A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings

Murielle Véniant, Shu-Chen Lu, Larissa Atangan, Renee Komorowski, Shanaka Stanislaus, Yuan Cheng, Bin Wu, James Falsey, Todd Hager, Veena Thomas, Malhar Ambhaikar, Lucie Sharpsten, Yineng Zhu, Vamsi Kurra, Rohini Jeswani, Rajneet Oberoi, Jane Parnes, Narimon Honarpour, Joel Neutel, Jennifer Strande (2024) A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings Nat Metab (IF: 20.8) 6(2) 290-303

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.© 2024. The Author(s).

Links

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10896721
http://www.ncbi.nlm.nih.gov/pubmed/38316982
http://dx.doi.org/10.1038/s42255-023-00966-w

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