Maritide (AMG 133)
Maritide (AMG 133/MariTide) is a first-in-class bispecific antibody-peptide conjugate that simultaneously activates GLP-1 receptors and antagonizes GIP receptors, developed by Amgen for obesity and metabolic disease with monthly or less frequent dosing.
Maritide (AMG 133, also referred to as MariTide) is a novel bispecific antibody-peptide conjugate developed by Amgen for the treatment of obesity and related metabolic conditions. It represents a fundamentally new pharmacological approach by combining GLP-1 receptor agonism with GIP receptor antagonism in a single molecule, distinguishing it from dual agonist approaches such as tirzepatide.
Overview
Maritide was designed to address the limitations of existing incretin-based therapies by engineering a long-acting bispecific molecule that leverages two complementary mechanisms of action. The anti-GIPR antibody backbone provides an extended half-life characteristic of IgG molecules (approximately 3-4 weeks), while the conjugated GLP-1 agonist peptides stimulate GLP-1 receptor signaling. This dual-action approach — activating GLP-1 receptors while simultaneously blocking GIP receptors — is pharmacologically opposite to tirzepatide, which activates both GLP-1 and GIP receptors. The rationale for GIP receptor antagonism stems from preclinical evidence suggesting that GIPR blockade in the context of GLP-1R agonism may enhance weight loss through improved energy expenditure, reduced fat storage, and complementary appetite suppression pathways.
The molecule entered clinical development in 2020, with Phase 1 data published in 2023 and Phase 2 results reported in 2024. Phase 2 results demonstrated up to 14.5% body weight loss at 12 weeks, with continued weight loss trajectories suggesting further reductions with extended treatment. Amgen has advanced maritide into Phase 3 clinical trials, positioning it as a potential next-generation obesity therapeutic with a differentiated dosing schedule and mechanism.
Mechanism of Action
Maritide operates through two coordinated but mechanistically distinct pharmacological activities within a single molecule:
GLP-1 Receptor Agonism: The two GLP-1 analogue peptides conjugated to the antibody backbone bind to and activate GLP-1 receptors on pancreatic beta cells, hypothalamic neurons, and other GLP-1R-expressing tissues. This stimulates glucose-dependent insulin secretion, suppresses glucagon release, slows gastric emptying, and reduces appetite through central nervous system signaling. The peptide sequences are engineered for enhanced receptor affinity and resistance to DPP-IV degradation.
GIP Receptor Antagonism: The anti-GIPR antibody component binds with high affinity to the glucose-dependent insulinotropic polypeptide receptor, blocking endogenous GIP signaling. In adipose tissue, GIP promotes lipid uptake and storage; antagonizing this pathway may reduce fat accumulation. In the central nervous system, GIPR blockade may enhance the anorexigenic effects of GLP-1 signaling. Preclinical studies in GIPR-knockout mice demonstrated resistance to diet-induced obesity, providing the biological rationale for this approach.
Synergistic Weight Loss Mechanism: The combination of GLP-1R activation and GIPR blockade appears to produce additive or synergistic weight loss effects beyond what either mechanism achieves alone. Preclinical data from Amgen showed that the bispecific molecule produced greater weight loss and metabolic improvements than either a GLP-1 agonist or GIPR antagonist administered individually.
Extended Duration of Action: The IgG2 antibody backbone undergoes neonatal Fc receptor (FcRn)-mediated recycling, conferring an extended pharmacokinetic half-life of approximately 3-4 weeks. This enables monthly or less frequent subcutaneous dosing, a significant advantage over weekly or daily GLP-1 agonists.
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Maritide (AMG 133)
Maritide (AMG 133, also referred to as MariTide) is a novel bispecific antibody-
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Research
Phase 2 Clinical Results
The Phase 2 study (NCT05669599) evaluated multiple-dose regimens of maritide in adults with obesity (BMI >=30 kg/m2 or >=27 kg/m2 with comorbidities). Data presented at scientific conferences and in Amgen reports showed that participants receiving maritide achieved up to 14.5% body weight loss at 12 weeks, with weight loss curves still declining at the end of the treatment period. Multiple dosing regimens were evaluated, including monthly and every-two-month schedules. The extended dosing intervals were made possible by the antibody component's long half-life and sustained pharmacodynamic effects. Weight regain after discontinuation appeared to occur more slowly than with traditional GLP-1 agonists, potentially due to the prolonged pharmacokinetic profile.
