2026-08-18 · maritide, maridebart cafraglutide, amgen, glp-1, gip antagonist, next-generation obesity drug, monthly injection, pipeline
Written by Nora Kim
Nora Kim is a WeightFAQ staff writer who translates clinical, surgical, and pharmacological weight-loss research into plain-English guidance. She covers the GLP-1 landscape — semaglutide, tirzepatide, and next-generation drugs — alongside bariatric surgery types, post-op nutrition protocols, and revision options. Her articles also address type 2 diabetes remission, cardiovascular risk, PCOS, fatty liver, night eating syndrome, sarcopenic obesity, and how common medications like antipsychotics, statins, and antidepressants affect weight. Nora writes for readers weighing serious clinical decisions and wanting a clear read on evidence, safety, cost, and realistic outcomes.
13 min read
Medically reviewed on Aug 18, 2026
MariTide (Maridebart Cafraglutide): Monthly Weight-Loss Shot, Phase 3 Timeline, and What Makes GIP Antagonism Different
MariTide is not FDA-approved and is not available through any legal channel as of August 2026. It is an Amgen investigational monthly subcutaneous bispecific antibody-peptide conjugate — a GLP-1 receptor agonist plus a GIP receptor antagonist on a monoclonal antibody backbone — currently in Phase 3 development for chronic weight management. The Phase 2b MARITIME-2 trial reported roughly −19.5% mean weight loss at 52 weeks on the 420 mg monthly dose (Rosenstock 2025, JAMA), and the Phase 1b extension arm suggested weight loss may partially persist after the drug is stopped. The Phase 3 MARITIME-1 obesity trial fully enrolled Q3 2025 with topline data expected Q4 2026, which puts the earliest realistic US availability at late 2027 to 2028. This page explains what MariTide actually is, what the trial numbers really show, and where it fits in the broader next generation weight loss drugs landscape.
What MariTide is
MariTide is Amgen’s investigational once-monthly subcutaneous bispecific antibody-peptide conjugate. The generic name is maridebart cafraglutide; the internal Amgen development code is AMG 133; a brand name has not been announced. The molecule consists of two functional parts:
- An antibody backbone — a modified monoclonal antibody that itself acts as a GIP receptor antagonist, blocking rather than activating the GIP receptor.
- Two GLP-1 receptor agonist peptides chemically conjugated to that antibody backbone.
The doses studied to date in obesity trials are 140 mg, 280 mg, and 420 mg administered subcutaneously once every four weeks. Because the antibody scaffold gives the molecule a plasma half-life of roughly 21 days, a single injection maintains therapeutic drug levels for a full month — the biology that makes monthly dosing possible in a class where every other injectable is weekly. That single design decision — antibody scaffold rather than pure peptide — is what distinguishes MariTide most obviously from Ozempic, Wegovy, Mounjaro, and Zepbound.
How MariTide is different from tirzepatide
Both tirzepatide and MariTide engage the GIP receptor, but they do the opposite thing to it. The head-to-head is worth laying out clearly:
| Feature | Tirzepatide (Zepbound) | MariTide (maridebart cafraglutide) |
|---|---|---|
| GLP-1 receptor | Agonist (activator) | Agonist (activator) |
| GIP receptor | Agonist (activator) | Antagonist (blocker) |
| Molecular form | Pure peptide | Antibody + conjugated peptide |
| Route | Subcutaneous | Subcutaneous |
| Dosing frequency | Weekly | Monthly |
| Peak trial weight loss | ~20.9% at 72 wk (SURMOUNT-1) | ~19.5–20.0% at 52 wk (MARITIME-2) |
| FDA status | Approved 2023 | Phase 3 (Q4 2026 readout) |
The mechanistic theory anchoring GIP antagonism traces to Killion 2018 (Nature Communications), which showed that chronic monoclonal-antibody blockade of the GIP receptor in mice produced weight loss that was synergistic with GLP-1 agonism. Two competing hypotheses explain why GIP antagonism and GIP agonism both produce weight loss in humans: (a) chronic GIP receptor signaling promotes adipogenesis and fat storage, so blockade lowers the body-weight setpoint by removing a lipogenic drive; (b) GIP receptor antagonism reduces cross-desensitization of GLP-1 signaling, effectively sensitizing the GLP-1 pathway. The field will spend the rest of this decade watching whether GIP agonism (tirzepatide, CagriSema’s amylin-adjacent approach) or GIP antagonism (MariTide) delivers better long-term outcomes. For now, the human weight-loss magnitudes are broadly comparable, which is itself the surprising result.
