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

Authors and Contact Information

  • Dr. Jastreboff can be contacted at:

    • Email: ania.jastreboff@yale.edu

    • Affiliation: Section of Endocrinology and Metabolism, Department of Medicine, Yale University School of Medicine, 333 Cedar St., P.O. Box 208020, New Haven, CT 06520

  • Full names, academic degrees, and affiliations of all authors at the end of the article.

  • Copyright: Copyright © 2025 Massachusetts Medical Society.

  • DOI: 10.1056/NEJMoa2504214

Background

  • Maridebart Cafraglutide (MariTide):

    • Long-acting peptide-antibody conjugate.

    • Combines glucagon-like peptide-1 (GLP-1) receptor agonism and glucose-dependent insulinotropic polypeptide (GIP) receptor antagonism.

    • Intended for the treatment of obesity.

Methods

Study Design

  • Phase 2, double-blind, randomized, placebo-controlled, dose-ranging trial.

  • Included 11 groups within 2 cohorts.

  • Cohorts:

    • Obesity Cohort: Participants with obesity.

    • Obesity-Diabetes Cohort: Participants with obesity and type 2 diabetes.

  • Random Assignments:

    • Obesity Cohort: 3:3:3:2:2:2:3 ratio for maridebart cafraglutide doses of 140 mg, 280 mg, or 420 mg every 4 weeks without escalation; 420 mg every 8 weeks; 420 mg every 4 weeks with 4-week or 12-week dose escalation; or placebo.

    • Obesity-Diabetes Cohort: 1:1:1:1 ratio for doses of 140 mg, 280 mg, or 420 mg every 4 weeks (all without dose escalation) or placebo.

  • Primary Endpoint: Percent change in body weight from baseline to week 52.

Results

Enrollment

  • Total Participants: 592

    • Obesity Cohort: 465 participants

      • Female sex: 63%

      • Mean age: 47.9 years

      • Mean BMI: 37.9

    • Obesity-Diabetes Cohort: 127 participants

      • Female sex: 42%

      • Mean age: 55.1 years

      • Mean BMI: 36.5

Percent Change in Body Weight

  • Obesity Cohort:

    • Mean percent change ranged from -12.3% (95% CI, -15.0 to -9.7) to -16.2% (95% CI, -18.9 to -13.5) with maridebart cafraglutide, compared to -2.5% (95% CI, -4.2 to -0.7) with placebo.

  • Obesity-Diabetes Cohort:

    • Mean percent change ranged from -8.4% (95% CI, -11.0 to -5.7) to -12.3% (95% CI, -15.3 to -9.2) with maridebart cafraglutide, versus -1.7% (95% CI, -2.9 to -0.6) with placebo.

  • Glycated Hemoglobin Levels:

    • Change in levels ranged from -1.2 to -1.6 percentage points in maridebart cafraglutide groups, with 0.1 percentage points in the placebo group.

  • Adverse Events: Gastrointestinal adverse events were common but less frequent with dose escalation and a lower starting dose. No unexpected safety signals were reported.

Conclusions

  • In the phase 2 trial, once-monthly maridebart cafraglutide led to substantial weight loss in participants with obesity, both with and without type 2 diabetes.

Introduction to Once-Monthly Therapeutics for Obesity

  • Once-monthly therapies may provide sustainable options for treating obesity, a prevalent chronic disease.

  • Current Treatments:

    • Once-weekly GLP-1 receptor modulators, like semaglutide and tirzepatide, show significant weight loss and tackle obesity-related complications.

    • However, access and adherence issues remain.

  • Maridebart Cafraglutide:

    • Long half-life of approximately 21 days allows for monthly or less frequent dosing.

    • Phase 1 study showed acceptable safety with dose-dependent weight loss maintained for up to 150 days.

Methods - Trial Design

  • Cohorts:

    • Persons with obesity (Cohort A)

    • Persons with obesity and type 2 diabetes (Cohort B)

  • Trial conducted per Declaration of Helsinki and Good Clinical Practice guidelines, approved by ethics committee at trial sites.

  • Participants:

    • 18 years or older; BMI ≥30, or ≥27 with complications; glycated hemoglobin <6.5% for Cohort A; BMI ≥27 with T2D diagnosis and glycated hemoglobin 7 to ≤10% for Cohort B.

  • Exclusions:

    • History of pancreatitis, recent weight change, previous weight loss surgery, obesity-promoting medications.

Procedures

  • Random Assignment:

    • Obesity cohort: assigned to multiple maridebart cafraglutide regimens or placebo in various ratios.

    • Obesity-Diabetes cohort: assigned to 52 weeks of maridebart cafraglutide or placebo with 1:1:1:1 ratio.

  • Endpoints:

    • Primary: percent change in body weight at 52 weeks.

    • Secondary: weight reduction milestones (≥5%, 10%, 15%, 20%), changes in glycated hemoglobin, pharmacokinetics, glucose metabolism.

  • Statistical Analysis:

    • Power analysis for cohort sample sizes.

    • Two estimands: treatment policy estimand (intention-to-treat) and efficacy estimand (adherence assumed).

    • Efficacy analyses performed by cohort.

Participants and Their Results

  • Total participants: 592

    • Completion rate: 72% overall

    • The demographic data for both cohorts were consistent across trial groups.

Mean Percent Change in Body Weight Summary

Obesity Cohort

  • Ranging from -12.3% to -16.2% with maridebart cafraglutide compared to -2.5% with placebo.

Obesity-Diabetes Cohort

  • Ranging from -8.4% to -12.3% with maridebart cafraglutide compared to -1.7% with placebo.

Anthropometric and Cardiometabolic Variables

  • Significant improvements in glycated hemoglobin levels, waist circumference, BMI, blood pressure, hs-CRP, and lipid profiles.

  • Body composition analysis showed greater reductions in fat mass versus lean mass.

Side-Effect Profile and Safety

  • High incidence of adverse events was observed with maridebart cafraglutide compared to placebo, with a substantial emphasis on gastrointestinal issues.

  • Discussed the characteristics and consequences of serious adverse events, including two deaths deemed unrelated.