Preclinical Metabolic Studies
In preclinical models, AMG 133 demonstrated superior weight loss and metabolic improvements compared to either GLP-1 agonism or GIPR antagonism alone. Non-human primate studies showed dose-dependent reductions in body weight, food intake, and adiposity. The bispecific molecule also improved glucose tolerance and insulin sensitivity. Notably, preclinical data suggested favorable effects on body composition, with preferential loss of fat mass over lean mass, a critical consideration for anti-obesity therapeutics.
Phase 1 Clinical Results
The first-in-human Phase 1 study of maritide (NCT04478708) was a randomized, double-blind, placebo-controlled trial evaluating single ascending doses in adults with overweight or obesity (BMI 30-40 kg/m2). Published by Vosoughi et al. in 2023, the study demonstrated dose-dependent weight loss with maritide, with participants receiving the highest single dose achieving a mean weight reduction of approximately 7.2% at day 85. The drug was generally well tolerated, with gastrointestinal adverse events (nausea, vomiting, diarrhea) being the most common treatment-related events. Importantly, these GI effects appeared less frequent and less severe than those typically observed with GLP-1 receptor agonists at comparable efficacy levels. Vosoughi et al. (2023) — Obesity
GLP-1 Agonism vs. GIP Antagonism Debate
The question of whether GIP receptor agonism or antagonism is the optimal approach for obesity treatment remains an active area of scientific debate. Tirzepatide achieves substantial weight loss (up to 22.5%) through dual GLP-1/GIP receptor agonism, seemingly contradicting the rationale for GIPR antagonism. However, the two approaches may not be mutually exclusive: GIP receptor activation versus blockade may have different downstream effects depending on the metabolic context, tissue type, and concurrent GLP-1R stimulation. Maritide's clinical results provide evidence that GIPR antagonism combined with GLP-1R agonism is indeed a viable and effective approach, though head-to-head comparisons with dual agonists will be needed to determine relative efficacy. Killion et al. (2020) — Sci. Transl. Med.
Safety Profile
Based on Phase 1 and Phase 2 clinical trial data, maritide has demonstrated a generally favorable safety profile. The most commonly reported adverse events are gastrointestinal in nature, including nausea, vomiting, and diarrhea. These effects appear to be dose-related and transient, typically resolving without intervention. Importantly, the incidence and severity of GI adverse events appeared comparable to or lower than those reported with GLP-1 receptor agonists achieving similar weight loss magnitudes, possibly because the antibody-mediated delivery of GLP-1 agonist peptides provides more sustained, lower-peak receptor stimulation compared to bolus injection of free peptides.
No serious safety signals were identified in early clinical trials. As with other GLP-1 receptor agonists, monitoring for pancreatitis, gallbladder events, and thyroid effects is recommended. The long half-life of maritide is an important consideration: in the event of adverse effects, drug clearance will be slow, and effects may persist for weeks after the last dose. No injection site reactions of clinical significance were reported. Longer-term safety data from Phase 3 trials are awaited.
Clinical Research Protocols
- Dosing (Phase 2): Multiple-dose subcutaneous regimens evaluated, including monthly (every 4 weeks) and bimonthly (every 8 weeks) schedules. Doses ranged from 140 mg to 420 mg per injection.
- Dose escalation: Gradual dose escalation employed in clinical trials to mitigate gastrointestinal adverse events.
- Key trials: NCT04478708 (Phase 1, single ascending dose), NCT05669599 (Phase 2, multiple dose), Phase 3 studies initiated 2024-2025.
- Duration: Phase 1 follow-up to 85+ days post-dose. Phase 2 treatment periods of 12-52 weeks.
- Routes: Subcutaneous injection only. Oral formulation not feasible due to antibody component.
Subpopulation Research
- Obese without diabetes: Primary clinical development population. Phase 2 demonstrated up to 14.5% weight loss at 12 weeks in this population.
