Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial

Jastreboff, Ania M. M.D., Ph.D.
Ryan, Donna H. M.D.
Bays, Harold E. M.D.
Ebeling, Peter R. M.D.
Mackowski, Mia G. Pharm.D.
Philipose, Nisha B.Pharm., M.Sc.
Ross, Leorah M.D., Ph.D.
Liu, Yimeng M.P.H., Ph.D.
Burns, Cassandra E Ph.D.
Abbasi, Siddique A. M.D.
Pannacciulli, Nicola M.D., Ph.D.

¹Section of Endocrinology and Metabolism, Department of Medicine, Yale School of Medicine, New Haven, CT
²Section of Pediatric Endocrinology, Department of Pediatrics, Yale School of Medicine, New Haven, CT
³Yale Obesity Research Center (Y-Weight), Yale School of Medicine, New Haven, CT
⁴Pennington Biomedical Research Center, Baton Rouge, LA
⁵Louisville Metabolic and Atherosclerosis Research Center, University of Louisville School of Medicine, Louisville, KY
⁶Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
⁷Amgen, Thousand Oaks, CA

Dr. Jastreboff can be contacted at [email protected] or at Section of Endocrinology and Metabolism, Department of Medicine, Yale University School of Medicine, 333 Cedar St., P.O. Box 208020, New Haven, CT 06520.

^*A complete list of the principal investigators is provided in the Supplementary Appendix, available at NEJM.org.

This article was published on June 23, 2025, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

Supported by Amgen.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

New England Journal of Medicine 393(9):p 843-857, September 4, 2025. | DOI: 10.1056/NEJMoa2504214

Abstract

Background

Maridebart cafraglutide (known as MariTide) is a long-acting peptide-antibody conjugate that combines glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism and that is intended for the treatment of obesity.

Methods

We conducted a phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial that included 11 groups as two cohorts. Participants with obesity (obesity cohort) were randomly assigned in a 3:3:3:2:2:2:3 ratio to receive maridebart cafraglutide subcutaneously at a dose of 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 4-week dose escalation; 420 mg every 4 weeks with 12-week dose escalation; or placebo. Participants with obesity with type 2 diabetes (obesity-diabetes cohort) were randomly assigned in a 1:1:1:1 ratio to receive maridebart cafraglutide at a dose of 140, 280, or 420 mg every 4 weeks (all without dose escalation) or placebo. The primary end point was the percent change in body weight from baseline to week 52.

Results

We enrolled 592 participants. In the obesity cohort (465 participants; female sex, 63%; mean age, 47.9 years; mean body-mass index [BMI, the weight in kilograms divided by the square of the height in meters], 37.9), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand (intention-to-treat approach) ranged from −12.3% (95% confidence interval [CI], −15.0 to −9.7) to −16.2% (95% CI, −18.9 to −13.5) with maridebart cafraglutide, as compared with −2.5% (95% CI, −4.2 to −0.7) with placebo. In the obesity-diabetes cohort (127 participants; female sex, 42%; mean age, 55.1 years; mean BMI, 36.5), the mean percent change in body weight from baseline to week 52 on the basis of the treatment policy estimand ranged from −8.4% (95% CI, −11.0 to −5.7) to −12.3% (95% CI, −15.3 to −9.2) with maridebart cafraglutide, as compared with −1.7% (95% CI, −2.9 to −0.6) with placebo. The mean change in the glycated hemoglobin level on the basis of the treatment policy estimand in this cohort was −1.2 to −1.6 percentage points in the maridebart cafraglutide groups and 0.1 percentage points in the placebo group. Gastrointestinal adverse events were common with maridebart cafraglutide, although less frequent with dose escalation and a lower starting dose. No unexpected safety signals emerged.

Conclusions

In this phase 2 trial, once-monthly maridebart cafraglutide resulted in substantial weight reduction in participants with obesity with or without type 2 diabetes. (Funded by Amgen; ClinicalTrials.gov number, NCT05669599.)

Once-Monthly Maridebart Cafraglutide for Obesity

A phase 2 trial of once-monthly maridebart cafraglutide, a peptide-antibody conjugate, showed substantial weight reduction in participants with obesity with or without type 2 diabetes.