A GIPR Antagonist Conjugated to GLP-1 Analogues Promotes Weight Loss with Improved Metabolic Parameters in Preclinical and Phase 1 Settings

Overview

Journal Nat Metab

Publisher Springer Nature

Specialty Endocrinology

Date 2024 Feb 5

PMID 38316982

Authors

Murielle M Veniant

Shu-Chen Lu

Larissa Atangan

Renee Komorowski

Shanaka Stanislaus

Yuan Cheng

Bin Wu

James R Falsey

Todd Hager

Veena A Thomas

Malhar Ambhaikar

Lucie Sharpsten

Yineng Zhu

Vamsi Kurra

Rohini Jeswani

Rajneet K Oberoi

Jane R Parnes

Narimon Honarpour

Joel Neutel

Jennifer L Strande

Affiliations

Soon will be listed here.

Abstract

Obesity is a major public health crisis. Multi-specific peptides have emerged as promising therapeutic strategies for clinical weight loss. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are endogenous incretins that regulate weight through their receptors (R). AMG 133 (maridebart cafraglutide) is a bispecific molecule engineered by conjugating a fully human monoclonal anti-human GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. Here, we confirm the GIPR antagonist and GLP-1R agonist activities in cell-based systems and report the ability of AMG 133 to reduce body weight and improve metabolic markers in male obese mice and cynomolgus monkeys. In a phase 1, randomized, double-blind, placebo-controlled clinical study in participants with obesity ( NCT04478708 ), AMG 133 had an acceptable safety and tolerability profile along with pronounced dose-dependent weight loss. In the multiple ascending dose cohorts, weight loss was maintained for up to 150 days after the last dose. These findings support continued clinical evaluation of AMG 133.

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