MariTide

What is MariTide?#

MariTide (maridebart cafraglutide, formerly AMG 133) is a first-in-class antibody-peptide conjugate developed by Amgen for the treatment of obesity and type 2 diabetes. It is a bispecific molecule that combines GLP-1 receptor agonism with GIP receptor antagonism -- the opposite GIP approach to tirzepatide, which is a GIP/GLP-1 dual agonist.

MariTide is engineered by conjugating a fully human monoclonal anti-GIPR antagonist antibody to two GLP-1 analogue agonist peptides using amino acid linkers. The resulting molecule has a molecular weight of approximately 153,514 Da and a half-life of approximately 21 days, enabling monthly or less frequent subcutaneous dosing.

In Phase 2 (published in the NEJM), MariTide achieved approximately 20% weight loss at 52 weeks in people with obesity without T2D, with no plateau observed. The Phase 3 MARITIME program has been initiated.

Mechanism of Action#

MariTide has a unique dual mechanism:

GLP-1 receptor agonism (via conjugated peptides):

• Appetite suppression via hypothalamic and brainstem receptors
• Glucose-dependent insulin secretion
• Glucagon suppression
• Gastric emptying delay

GIP receptor antagonism (via antibody component):

• Blocks GIPR signaling
• May reduce fat storage and lipogenesis
• Complementary weight loss pathway distinct from GLP-1 agonism
• Triggers receptor internalization when both receptors are present

The GIPR antagonism is particularly notable because it represents the opposite approach to tirzepatide. While tirzepatide achieves weight loss through GIPR agonism, MariTide achieves it through GIPR antagonism. Both approaches produce substantial weight loss (~20%), suggesting that modulating GIP signaling in either direction can be beneficial when combined with GLP-1 agonism.

A mechanistic study suggested that the bispecific molecule binds to GIPR and GLP-1R simultaneously, triggering receptor internalization and amplifying endosomal cAMP signaling in cells expressing both receptors.

Research Overview#

Phase 1 (Nature Metabolism, 2024)#

Published in Nature Metabolism (PMID 38316982), AMG 133 showed dose-dependent weight loss with an acceptable safety profile in a Phase 1 trial.

Phase 2 (NEJM, 2025)#

Published in the New England Journal of Medicine (PMID 40549887), the Phase 2 trial enrolled 592 participants in two cohorts:

Obesity without T2D:

• ~20% weight loss at 52 weeks (highest dose)
• No weight loss plateau at 52 weeks

Obesity with T2D:

• ~17% weight loss at 52 weeks
• HbA1c reduction of up to 2.2 percentage points

Phase 3 MARITIME Program#

The Phase 3 MARITIME program includes 72-week chronic weight management studies in participants with obesity or overweight, with and without T2D.

Important Considerations#

• MariTide is investigational and not yet FDA-approved
• Monthly dosing is a significant convenience advantage
• The antibody-peptide conjugate format is novel and distinct from standard peptide drugs
• GIPR antagonism vs agonism debate remains active in the field
• Phase 3 MARITIME program initiated; results pending
• No cardiovascular outcomes data available

Key Research Findings#

Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial, published in New England Journal of Medicine (Jastreboff AM et al., 2025; PMID: 40549887):

• The study showed up to 16.2% mean weight loss at 52 weeks in obesity without T2D
• The study showed up to 12.3% mean weight loss at 52 weeks in obesity with T2D
• The study showed HbA1c reduction of 1.2-1.6 percentage points in T2D cohort

Related Reading#

• MariTide research studies and evidence
• MariTide dosing protocols
• MariTide side effects profile
• CagriSema research guide
• Retatrutide research guide