Once-Monthly Maridebart Cafraglutide Shows Up to 16% Weight Loss

Investigational obesity medicine maridebart cafraglutide (Amgen) showed clinically meaningful and dose-dependent weight loss among adults with obesity, with or without type 2 diabetes (T2D), according to phase 2 trial findings published in The New England Journal of Medicine.1

The once-monthly long-acting peptide–antibody conjugate works by combining glucagon-like peptide-1 (GLP-1) receptor agonism with glucose-dependent insulinotropic polypeptide (GIP) receptor antagonism, supporting the development of less frequent dosing intervals for chronic weight management.

“Although the findings are not conclusive and require confirmation in a larger, longer trial, the use of a lower starting dose and dose escalation resulted in fewer gastrointestinal adverse events, as shown in the PK-LDI study, which is informing the phase 3 approach to improve the side-effect profile,” the investigators said.

1-Year Weight Loss With Maridebart Cafraglutide

The trial (NCT05669599) included 592 adults and tested 11 dosing strategies across 2 cohorts, with a primary end point of percent change in body weight between baseline and week 52.

Patients with obesity alone (n = 465) were randomized to one of the following groups:

1. Maridebart cafraglutide 140, 280, or 420 mg every 4 weeks without dose escalation
2. Maridebart cafraglutide 420 mg every 8 weeks without dose escalation
3. Maridebart cafraglutide 420 mg every 4 weeks with 4-week dose escalation
4. Maridebart cafraglutide 420 mg every 4 weeks with 12-week dose escalation
5. Placebo

Participants with obesity and T2D (n = 127) had fewer treatment options during the study and were randomized to one of the following groups:

• Maridebart cafraglutide 140, 280, or 420 mg every 4 weeks without dose escalation
• Placebo

Based on the treatment policy estimand—or the intention-to-treat—participants with obesity lost a mean of 12.3% to 16.2% of body weight at 52 weeks across the maridebart cafraglutide subgroups, compared with 2.5% weight loss with placebo. Patients with both obesity and T2D lost a mean 8.4% to 12.3% of their weight with treatment compared with 1.7% with placebo.

On the basis of the efficacy estimand—or under ideal scenarios where patients adhere to treatment as prescribed for the full 52 weeks—patients saw even more weight loss, the authors said. Patients with obesity saw weight loss from 16.3% to nearly 20% when taking maridebart cafraglutide compared with just 2.6% with placebo; patients with both obesity and diabetes lost 12.1% to 17% of their weight with treatment compared with only 1.4% weight loss with placebo.

Researchers also observed improved waist circumference and systolic and diastolic blood pressure. | Image credit: alones – stock.adobe.com

“A consistent observation from clinical trials with nutrient-stimulated hormone receptor modulators is that persons with obesity and type 2 diabetes lose less weight than those without type 2 diabetes; the mechanisms of the response are unknown,” the study authors wrote.

Weight loss did not appear to plateau at week 52, suggesting longer treatment may lead to even further reductions.

Fat vs Lean Mass

Researchers also looked specifically at the loss of fat and lean tissue. Participants receiving the once-monthly injection lost substantially more fat mass than those receiving placebo, with reductions of about 26% to 37% in adults with obesity and about 17% to 34% in adults with obesity and T2D, compared with 9% and 4% in the placebo groups, respectively.

Lean mass also decreased but to a lesser degree, with losses of about 9% to 12% in adults with obesity and about 7% to 10% in adults with obesity and T2D, compared with 2% in placebo recipients. Overall, the body composition data indicate that most of the weight lost with maridebart cafraglutide came from fat rather than lean tissue, consistent with patterns seen with other GLP-1 therapies.

Glycemic Effects and Body Composition

Among participants with obesity and T2D, maridebart cafraglutide lowered glycated hemoglobin up to 1.6 percentage points on the treatment-policy estimand and up to 2.2 points on the efficacy estimand, compared with a 0.1-point increase with placebo. By week 52, between 81% and 87% of patients taking the once-monthly injection reached an A1C of 6.5% or lower, compared with only 9% of patients taking placebo. Additionally, 30% to 70% of these patients achieved normoglycemia (A1C < 5.7%), but no patients in the placebo arm reached this.

About a third of adults with obesity in the study had prediabetes at baseline and available data on the glycated hemoglobin level at week 52. Of these patients, 70% to 95% reverted to normoglycemia with treatment compared with only 17% with placebo.

“Given the contribution of obesity to the development of type 2 diabetes, achieving normoglycemic levels is becoming a treatment goal,” the researchers said.

Maridebart cafraglutide was also tied to improved waist circumference, systolic and diastolic blood pressure, fasting glucose, insulin, and high-sensitivity C-reactive protein.

Safety Profile and GI Tolerability

Among patients with obesity only, 90% to 99% of participants receiving maridebart cafraglutide reported at least 1 adverse event compared with 68% on placebo in the obesity cohort. Patients with both obesity and diabetes had a similar adverse event rate with treatment (91% to 97%) but had more adverse events with placebo (81%) than patients with obesity alone.

Gastrointestinal (GI) adverse events were the most common side effects, as seen in approved GLP-1 receptor agonists.2 Discontinuation due to GI symptoms occurred in 12% to 27% of no-escalation groups, but only 8% of dose-escalation groups.1

No unexpected safety signals emerged from the study. Two deaths occurred during the study—1 due to traumatic intracranial hemorrhage and 1 sudden cardiac death in a participant with multiple cardiovascular risk factors—although both were deemed unrelated to treatment by site investigators. Hypersensitivity events were mild, gallbladder events occurred more often with active treatment, and no cases of pancreatitis, diabetic retinopathy, or thyroid C-cell hyperplasia were reported.

References

1. Jastreboff AM, Ryan DH, Bays HE, et al. Once-monthly maridebart cafraglutide for the treatment of obesity - a phase 2 trial. N Engl J Med. 2025;393(9):843-857. doi:10.1056/NEJMoa2504214
2. Klein HE. How effective and safe are GLP-1s for weight loss? AJMC®. November 18, 2025. Accessed December 4, 2025. https://www.ajmc.com/view/how-effective-and-safe-are-glp-1s-for-weight-loss-