MariTide
Amgen's first-in-class once-monthly bispecific antibody-peptide conjugate for obesity — GLP-1 receptor agonist + GIP receptor antagonist. Phase 2 NEJM showed up to 21.6% weight loss at 52 weeks with no plateau.
What is MariTide?
MariTide (maridebart cafraglutide, AMG 133) is Amgen's first-in-class bispecific antibody-peptide conjugate for obesity. It combines a fully human anti-GIPR monoclonal antagonist antibody with two GLP-1 agonist peptide arms — creating a single molecule that activates the GLP-1 receptor while simultaneously blocking the GIP receptor. This is the opposite direction from tirzepatide (which agonizes both), based on human genetics data showing loss-of-function GIPR variants are associated with lower BMI. The antibody scaffold gives MariTide a remarkable ~21-day half-life, enabling once-monthly (Q4W) or even Q8W subcutaneous dosing — approximately 12 injections per year vs. 52 for weekly agents. Phase 2 NEJM (Sept 2025, 592 participants, 52 weeks): up to 16.2% weight loss (treatment-policy estimand) with topline reports noting ~21.6% at the top dose. Weight loss was maintained up to 150 days post-treatment in Phase 1. Phase 3 MARITIME program (4,500+ participants) launched March 2025, with MARITIME-1 readout expected early 2027.
What MariTide Is Investigated For
MariTide is Amgen's investigational once-monthly bispecific antibody-peptide conjugate for obesity and type 2 diabetes, combining GLP-1 receptor agonism with GIP receptor antagonism — a mechanistic inversion of tirzepatide's dual agonism, motivated by human genetics data linking loss-of-function GIPR variants to lower BMI. The strongest evidence is the 2025 NEJM Phase 2 trial (n=592, 52 weeks) showing up to ~21.6% weight loss (efficacy estimand) with no observed plateau at trial end, and HbA1c reductions of 1.2–1.6 percentage points in the obesity+T2D cohort. The antibody scaffold produces a ~21-day half-life enabling monthly (or Q8W) dosing — 12 injections per year vs. 52 for weekly agents — and Phase 1 data showed weight loss preserved up to 150 days after the last dose, meaningfully softer than the rebound seen with weekly GLP-1s. The honest caveats are that MariTide is not FDA-approved, Phase 3 MARITIME readouts are not expected until early 2027, cross-trial comparisons with tirzepatide are not head-to-head, and monthly dosing creates a tolerability asymmetry: GI side effects cannot be quickly dose-reduced given the long half-life. The antibody-peptide format also cannot be reproduced by standard peptide synthesis, so any product sold as 'MariTide' outside Amgen's trials is not MariTide.
History & Discovery
MariTide — originally known by its internal Amgen code AMG 133 and formally named maridebart cafraglutide — originated in Amgen's metabolic biologics program in the late 2010s and early 2020s. The mechanistic rationale leaned heavily on human genetics: large-scale sequencing had linked loss-of-function variants in the GIPR gene to lower BMI, suggesting that pharmacologic GIPR antagonism, rather than agonism, might be weight-reducing. Amgen chose to test this in the most direct way available — by engineering a bispecific molecule combining a fully human GIPR-antagonist monoclonal antibody with GLP-1-agonist peptide arms attached via amino acid linkers. The format is unusual in obesity: antibody scaffolds are well-established in oncology and autoimmune biologics but had not previously been deployed in the incretin class. Phase 1 results published in Nature Metabolism in early 2024 (Véniant et al.) demonstrated dose-dependent weight loss and a remarkably prolonged post-treatment effect, with weight loss maintained up to 150 days after the last dose. The Phase 2 NEJM publication in September 2025 (n=592, 52 weeks) reported up to ~21.6% weight loss at the highest dose (efficacy estimand), with curves still sloping downward at trial end — no plateau observed. The Phase 3 MARITIME program launched in March 2025 with MARITIME-1 and MARITIME-2 targeting obesity and obesity+T2D respectively, alongside planned MARITIME-CV, MARITIME-HF, OSA, and CKD programs. As of the site's current revision, MariTide is not FDA-approved.