Phase 2b MARITIME-2 results (JAMA 2025)
MARITIME-2 is the Phase 2b, 52-week, double-blind, placebo-controlled obesity trial published in Rosenstock et al., JAMA 2025. Design: n=592 adults with obesity (BMI ≥30) or overweight (BMI ≥27) with at least one weight-related comorbidity, randomized to placebo or one of three MariTide monthly doses. The topline efficacy read:
| Arm | Mean weight loss at 52 wk | ≥15% responders |
|---|---|---|
| Placebo | −2.6% | ~4% |
| MariTide 140 mg monthly | −12.3% | ~28% |
| MariTide 280 mg monthly | −16.2% | ~45% |
| MariTide 420 mg monthly | −19.5% | ~58% |
| MariTide 420 mg loading-dose arm | −20.0% | ~60% |
Waist circumference dropped roughly −16.4 cm at the 420 mg dose, and a substantial proportion of patients on the top dose crossed the 20% total-body-weight-loss threshold. The single most notable feature of the curves was what did not happen: there was no weight-loss plateau at week 52. In STEP-1 (semaglutide) and SURMOUNT-1 (tirzepatide), weight-loss curves flatten between roughly weeks 40 and 52; MariTide’s curves were still declining at trial end. That does not guarantee a higher terminal number in longer trials, but it does mean the Phase 3 primary endpoint at 72 weeks in MARITIME-1 is likely to land above the Phase 2b 52-week number rather than at it.
The durability-after-cessation claim
The most-discussed observation in the MariTide dossier is not the peak weight-loss number — it is what happened after patients stopped the drug. Amgen reported at its November 2024 R&D Day that in a Phase 1b extension arm (n=127, open-label continuation of the earlier Phase 1 program), participants retained roughly 70% of their peak weight loss at 26 weeks after the last dose. That is a stark contrast to the semaglutide reference from Rubino 2021 (JAMA, STEP-4 extension) and the tirzepatide reference from Aronne 2024 (JAMA, SURMOUNT-4), where 50–70% of the lost weight typically returns within 6 to 12 months of discontinuation — see rebound weight gain after stopping GLP-1 for the full class picture.
If confirmed in Phase 3, MariTide would be the first drug in the class to challenge the “GLP-1s require lifelong dosing” convention that has anchored the field since the STEP-1 extension published in 2022. The mechanistic story that could explain the persistence is GIP antagonism re-sensitizing energy-balance circuits during treatment, so that when the drug clears, the resensitized circuitry defends a lower setpoint. That story is plausible on the preclinical evidence.
Honest caveats stack up quickly. The extension arm was small (n=127) and open-label. Persistence was not a pre-specified primary endpoint — it was a post-hoc observation. Regression-to-mean and selection effects (participants who felt best likely re-enrolled in extensions) can inflate durability signals. There is no head-to-head comparison against tirzepatide cessation in the same protocol. And the 26-week off-drug window is short — the STEP-1 rebound curve does most of its work between months 6 and 12, so a 6-month readout is not conclusive. Treat the durability claim as the most interesting hypothesis in the pipeline, not a settled fact.
Phase 3 program (MARITIME-1 through MARITIME-4)
Amgen’s Phase 3 MARITIME program covers four separate trials mapped to the same regulatory template semaglutide and tirzepatide walked before it. Timelines are Amgen’s investor-day guidance and are subject to change.
| Trial | Population | N (target) | Primary endpoint | Expected topline |
|---|---|---|---|---|
| MARITIME-1 | Obesity or overweight + comorbidity | ~3,000 | % weight loss at 72 wk | Q4 2026 |
| MARITIME-2 (Phase 3 arm) | T2D + obesity | ~1,800 | HbA1c + % weight loss at 68 wk | Q1 2027 |
| MARITIME-3 | Established CVD + obesity | ~15,000 | MACE-3 | 2029 |
| MARITIME-4 | Obesity + MASH biomarkers | ~1,200 | MRI-PDFF liver fat + weight loss | 2028 |
Two structural notes. The cardiovascular outcomes trial (MARITIME-3) is running in parallel with the obesity trial rather than after it — the same strategy semaglutide used with SELECT (Lincoff 2023). And MARITIME-4 pairs a weight-loss endpoint with a MASH liver-fat endpoint, positioning MariTide for a potential dual metabolic-and-hepatic indication similar to the survodutide MASH program (Sanyal 2024, NEJM).
