MariTide

MariTide is a bispecific conjugate: a monoclonal antibody that antagonises the GIP receptor, with two GLP-1 receptor agonist peptides chemically attached. This is the opposite of tirzepatide's approach on the GIP arm, and the fact that both directions produce weight loss is one of the genuinely unresolved puzzles in incretin pharmacology - the leading explanation is that chronic GIPR agonism functionally desensitises the receptor, converging on the same endpoint. The antibody scaffold gives a very long half-time, allowing monthly or even less frequent dosing, and phase 2 showed unusually persistent weight loss for around 150 days after the last dose.

Targets: GIP receptor (antagonist), GLP-1 receptor (agonist)

• · Phase 2 used 140, 280 or 420 mg every four weeks without escalation, plus 420 mg every eight weeks, and 420 mg every four weeks with 4- or 12-week escalation. Mean weight change at 52 weeks ranged from about -12.3% to -16.2% in the non-diabetic obesity cohort. These are very large milligram doses because most of the mass is antibody.

Work out your exact syringe units →

• very commonNausea— Substantially reduced by dose escalation.
• commonVomiting— Was the leading cause of discontinuation in early phase 2 arms without escalation.
• commonConstipation
• commonInjection-site reaction— Large-volume subcutaneous antibody injections.
• uncommonLoss of bone mineral density— A signal Amgen has been tracking, plausibly related to GIPR antagonism in bone.

• Pregnancy.
• History of pancreatitis - class caution.
• Long-term safety is unestablished; phase 3 is ongoing.

• conflicttirzepatide — Tirzepatide agonises the GIP receptor that MariTide blocks; combining them is pharmacologically incoherent.
• redundantsemaglutide — GLP-1 agonism already present.

• · Weight and body composition.
• · Bone mineral density on long-term use.
• · HbA1c.
• · Nausea during escalation.

Investigational; not approved anywhere. As an antibody conjugate it cannot be legitimately obtained outside a trial.

• Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial, NEJM 2025 (trial)
• Amgen 2025-2026, MARITIME phase 3 programme announcements (other)

MariTide is the most conceptually interesting molecule in this class because it does the opposite of tirzepatide at one of its two targets and gets a similar result. Tirzepatide agonises GIPR; MariTide blocks it with a monoclonal antibody while simultaneously agonising GLP1R with conjugated peptides. Both produce substantial weight loss, which is the central paradox of GIP biology and remains unresolved. The leading reconciliation is that chronic GIPR agonism produces functional receptor desensitisation that is pharmacologically equivalent to antagonism, so the two approaches converge - but there are competing explanations involving different tissue distributions of agonist versus antibody, and the field has not settled it. The clinically distinctive property is the shape of the curve after stopping. Because the antibody has a three-week half-life and target-mediated clearance, exposure declines over months rather than days, and the phase 2 data showed unusually slow weight regain after discontinuation. If that holds up, it changes the practical calculus of these drugs more than another few percentage points of weight loss would, because regain on discontinuation is the single biggest problem with the entire class. The other consequence of the long half-life is dose spacing: monthly, and in some phase 2 arms every two months, which is a genuinely different treatment experience. The trade-off is that dose-related nausea cannot be managed by skipping a week, and adverse events last as long as the exposure does.

There is no consumer supply and there cannot be one, so anything sold as MariTide is fraudulent by definition. Within trials, the practical issue is that a three-week half-life means side effects cannot be dialled back quickly - if a dose is too high, you live with it for a month. The unknowns worth flagging are the long-term consequences of chronic GIP receptor blockade, particularly on bone, which nobody has data on.

• GIP receptor (GIPR) — Monoclonal antibody antagonist; affinity not published in verifiable form

  Blockade rather than agonism. Contributes to weight loss through a mechanism that is not fully explained, and is the reason MariTide is not simply a long-acting tirzepatide.

• GLP-1 receptor (GLP1R) — Conjugated peptide agonists; affinity not published in verifiable form

  Standard GLP-1 agonism - appetite suppression, delayed gastric emptying, glucose-dependent insulin secretion.

• MariTide phase 2 (maridebart cafraglutide) Phase 2 · n=592 · 52 weeks · 2025

  Once-monthly maridebart cafraglutide produced substantial weight reduction with no plateau at 52 weeks.

Weight loss begins within weeks of the first dose and had not plateaued at 52 weeks in phase 2. Steady state takes roughly three months given the three-week half-life. After stopping, exposure declines over months and regain was notably slower than with weekly incretins.

Not obtainable outside a trial - this is an antibody conjugate, not a peptide anyone can synthesise or buy. It contains a full GLP-1 arm, so it would be redundant with any incretin, and adding tirzepatide would put a GIPR agonist and a GIPR antagonist in the same person, which is pharmacological nonsense.

Against tirzepatide: opposite direction at GIPR, comparable weight loss, monthly rather than weekly dosing, and slower regain after stopping. Against retatrutide and CagriSema: MariTide's phase 2 numbers are lower, but the dosing interval and the discontinuation profile are genuinely differentiated in a way another few percentage points is not. Against everything else in the class: it is the only molecule whose main selling point is what happens after you stop taking it.

Investigational; no legitimate supply and no price. Antibody manufacturing is substantially more expensive than peptide synthesis, so if it reaches market it is unlikely to be a cheap option.

• ?No verifiable pharmacokinetic parameters - volume of distribution, clearance, protein binding and tmax are all unpublished.
• ?The GIP paradox - that agonism and antagonism both cause weight loss - is unresolved.
• ?The reported 16-20% weight-loss range and the slow-regain observation come from a phase 2 trial and sponsor communications; the precise primary outcome values were not extracted from the paper in this session.
• ?Long-term effects of chronic GIP receptor blockade, especially on bone, are entirely uncharacterised.
• ?Phase 3 (MARITIME) results were not available in verifiable form as of this session.
• ?The 592-participant figure was not individually re-verified against the paper.

• Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity - A Phase 2 Trial Jastreboff AM et al., N Engl J Med, 2025 · PMID 40549887

  The phase 2 trial. The source for the monthly dosing data and the slow-regain observation.