How It Works
MariTide is a molecular hybrid — part antibody, part peptide. The antibody part blocks the GIP receptor, and two peptide arms activate the GLP-1 receptor. The antibody gives MariTide an extremely long half-life (about 3 weeks), which is why it only needs to be injected once a month instead of weekly like Ozempic or Zepbound. When you stop, it slowly washes out over several months, which may soften the dramatic weight regain that happens after stopping weekly GLP-1s.
MariTide (maridebart cafraglutide) is a bispecific antibody-peptide conjugate combining one fully human anti-GIPR monoclonal antagonist antibody (the 'cafraglutide' scaffold) with two GLP-1 agonist peptide arms (the 'maridebart' moieties) attached via amino acid linkers. GLP-1R agonism drives appetite suppression, slowed gastric emptying, and glucose-dependent insulin secretion. GIPR antagonism targets the paradoxical human genetics signal (loss-of-function GIPR variants → lower BMI). The antibody scaffold confers ~21-day half-life (vs semaglutide ~1 week, tirzepatide ~5 days), enabling once-monthly or even Q8W dosing. Phase 2 (NCT05669599, 592 participants, 52 weeks, NEJM 2025): obesity cohort weight loss −12.3% to −16.2% (treatment-policy estimand), up to ~21.6% efficacy estimand; obesity+T2D cohort −8.4% to −12.3% with HbA1c reductions of −1.2 to −1.6 percentage points. No weight-loss plateau observed at 52 weeks. Dose escalation (4-week or 12-week) substantially reduced GI AEs. Phase 1 showed weight loss maintained up to 150 days post-last-dose.
Evidence Snapshot
Human Clinical Evidence
Moderate. Phase 1 (NCT04478708, Nature Metabolism 2024, PMID: 38316982): dose-dependent weight loss, weight maintained up to 150 days after last dose. Phase 2 (NEJM 2025, PMID: 40549887): 592 participants across obesity and obesity+T2D cohorts over 52 weeks with up to 21.6% weight loss. Phase 3 MARITIME-1 (~3,500 patients, 72 weeks) and MARITIME-2 (~999 patients, obesity+T2D) started March 2025. MARITIME-CV, MARITIME-HF, OSA, and CKD programs also planned.
Animal / Preclinical
Strong. Preclinical data in DIO mice and cynomolgus monkeys confirmed GIPR antagonism + GLP-1R agonism mechanism, weight reduction, and improved metabolic parameters (Véniant et al., Nat Metab 2024).
Mechanistic Rationale
Strong but paradoxical. Both GIPR antagonism (MariTide) and GIPR agonism (tirzepatide) produce weight loss — both are clinically validated despite opposite receptor directions. Characterization studies of GIPR variants (Kizilkaya et al., Nat Metab 2024, PMID: 38871982) support the antagonism approach, while tirzepatide's success validates agonism. The antibody-peptide conjugate format is well-established in biologics but novel in obesity.
Research Gaps & Open Questions
What the current literature has not yet settled about MariTide:
- 01Phase 3 efficacy and safety readouts — MARITIME-1 and MARITIME-2 are in follow-up as of the site's current revision, with early 2027 primary readouts expected; the weight-loss plateau beyond 52 weeks has not been characterized.
- 02Cardiovascular outcomes — MARITIME-CV is designed to test MACE reduction; until it reports, cardiovascular benefit is inferred from class effects rather than directly established for MariTide.
- 03Direct head-to-head vs. tirzepatide and semaglutide — cross-trial comparisons favor MariTide on dosing convenience and trajectory, but no head-to-head randomized comparison has been reported.
- 04Long-term immunogenicity — anti-drug antibody development over 2+ years of monthly dosing needs extended follow-up to establish durability of efficacy and any safety signals.
- 05Real-world management of monthly dosing — tolerability-driven dose reduction is logistically harder with a monthly agent than with weekly peptides; whether this changes discontinuation patterns in practice is untested outside trial settings.