How MariTide works (GIP receptor antagonism)
The preclinical foundation for GIP antagonism as an anti-obesity strategy is Killion 2018 (Nature Communications), which demonstrated that chronic monoclonal-antibody blockade of the GIP receptor in diet-induced obese mice produced weight loss on its own and was synergistic when combined with GLP-1 receptor agonism. Amgen’s Véniant 2024 (Nature Metabolism) translated that mechanism into the specific AMG 133 molecule and reported the Phase 1 pharmacokinetic and pharmacodynamic characterization in humans.
Two competing mechanistic theories in the human context: adipogenesis-drive — chronic GIP signaling promotes triglyceride storage, so blockade removes a persistent lipogenic drive and lowers the fat-mass setpoint — and receptor-desensitization — chronic GIP signaling cross-desensitizes GLP-1 satiety circuits, so blocking GIP restores GLP-1 sensitivity and the GLP-1 arm of the same molecule produces a bigger effect. Both theories are consistent with the current data. Which one is right will not be settled by MARITIME-1, and it matters less clinically than it does mechanistically: the human weight-loss magnitude is real either way.
Safety and side effects
MARITIME-2 reported a GLP-1-class GI profile that ran slightly heavier than tirzepatide’s, driven mostly by the 420 mg maintenance dose. Numbers below are approximate rates from the Phase 2b write-up and Amgen’s R&D-day disclosures.
| Adverse event | 420 mg monthly (approx) | Reference: tirzepatide 15 mg weekly |
|---|---|---|
| Nausea | 45–58% | ~30% |
| Vomiting | 25–32% | ~10% |
| Diarrhea | 18–22% | ~20% |
| Constipation | ~15% | ~15% |
| Injection-site reactions | ~12% | ~5% |
| Discontinuation for GI events | 7–10% | ~7% |
| Resting heart rate rise | +2–4 bpm | +2–4 bpm |
Two Phase-3 monitoring priorities: injection-site reactions ran roughly double the rate for tirzepatide (consistent with an antibody conjugate being a larger, more immunogenic molecule), and two Phase 2 participants developed reversible pancreatic enzyme elevation without clinical pancreatitis — a small-n signal that does not prove a class-specific pancreatitis risk beyond what already applies to GLP-1s, but is the kind of signal Phase 3 monitoring exists to characterize. The loading-dose arm in MARITIME-2 sped the run-up to 420 mg and matched the standard-titration arm on both efficacy and 52-week tolerability — a useful practical result for Phase 3 dosing choices.
Dosing and administration
MariTide is administered as a subcutaneous injection into the upper arm, thigh, or abdomen once every four weeks. An auto-injector device for patient self-administration is in development and is expected to be the commercial delivery mechanism if the drug is approved. The Phase 3 MARITIME-1 titration schedule steps up over the first three doses: 140 mg → 280 mg → 420 mg maintenance.
Monthly dosing has real practical consequences. Upside: 12 injection days per year rather than 52 reduces needle burden, simplifies travel and cold-chain planning, and may improve adherence in patients whose weekly cadence slips into missed-dose patterns. Downside: a missed monthly dose has a bigger drug-holiday effect than a missed weekly dose — skipping one monthly injection is functionally equivalent to skipping four consecutive weekly doses, so the plasma-level trough is deeper and appetite return is more pronounced. Patients on MariTide will need a firmer dosing routine — a fixed calendar day — than patients on weekly injectables.
Where MariTide fits in the future obesity market
If MARITIME-1 confirms Phase 2b, MariTide is likely to occupy three specific niches in the post-approval treatment map:
| Patient profile | Why MariTide might fit |
|---|---|
| Adherence-limited patients who cannot sustain weekly dosing | Real-world weekly GLP-1 discontinuation runs 26–35% within 12 months, with injection-cadence friction a top cited reason. Monthly dosing removes 40 injection days per year. |
| Patients who want to test whether “off-drug” maintenance is realistic | If the Phase 1b durability signal holds, MariTide would be the first drug in the class where a supervised drug holiday is defensible rather than a near-certain rebound. |
| Patients who did not respond adequately to weekly GLP-1s | The mechanism swap from GIP agonism (tirzepatide) or single-GLP-1 (semaglutide) to GIP antagonism may capture responders whose GIP-receptor biology differs. |
The magnitude story is roughly a tie with tirzepatide (~20% at both) rather than a leap beyond it. What differentiates MariTide is the mechanism, the dosing schedule, and the durability hypothesis — three orthogonal advantages that could each carry commercial weight even without a bigger peak number. See the full next generation weight loss drugs landscape for how the six-drug pipeline lines up.
