Maridebart
Cafraglutide (MariTide)

Maridebart cafraglutide (AMG 133, MariTide) is an investigational antibody-peptide conjugate developed by Amgen. It joins a fully human monoclonal antibody that blocks the glucose-dependent insulinotropic polypeptide receptor (GIPR) to two GLP-1 analogue peptides attached through amino acid linkers. The result is a single molecule that combines GLP-1 receptor agonism with GIPR antagonism and carries the long half-life typical of antibodies.

The design grew out of human genetic studies associating GIPR loss-of-function variants with lower body mass index, and out of Amgen's in vitro studies and animal models.">preclinical work in mice and non-human primates showing that GIPR blockade combined with GLP-1 agonism reduced body weight more than either alone. Phase 1 results were published in 2024, phase 2 findings followed, and a phase 3 programme began in 2025. The molecule is not approved by any regulator. Maridebart cafraglutide is particularly interesting to researchers because it takes the opposite approach to incretin hormone from intestinal K cells; its receptor is a target of dual and triple agonists.">GIP receptor co-agonists such as tirzepatide, raising fundamental questions about GIP biology in energy balance.

The antibody component binds GIPR with high affinity and prevents activation by endogenous incretin hormone from intestinal K cells; its receptor is a target of dual and triple agonists.">GIP, while the conjugated peptides activate the GLP-1 receptor and its Gs-cAMP signalling. GLP-1 receptor engagement promotes satiety, slows gastric emptying and enhances glucose-dependent insulin secretion. The contribution of GIPR blockade is less settled. One hypothesis is that sustained agonism and antagonism both reduce functional GIPR signalling, because chronic agonist exposure desensitises and internalises the receptor. Another highlights GIPR's roles in adipose tissue lipid handling and in central nausea and food-intake circuits. The antibody scaffold supports neonatal Fc receptor recycling, giving the conjugate a long half-life.