- 06Washout and weight-regain kinetics — Phase 1 showed preservation up to 150 days post-dose, but whether the softer washout translates into different 12–24 month regain curves vs. weekly GLP-1s is a question for post-Phase 3 observational data.
- 07The biology of GIPR antagonism itself — why pharmacologic GIPR antagonism and chronic GIPR agonism both produce weight loss (the 'GIPR paradox') is an active research question with implications beyond MariTide.
Forms & Administration
MariTide is administered as a once-monthly (Q4W) or once-every-8-weeks (Q8W) subcutaneous injection. Phase 2 tested doses from 140 mg to 420 mg with dose escalation schemes. Currently only available through clinical trials.
Dosing & Protocols
The ranges below reflect protocols commonly discussed in the literature and by clinicians — not a prescription. Actual dosing for any individual should be determined by a qualified healthcare provider who knows the patient.
Typical Range
Phase 2 (NCT05669599) tested dose levels from approximately 140 mg to 420 mg subcutaneously, with dose-escalation schemes running either 4-week or 12-week ramps before reaching maintenance. The highest maintenance dose that produced the ~21.6% weight loss figure sat at the upper end of this range. No FDA-labeled dose exists; Phase 3 MARITIME is refining the maintenance targets and escalation cadences.
Frequency
Once-monthly (Q4W) subcutaneous injection is the primary dosing paradigm, enabled by the ~21-day half-life conferred by the antibody scaffold. Every-8-weeks (Q8W) dosing has also been studied in selected arms, and Amgen has publicly discussed Q8W as a potential maintenance-phase option. In practical terms, monthly administration translates to roughly 12 injections per year vs. 52 for weekly GLP-1s.
Timing Considerations
No specific timing requirements: can be administered at any time of day, with or without food, and is not tied to exercise timing. Consistency matters more than the specific clock — dose at roughly the same time each day (or same day each week, for weekly protocols) to keep exposure steady.
Cycle Length
MariTide is being developed for indefinite chronic use in obesity — the same treatment framework as semaglutide and tirzepatide. The long half-life, however, introduces a softer discontinuation profile: Phase 1 data showed weight loss maintained up to 150 days after the last dose, meaning the effective washout window is several months rather than the ~5 weeks seen with weekly GLP-1s.
Protocol Notes
The antibody-peptide conjugate format has practical implications that differ from pure peptide GLP-1s. Injection volumes tend to be larger, and formulation and delivery considerations are more complex. Monthly dosing is attractive for adherence but creates a tolerability asymmetry: if a patient has significant GI side effects during the first few weeks of a new dose level, there is no immediate option to reduce exposure — the drug will persist at pharmacologic levels for roughly three weeks regardless. Amgen addressed this in Phase 2 by using dose-escalation protocols (4-week and 12-week ramps) that substantially reduced GI adverse events relative to starting at maintenance doses. Immunogenicity — the development of anti-drug antibodies — is a standard consideration for antibody biologics and is being monitored across the MARITIME program; early data suggest it is manageable, but long-term rates and clinical consequences require extended follow-up.
MariTide is not FDA-approved for any indication as of the site's current revision. These dose ranges reflect published trial protocols and are not prescriptions. Access outside of enrollment in Amgen's MARITIME program or related clinical trials is not legitimate.
Timeline of Effects
Onset
In Phase 2, separation from placebo on weight loss was visible within the first few weeks and accelerated once participants reached maintenance doses. Because the antibody scaffold produces steady-state exposure over the monthly dosing interval, appetite suppression and early satiety develop and persist smoothly rather than oscillating as with shorter-half-life peptides. Subjective effects are typically reported in the first 1–2 weeks post-first-dose.
Peak Effect
Phase 2 showed mean weight loss of approximately 16.2% (treatment-policy estimand) with up to ~21.6% on the highest dose (efficacy estimand) at 52 weeks, with no plateau — the weight-loss curves were still declining at trial end. This trajectory suggests peak weight loss has not yet been characterized in the reported data; MARITIME Phase 3 at 72 weeks is designed to identify where the curves flatten. HbA1c reductions in the obesity+T2D cohort ranged from −1.2 to −1.6 percentage points, comparable to other high-efficacy incretin agents.
