Weight-Loss Drug Maridebart Cafraglutide Shows Efficacy in Phase 2 Trial

Patients with obesity who received maridebart cafraglutide (MariTide; Amgen), a once-monthly obesity medication, demonstrated weight loss of up to 19.9% in a phase 2 trial (NCT05669599).¹ Those with obesity and type 2 diabetes showed weight loss of up to 17%.

Maridebart cafraglutide is a long-acting peptide–antibody conjugate that combines glucagon-like peptide-1 (GLP-1) receptor agonism and glucose-dependent insulinotropic polypeptide (GIP) receptor antagonism. The 2 identical GLP-1 peptide analogs conjugated to a single monoclonal antibody antagonist to the GIP receptor result in a 21-day half-life, 3 times longer than the FDA approved longest-acting once-weekly anti-obesity medication, semaglutide. The extended half-life can potentially lead to increased access and adherence for those whose health and access to health care are disproportionately affected by socioeconomic status.² 

The mean percent change in body weight from the obesity cohort from baseline to 52 weeks ranged from −12.3% to −16.2% to −16.2%. | Image Credit: ricka_kinamoto - stock.adobe.com

“[Maridebart cafraglutide]'s monthly or less frequent dosing has the potential to improve adherence and long-term weight control, providing the opportunity to optimize health outcomes for people living with obesity, type 2 diabetes, and related conditions," Jay Bradner, MD, executive vice president of Research and Development at Amgen, said in a press release.³ “[Maridebart cafraglutide] delivered strong efficacy, including sustained weight loss without a plateau in the 52-week phase 2 study and meaningful improvements in cardiometabolic risk factors, representing a defining advance for the obesity field.”

Phase 2 of the trial tested the efficacy, adverse event profile, and safety of maridebart cafraglutide at various doses with and without escalation.¹ The study enrolled 592 participants—465 in the obesity cohort and 127 in the obesity-diabetes cohort. The obesity cohort was randomly assigned in a 3:3:3:2:2:2:3 ratio to receive either 52 weeks of maridebart cafraglutide subcutaneously at 140, 280, or 420 mg every 4 weeks without dose escalation; 420 mg every 8 weeks without dose escalation; 420 mg every 4 weeks with either a 4- or 12-week dose escalation; or a placebo. Participants in the obesity-diabetes cohort were randomly assigned in a 1:1:1:1 ratio to receive maridebart cafraglutide over 52 weeks at a dosage of 140, 280, or 420 mg every 4 weeks or a placebo.

The mean percent change in body weight from the obesity cohort from baseline to 52 weeks ranged from −12.3% to −16.2% (95% CI, −15.0 to −9.7) to −16.2% (95% CI, −18.9 to −13.5). The obesity-diabetes cohort mean percent change in body weight ranged from −8.46% (95% CI, −11.0 to −5.7) to −12.3% (95% CI, −15.3 to −9.2).

Those in both cohorts who received maridebart cafraglutide also showed a significant difference in the percentage points of glycated hemoglobin (HbA1c) levels when analyzed using the treatment policy estimand. The obesity cohort had a mean difference of –0.32 (95% CI, –0.5 to –0.2) percentage points measuring glycated hemoglobin levels. Similarly, the obesity-diabetes cohort showed a mean difference of –1.43 (95% CI, –1.9 to –0.7) percentage points in glycated hemoglobin. When analyzed using the efficacy demand, the obesity cohort did not show a significant difference in weight loss; however, the obesity-diabetes cohort did, with –2.03 (95% CI, –2.4 to –1.6) percentage points.

Participants in both cohorts experienced improvement in additional secondary end points, including differences in systolic and diastolic blood pressure, high-sensitivity C-reactive protein (hs-CRP), and select lipid variables. Furthermore, those receiving a dose escalation over 4 or 12 weeks did not show significant differences in primary or secondary end points when compared with those that did not receive dose escalation.

Adverse events occurred in an average of 93.5% of participants across both cohorts. The most common adverse events (AEs) were gastrointestinal, which included mild to moderate nausea, vomiting, constipation, retching, and diarrhea. There was a lower incidence of adverse events in the groups with dose escalation and those starting at a lower dose across both cohorts.

Of the 592 participants in the obesity cohort, 8% in the dose escalation group discontinued the trial due to GI AEs, as opposed to the 12% to 17% in the no–dose escalation groups. Similarly, 6% to 16% of participants in the obesity-diabetes cohort discontinued due to GI-related adverse events. Other predefined adverse events varied in severity, ranging from mild to moderate, and included injection-site rash, reactions, and/or urticaria.

“These results, alongside the phase 1 pharmacokinetics low-dose initiation data, have shaped our phase 3 MARITIME program," Bradner said.³

References

1. Jastreboff AM, Ryan DH, Bays HE, et al. Once-monthly maridebartcafraglutide for the treatment of obesity — a phase 2 trial. New England Journal of Medicine. Published online June 23, 2025. doi:10.1056/nejmoa2504214
2. Eberly LA, Yang L, Essien UR, et al. Racial, ethnic, and socioeconomic inequities in glucagon-like peptide-1 receptor agonist use among patients with diabetes in the US. JAMA Health Forum. 2021;2(12): e214182. doi:10.1001/jamahealthforum.2021.4182
3. Results from Amgen’s phase 2 obesity study of monthly maritide presented at the American Diabetes Association 85th Scientific Sessions. Amgen. June 23, 2025. Accessed June 25, 2025. https://www.amgen.com/newsroom/press-releases/2025/06/results-from-amgens-phase-2-obesity-study-of-monthly-maritide-presented-at-the-american-diabetes-association-85th-scientific-sessions