A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.
Murielle M VéniantShu-Chen LuLarissa AtanganRenee KomorowskiShanaka StanislausYuan ChengBin WuJames R FalseyTodd HagerVeena A ThomasMalhar AmbhaikarLucie SharpstenYineng ZhuVamsi KurraRohini JeswaniRajneet K OberoiJane R ParnesNarimon HonarpourJoel NeutelJennifer L StrandePublished in: Nature metabolism (2024)
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.
Keyphrases
- weight loss
- double blind
- placebo controlled
- bariatric surgery
- public health
- roux en y gastric bypass
- body weight
- clinical trial
- amino acid
- endothelial cells
- gastric bypass
- phase iii
- phase ii
- weight gain
- induced pluripotent stem cells
- study protocol
- phase ii study
- glycemic control
- open label
- pluripotent stem cells
- adipose tissue
- randomized controlled trial
- stem cells
- squamous cell carcinoma
- cell therapy
- pulmonary artery
- blood pressure
- photodynamic therapy
- single cell
- physical activity
- insulin resistance
- mesenchymal stem cells
- skeletal muscle
- high fat diet induced