After Discontinuation
This is one of MariTide's most distinctive features. Phase 1 data showed weight loss maintained up to 150 days (~5 months) after the last dose — substantially longer than the ~4–6 week washout seen with weekly GLP-1s. The explanation is straightforward: the antibody scaffold has a ~21-day half-life, so it takes roughly 3–4 months for plasma levels to fall below pharmacologically active thresholds. Whether this longer washout translates into slower or less pronounced weight regain over 12–24 months compared with weekly GLP-1s has not been directly tested — the 150-day Phase 1 observation is suggestive but not definitive. Rebound biology (appetite set-point restoration) is expected eventually even with slower drug clearance.
Common Questions
Who MariTide Is NOT For
- •Personal or family history of medullary thyroid carcinoma (MTC) — applied by analogy to the GLP-1 class given the rodent C-cell tumor signal; MARITIME exclusion criterion.
- •Multiple Endocrine Neoplasia syndrome type 2 (MEN2) — same rationale as MTC.
- •Pregnancy and breastfeeding — no human reproductive safety data; the ~21-day half-life means the drug persists for months after discontinuation, making pre-pregnancy washout windows lengthy.
- •Type 1 diabetes — not studied in the MariTide program; the dual-receptor mechanism in insulin-dependent patients has not been characterized.
- •Prior serious hypersensitivity to the formulation — standard for any antibody biologic; anti-drug antibodies and infusion-style reactions are monitored.
- •Severe gastroparesis or significant gastrointestinal motility disorders — GLP-1-mediated delayed gastric emptying can worsen these conditions and is harder to reverse quickly given the monthly dosing interval.
- •History of severe pancreatitis — applied by analogy to the GLP-1 class pending dedicated pharmacovigilance.
Drug & Supplement Interactions
No FDA-labeled interaction profile exists for MariTide because the drug is not approved. The framework is extrapolated from the GLP-1 class and from general antibody-biologic considerations. The most clinically relevant GLP-1-class interactions — hypoglycemia risk with insulin or sulfonylureas, altered oral drug absorption from delayed gastric emptying — apply here, with the important caveat that MariTide's monthly dosing interval creates an unusual pharmacokinetic landscape: drug exposure is steady rather than pulsatile, which may change how interactions manifest compared with weekly peptides. Narrow-therapeutic-index oral agents (warfarin, levothyroxine, certain antiepileptics) warrant the same attention they receive with other GLP-1s. The GIPR-antagonism component is pharmacologically novel in clinical use; there are no established interaction datasets for it, and the effect on lipid handling, postprandial triglycerides, and adipose biology in the context of co-administered metabolic therapies is being characterized in MARITIME. Immunogenicity — anti-drug antibody development — is the one interaction domain distinct from small-molecule peptides and requires monitoring over extended use.
Safety Profile
Common Side Effects
Cautions
- • Not FDA-approved — investigational drug in Phase 3
- • 11% discontinuation due to AEs in dose-escalation arms
- • GI side effects may be harder to manage given monthly dosing (cannot quickly adjust dose)
- • Long half-life (~21 days) means drug persists weeks after discontinuation
What We Don't Know
Cardiovascular outcomes data pending from MARITIME-CV. Long-term safety beyond 52 weeks not yet established. Real-world tolerability of monthly dosing vs weekly (where dose adjustment is quicker) is untested. Immunogenicity concerns inherent to antibody-peptide conjugates require longer-term monitoring.
Legal Status
United States
MariTide (maridebart cafraglutide) is not FDA-approved for any indication as of the site's current revision. Access is limited to enrollment in Amgen's MARITIME Phase 3 program or related clinical trials. Because MariTide is an antibody-peptide conjugate rather than a simple peptide, compounded versions are not realistically feasible — the molecule cannot be reproduced by standard peptide synthesis. Any product marketed outside registered trials claiming to be MariTide should be treated with extreme skepticism.
International
No regulatory authority has authorized MariTide for marketing. MARITIME trial sites are distributed across North America, Europe, and parts of Asia, but availability is investigational worldwide.
