Maridebart cafraglutide (AMG 133, known as MariTide) is Amgen's investigational obesity therapy combining a monoclonal antibody targeting GIP receptor antagonism with two conjugated GLP-1 receptor agonist peptides [1]. The design enables once-monthly subcutaneous administration, a substantially lower administration burden than weekly GLP-1 incretins [2].
Mechanism: GIP Antagonism plus GLP-1 Agonism
MariTide is mechanistically unusual: it agonises the GLP-1 receptor while antagonising the GIP receptor. This contrasts with Tirzepatide and VK2735, which agonise both. The rationale derives from preclinical and genetic evidence: genome-wide association studies have linked the GIP receptor to obesity, and in mice and monkeys GIP receptor-blocking antibodies reduced weight gain and added to the weight loss seen with GLP-1 receptor agonists [3].
Phase 2 Data
52-week Phase 2 results reported mean weight reductions of up to 16.2% in participants with obesity and up to 12.3% in those with obesity and type 2 diabetes, versus 2.5% and 1.7% with placebo, using a treatment-policy analysis. The trial tested 4-weekly and, in one group, 8-weekly schedules; gastrointestinal adverse events were common, and no unexpected safety signals emerged [2].
Format: Peptide-Antibody Conjugate
MariTide is not a conventional peptide. It is a bispecific peptide-antibody conjugate, structurally closer to therapeutic antibodies than to GLP-1 peptides [1]. This format is not amenable to standard solid-phase peptide synthesis and is not available as a research-grade compound from peptide suppliers.
Research Pathways
Laboratories interested in GIP antagonism alongside GLP-1 agonism currently model the combination using Semaglutide as the GLP-1 reference and dedicated GIP receptor antagonist tool compounds available through specialist chemistry suppliers. Tirzepatide serves as the dual agonist comparator.
References
- [1] Véniant MM, et al. "A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings." Nat Metab. 2024;6(2):290-303. PubMed 38316982
- [2] Jastreboff AM, et al. "Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial." N Engl J Med. 2025;393(9):843-857. PubMed 40549887
- [3] Killion EA, et al. "Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models." Sci Transl Med. 2018;10(472):eaat3392. PubMed 30567927