What is MariTide and how does it work?

MariTide (maridebart cafraglutide) is an investigational once-monthly injection that blocks the glucose-dependent insulinotropic polypeptide receptor (GIPR) while activating the glucagon-like peptide-1 receptor (GLP-1R). This dual action helps curb appetite, slow stomach emptying and improve insulin responses, producing up to 20% average weight loss over 52 weeks in Phase 2 studies.

What is MariTide?

MariTide is an investigational antibody-peptide conjugate developed by Amgen for treating obesity and Type 2 diabetes. The drug consists of a monoclonal antibody against GIPR conjugated to two peptidic GLP-1R agonist molecules via amino acid linkers. The medication is administered as a once-monthly subcutaneous injection, with researchers also exploring quarterly dosing schedules.

Current Status

Amgen has completed Phase 2 trials and announced plans to advance into the Phase 3 MARITIME program. The 72-week Phase 3 trials will assess safety, efficacy, and tolerability in adults with obesity or overweight, both with and without Type 2 diabetes. Participants will be randomized to one of three target doses, beginning at 21 mg, escalating to 35 mg, and then 70 mg over an eight-week optimized titration period.

How does MariTide work?

MariTide's unique approach involves two complementary mechanisms:

• GIPR antagonist: The monoclonal antibody component blocks GIP signaling, which may reduce fat storage and contribute to weight loss. This differs from existing medications that typically activate GIP receptors. It is unclear how blocking GIP receptors leads to weight loss, but genetic studies have also shown that having less GIP function is associated with a lower BMI.
• GLP-1R agonist: Two GLP-1 receptor agonist molecules are tethered to the antibody, stimulating insulin production, slowing gastric emptying, and suppressing appetite. Like semaglutide (Wegovy), MariTide activates GLP-1 receptors, but like tirzepatide (Zepbound), it also targets GIP receptors—though as an antagonist rather than an agonist.

Why Once-Monthly?

MariTide lasts longer in the body because it's built on an antibody structure and has a long half life. This means patients only need one shot per month instead of weekly shots like other weight loss drugs. Because it stays in the body longer, it might keep working better over time or help prevent people from gaining weight back after they stop taking it.

Efficacy to Date

In phase 2 trials, participants experienced average weight loss ranging from 16.3% to 19.9% at 52 weeks, compared to 2.6% weight loss in the placebo group. Notably, researchers observed that a weight plateau was not reached at 52 weeks, with weight continuing a downward trajectory.

Beyond weight loss, MariTide demonstrated robust improvements in cardiometabolic parameters:

• HbA1c levels decreased by 1.2 to 1.6 percentage points compared to a 0.1 rise with placebo.
• Systolic and diastolic blood pressure showed positive changes.
• Improvements were noted in waist circumference, body mass index, high-sensitivity C-reactive protein, and lipid levels.

However, the Phase 2 trial revealed high discontinuation rates, particularly among participants without Type 2 diabetes, largely due to gastrointestinal adverse events.

Side Effects of MariTide

The most common adverse events were gastrointestinal-related, including nausea, vomiting, and constipation. More than 90% of patients in each MariTide cohort experienced an adverse event, compared with 68% and 81% of those on placebo.

Importantly, nausea and vomiting were predominantly mild, transient and primarily associated with the first dose. The incidence of these side effects was substantially reduced with dose escalation strategies. In dose escalation arms of the obesity group, discontinuation rates due to GI adverse events was 8%.

Researchers are implementing optimized titration strategies in Phase 3 trials, starting with lower doses (21 mg → 35 mg → 70 mg) to improve tolerability.

How is MariTide different from Wegovy or Zepbound?

MariTide offers monthly dosing versus weekly injections required by current GLP-1 medications, potentially improving patient adherence. The drug uses an antibody scaffold rather than small peptides, which contributes to its extended dosing interval.

Early data suggest MariTide may achieve similar or greater weight loss compared to existing options—clinical trials show Zepbound (tirzepatide) led to 23% average weight loss over 88 weeks, while Wegovy achieved 15% weight loss over 68 weeks. However, MariTide appears to have more gastrointestinal adverse events at higher doses.

What Happens Next?

Amgen is advancing MariTide into Phase 3 clinical trials as part of the MARITIME program. While a specific FDA submission date has not been confirmed, the timing will largely depend on the outcomes of these upcoming trials. Results are expected in 2027. In addition to chronic weight management, Amgen plans to initiate Phase 3 outcome studies in 2025 for atherosclerotic cardiovascular disease, heart failure, and obstructive sleep apnea.

See also:

Medical Disclaimer