Sports & Competition
MariTide is not named on the WADA Prohibited List as of the site's current revision, but WADA's S0 category prohibits substances 'not currently approved by any governmental regulatory health authority for human therapeutic use' — which applies to MariTide. Athletes subject to WADA, USADA, UKAD, or equivalent bodies should assume use is prohibited.
Regulatory status changes over time. Verify current local rules with a qualified professional.
Myths & Misconceptions
Myth
MariTide is available now if you know where to look.
Reality
MariTide is an investigational antibody-peptide conjugate in active Phase 3 development. Legitimate access is limited to enrollment in Amgen's MARITIME program or related registered trials. The molecule cannot be meaningfully reproduced by peptide synthesis alone — the antibody scaffold requires mammalian cell-culture biologics manufacturing — so any product sold as 'MariTide' in research-chemical channels should be presumed not to be MariTide.
Myth
Monthly dosing means MariTide is strictly better than weekly GLP-1s.
Reality
Monthly dosing is a genuine convenience advantage, but it also removes the ability to quickly adjust exposure if side effects arise. GI tolerability during titration is harder to manage when the last dose persists for three weeks. Amgen has addressed this with extended dose-escalation schedules in Phase 2 and 3, which substantially reduced GI AEs, but the asymmetric tolerability-versus-convenience trade-off is a real feature of the dosing paradigm, not a marketing detail.
Myth
GIPR antagonism and GIPR agonism can't both work — one of them must be wrong.
Reality
Both mechanisms have produced meaningful weight loss in human trials: tirzepatide (GIP agonism + GLP-1 agonism) and MariTide (GIP antagonism + GLP-1 agonism). The working explanation in the field involves receptor desensitization — chronic agonism may functionally mimic antagonism through downregulation — but the full biology is still being characterized. The human-genetics signal (loss-of-function GIPR → lower BMI) specifically motivated the antagonist approach, and early clinical data has validated that motivation. 'The GIPR paradox' is an active research question, not a refutation of either program.
Myth
The 150-day post-treatment weight preservation means you only need occasional doses.
Reality
Phase 1 Phase-1 post-treatment observation showed weight loss maintained up to 150 days — a useful pharmacology data point — but this was observation after a short dosing course. It is not evidence that chronic obesity management can be accomplished with intermittent or occasional dosing. Obesity biology reasserts adipose set-points once the pharmacological signal is fully withdrawn; the 150-day observation tells us how long that withdrawal takes given MariTide's half-life, not that the underlying condition has been durably altered.
Myth
MariTide and tirzepatide produce the same weight loss, so it's just a convenience play.
Reality
Phase 2 MariTide reached up to ~21.6% at 52 weeks (efficacy estimand) with no observed plateau; SURMOUNT-1 tirzepatide reached ~20.2% at 72 weeks. Cross-trial comparison is not head-to-head, and estimand methodology differs. MariTide's Phase 3 readouts will determine whether the trajectory-without-plateau observation in Phase 2 holds out to 72 weeks. Calling the difference 'convenience only' or 'convenience plus efficacy' requires Phase 3 data that has not yet been reported.
Published Research
8 studiesObesity pharmacotherapy reimagined: The era of multi-receptor agonists and next-generation metabolic modulators.
A metabolic comparison of GIPR agonism versus GIPR antagonism in male mice.
Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.
Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial.
Phase 2, 592 participants, 52 weeks — up to 16.2% weight loss (treatment-policy), ~21.6% (efficacy estimand)
The Premise of the Paradox: Examining the Evidence That Motivated GIPR Agonist and Antagonist Drug Development Programs.
Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings.
Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1.
Quick Facts
- Class
- Antibody-Peptide Conjugate
- Tier
- A
- Evidence
- Moderate
- Safety
- Limited Data
- Updated
- Apr 2026
- Citations
- 8PubMed
Also known as
Tags
Peptide Families
Related Goals
Evidence Score
Clinical Trials
View Clinical TrialsLinks to ClinicalTrials.gov for reference. Listing does not imply endorsement.