Why block the GIP receptor when tirzepatide activates it?

This is one of the genuinely open questions in obesity pharmacology. Amgen's approach came from human genetics: variants that reduce GIP receptor function associate with lower body weight. Tirzepatide's GIP agonism also produces weight loss. Both directions appear to work, and the field does not yet have a settled explanation for why.

What does monthly dosing change in practice?

Adherence, primarily — twelve injections a year instead of fifty-two. The open question is tolerability: delivering a month of drug at once may concentrate gastrointestinal side effects around each dose rather than spreading them, and that is a central thing phase 3 needs to answer.

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Weight & Metabolic

Clinical

Maridebart Cafraglutide (MariTide)

Also known as: MariTide, AMG 133, Maridebart cafraglutide

MariTide is a once-monthly peptide-antibody conjugate that activates the GLP-1 receptor while blocking the GIP receptor — the opposite GIP strategy from tirzepatide, and the most mechanistically unusual drug in late-stage obesity development.

Mechanism of Action

Maridebart cafraglutide is a peptide-antibody conjugate: GLP-1 receptor agonist peptides conjugated to a monoclonal antibody that antagonizes the GIP receptor. The antibody scaffold confers a very long half-life, enabling monthly or less frequent dosing. Mechanistically it is notable for GIP receptor blockade — the opposite of tirzepatide's GIP agonism — a strategy supported by human genetics work with deCODE Genetics that identified GIP receptor loss-of-function variants as associated with lower body weight. That two opposing GIP strategies both produce weight loss remains an active question in the field.

Half-life: Antibody-conjugate design supports once-monthly or less frequent subcutaneous dosing
Administration Routes: subcutaneous
Research Status: Clinical