend
Novo Nordisk A/S
Altasciences Clinical Kansas
Roche Pharma Research & Early Development
Institute for Diabetes and Obesity
German Centre for Diabetes Research (DZD)
Ludwig-Maximilians-Universität München
University of Cincinnati College of Medicine
Helmholtz Munich
Indiana University Bloomington

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

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.

Original language	English
Article number	102129
Journal	Molecular Metabolism
Volume	96
DOIs	https://doi.org/10.1016/j.molmet.2025.102129
State	Published - Jun 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Clinical
Glucagon
Incretins
Obesity

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10.1016/j.molmet.2025.102129

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Finan, B., Douros, J. D., Goldwater, R., Hansen, A. M. K., Hjerpsted, J. B., Hjøllund, K. R., Kankam, M. K., Knerr, P. J., Konkar, A., Mowery, S. A., Müller, T. D., Nielsen, J. R., Nygård, S. B., Perez-Tilve, D., Raun, K., Yang, B., Tschöp, M. H., & DiMarchi, R. D. (2025). A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans. Molecular Metabolism, 96, Article 102129. https://doi.org/10.1016/j.molmet.2025.102129

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title = "A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans",

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.",

keywords = "Clinical, Glucagon, Incretins, Obesity",

author = "Brian Finan and Douros, \{Jonathan D.\} and Ronald Goldwater and Hansen, \{Ann Maria Kruse\} and Hjerpsted, \{Julie B.\} and Hj{\o}llund, \{Karina Rahr\} and Kankam, \{Martin K.\} and Knerr, \{Patrick J.\} and Anish Konkar and Mowery, \{Stephanie A.\} and M{\"u}ller, \{Timo D.\} and Nielsen, \{John R{\o}mer\} and Nyg{\aa}rd, \{Sune Boris\} and Diego Perez-Tilve and Kirsten Raun and Bin Yang and Tsch{\"o}p, \{Matthias H.\} and DiMarchi, \{Richard D.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors",

year = "2025",

month = jun,

doi = "10.1016/j.molmet.2025.102129",

language = "English",

volume = "96",

journal = "Molecular Metabolism",

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Finan, B, Douros, JD, Goldwater, R, Hansen, AMK, Hjerpsted, JB, Hjøllund, KR, Kankam, MK, Knerr, PJ, Konkar, A, Mowery, SA, Müller, TD, Nielsen, JR, Nygård, SB, Perez-Tilve, D, Raun, K, Yang, B, Tschöp, MH & DiMarchi, RD 2025, 'A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans', Molecular Metabolism, vol. 96, 102129. https://doi.org/10.1016/j.molmet.2025.102129

TY - JOUR

T1 - A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans

AU - Finan, Brian

AU - Douros, Jonathan D.

AU - Goldwater, Ronald

AU - Hansen, Ann Maria Kruse

AU - Hjerpsted, Julie B.

AU - Hjøllund, Karina Rahr

AU - Kankam, Martin K.

AU - Knerr, Patrick J.

AU - Konkar, Anish

AU - Mowery, Stephanie A.

AU - Müller, Timo D.

AU - Nielsen, John Rømer

AU - Nygård, Sune Boris

AU - Perez-Tilve, Diego

AU - Raun, Kirsten

AU - Yang, Bin

AU - Tschöp, Matthias H.

AU - DiMarchi, Richard D.

PY - 2025/6

Y1 - 2025/6

N2 - 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.

AB - 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.

KW - Clinical

KW - Glucagon

KW - Incretins

KW - Obesity

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DO - 10.1016/j.molmet.2025.102129

M3 - Article

C2 - 40139439

AN - SCOPUS:105003257780

SN - 2212-8778

VL - 96

JO - Molecular Metabolism

JF - Molecular Metabolism

M1 - 102129

ER -

A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans

Abstract

UN SDGs

Keywords

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