# MariTide (Maridebart Cafraglutide): Monthly Weight-Loss Shot, Phase 3 Timeline, and What Makes GIP Antagonism Different > **Summary:** MariTide (maridebart cafraglutide, AMG 133) is Amgen's investigational monthly subcutaneous GLP-1 receptor agonist / GIP receptor antagonist bispecific for chronic weight management. In the MARITIME-2 Phase 2b trial (n=592, 52 weeks), the 420 mg loading-dose arm produced roughly −20.0% weight loss with no plateau at week 52, and the Phase 1b extension suggested ~70% of peak loss was retained 26 weeks after the last dose. The Phase 3 MARITIME-1 obesity trial fully enrolled Q3 2025 with a topline readout expected Q4 2026; realistic earliest US availability is late 2027 to 2028. It is not FDA-approved as of August 2026 and cannot be compounded — the bispecific antibody-peptide conjugate is not accessible to 503A pharmacies. > **Publisher:** WeightFAQ > **Author:** WeightFAQ Staff > **Published:** 2026-08-18 > **Updated:** 2026-08-18 > **Canonical URL:** https://weightfaq.com/blog/maritide-weight-loss/ > **Content type:** Blog post > **Tags:** maritide, maridebart cafraglutide, amgen, glp-1, gip antagonist, next-generation obesity drug, monthly injection, pipeline > **Image:** https://weightfaq.com/_astro/maritide-weight-loss-hero.j2IQ8rRS.webp — Unbranded monthly-dose auto-injector on a calendar with the first of the month circled, stethoscope, and water on a light neutral surface. **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](https://weightfaq.com/weight-loss/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](https://weightfaq.com/weight-loss/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](https://weightfaq.com/weight-loss/compounded-semaglutide-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)](https://weightfaq.com/weight-loss/tirzepatide-weight-loss/) at ~20.9% in SURMOUNT-1 and [semaglutide (Wegovy)](https://weightfaq.com/weight-loss/semaglutide-weight-loss/) at ~14.9% in STEP-1. For the closest-to-US-approval pipeline sibling with meaningful magnitude, see [orforglipron for weight loss](https://weightfaq.com/weight-loss/orforglipron-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.