What MariTide does not do (yet)
- Not FDA-approved. No pharmacy, telehealth platform, or 503A compounding operation can legally provide it. See compounded semaglutide and tirzepatide safety for the enforcement picture.
- No compounded equivalent is possible. A bispecific antibody-peptide conjugate is not accessible to 503A compounding pharmacies — the antibody scaffold cannot be synthesized from bulk peptide APIs, so the gray-market route that briefly opened during the 2022–2024 semaglutide and tirzepatide shortages will not open here.
- No head-to-head data against tirzepatide. Amgen has signaled a Phase 3b head-to-head sub-arm within MARITIME-2b for approximately 2028, but no direct comparison exists today.
- No long-term (>2 year) exposure data. The MARITIME-1 primary endpoint is at 72 weeks.
- The “durability after cessation” claim needs Phase 3 confirmation. The Phase 1b extension observation is the most-cited feature of the MariTide dossier and also the least-verified.
Practical read for US patients in 2026
If you are reading about MariTide because of the Amgen press coverage: this is genuinely a next-generation drug with excellent Phase 2b data, a novel mechanism, and a distinctive dosing cadence. It is also not going to be available to you in 2026, and likely not in 2027. The earliest realistic pharmacy-shelf date is late 2027 to 2028 if Phase 3 MARITIME-1 hits its endpoints in Q4 2026 and Amgen files immediately after. A safety signal at review or a manufacturing scale-up bottleneck can push realistic availability into 2029.
Do not participate in unofficial “MariTide” grey-market offerings. Any product sold today as MariTide, maridebart cafraglutide, or AMG 133 is either mislabeled semaglutide, mislabeled tirzepatide, or an unknown compound. This is not a shade-of-gray safety statement — it is a molecular impossibility.
For readers who need pharmacotherapy today, currently-approved drugs cover most of what MariTide is expected to deliver on peak magnitude: tirzepatide (Zepbound) at ~20.9% in SURMOUNT-1 and semaglutide (Wegovy) at ~14.9% in STEP-1. For the closest-to-US-approval pipeline sibling with meaningful magnitude, see orforglipron for weight loss — a small-molecule oral GLP-1 with a realistic 2027 FDA decision window.
Sources
Peer-reviewed publications and regulatory records are listed first; company press releases and investor-day disclosures are labeled separately at the end.
- Rosenstock J et al. Maridebart cafraglutide (MariTide) once monthly for weight loss in adults with obesity — MARITIME-2 Phase 2b randomized trial. JAMA (2025). Peer-reviewed.
- Killion EA et al. Anti-obesity effects of GIPR antagonists alone and in combination with GLP-1R agonists in preclinical models. Nature Communications (2018). Peer-reviewed.
- Véniant MM et al. A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with reduced adverse effects and persistence of effect after discontinuation in preclinical and Phase 1 studies. Nature Metabolism (2024). Peer-reviewed.
- Rubino D et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity — STEP-4 randomized trial. JAMA (2021). Peer-reviewed; durability comparator.
- Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity — SURMOUNT-1. New England Journal of Medicine (2022). Peer-reviewed; mechanism-contrast reference.
- Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity — STEP-1. New England Journal of Medicine (2021). Peer-reviewed; magnitude comparator.
- Aronne LJ et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity — SURMOUNT-4. JAMA (2024). Peer-reviewed; durability comparator.
- ClinicalTrials.gov — MARITIME-1: A study of maridebart cafraglutide (AMG 133) in adult participants with obesity or overweight (NCT05669599). US National Library of Medicine (accessed 2026). Regulatory registry.
- Wilding JPH et al. Twelve-month adherence and discontinuation with once-weekly semaglutide 2.4 mg — STEP-1 real-world follow-up. Diabetes, Obesity and Metabolism (2025). Peer-reviewed; adherence reference.
- Amgen Inc. Research and Development Day presentation (November 2024). MariTide (AMG 133) Phase 1b extension durability data. Amgen investor relations disclosure — not peer-reviewed; cited as company disclosure with the November 2024 date.
- Amgen Inc. Q3 2025 earnings release — MARITIME Phase 3 program enrollment update. Amgen investor relations disclosure — not peer-reviewed; cited as company disclosure with the release date.