- Type 2 diabetes: Not yet formally studied in dedicated T2D trials, though glycemic improvements observed in obese participants with prediabetes or metabolic syndrome.
- Severe obesity (BMI >40): Subgroup analyses from Phase 2 trials are anticipated.
- Elderly populations: Safety and efficacy in older adults (>65 years) will require dedicated analysis.
Pharmacokinetic Profile
Maritide (AMG 133) — Pharmacokinetic Curve
Subcutaneous injection (monthly or less frequently)Ongoing & Future Research
- Phase 3 clinical program: Amgen initiated Phase 3 trials in 2024, with pivotal efficacy and safety studies expected to read out in 2026-2027.
- Cardiovascular outcomes: A dedicated cardiovascular outcomes trial (CVOT) is anticipated, following the precedent set by semaglutide's SELECT trial.
- Type 2 diabetes: Expansion into T2D indications is expected following obesity program maturation.
- Dosing optimization: Evaluation of whether bimonthly (every 8 weeks) or quarterly dosing is feasible while maintaining efficacy.
- Body composition: Detailed body composition studies (DXA, MRI) to assess fat mass vs. lean mass changes.
- GIP receptor biology: Continued mechanistic research to understand the divergent effects of GIPR agonism vs. antagonism in different metabolic contexts.
- Combination approaches: Potential evaluation of maritide with other metabolic agents.
Quick Start
- Route
- Subcutaneous injection (monthly or less frequently)
Molecular Structure
- Formula
- Proprietary (antibody-peptide conjugate)
- CAS
- 2562041-82-9
Research Protocols
oral
Oral formulation not feasible due to antibody component.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| General Research Protocol | 140 mg, 420 mg | Per protocol | — |
subcutaneous Injection
This enables monthly or less frequent subcutaneous dosing, a significant advantage over weekly or daily GLP-1 agonists. Clinical Research Protocols - Dosing (Phase 2): Multiple-dose subcutaneous regimens evaluated, including monthly (every 4 weeks) and bimonthly (every 8 weeks) schedules.
| Goal | Dose | Frequency | Duration |
|---|---|---|---|
| Dosing (Phase 2) | 140 mg, 420 mg | Monthly | 4 weeks(Route: Subcutaneous Injection) |
| Combination approaches | See literature | Single dose | — |
Interactions
Peptide Interactions
The anti-GIPR antibody backbone provides an extended half-life characteristic of IgG molecules (approximately 3-4 weeks), while the conjugated GLP-1 agonist peptides stimulate GLP-1 receptor signaling.
It represents a fundamentally new pharmacological approach by combining GLP-1 receptor agonism with GIP receptor antagonism in a single molecule, distinguishing it from dual agonist approaches such as tirzepatide.
What to Expect
What to Expect
Levels begin building after first administration; half-life of ~3-4 weeks (estimated from dosing intervals) means steady state reached over month 4-6
Dosing (Phase 2): Multiple-dose subcutaneous regimens evaluated, including monthly (every 4 weeks) and bimonthly (every 8 weeks) schedules.
Phase 2 results demonstrated up to 14.5% body weight loss at 12 weeks, with continued weight loss trajectories suggesting further reductions with...
Phase 2 treatment periods of 12-52 weeks.
Continued use as directed
Quality Indicators
What to look for
- Phase 3 clinical trial data available
- Well-established safety profile
- Oral administration available
Caution
- Short half-life may require frequent dosing
- Injection site reactions reported
Frequently Asked Questions
References (4)
- [1]Vosoughi, K. et al A Phase 1, Randomized, Double-Blind, Placebo-Controlled Study of AMG 133 in Subjects with Obesity Obesity (2023)
- [2]Killion, E. A. et al Anti-obesity effects of GIPR antagonism alone and in combination with GLP-1R agonism in preclinical models Sci. Transl. Med. (2020)
- [3]Lu, S. C. et al AMG 133 inhibits GIPR and activates GLP-1R: pharmacological characterization of a bispecific anti-obesity agent Cell Metab. (2021)
- [4]Briere, D. A. et al Mechanisms by which AMG 133, a bispecific GIPR antagonist/GLP-1R agonist, reduces body weight: Preclinical characterization Diabetes Obes. Metab. (2024)
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