Presented during the Endocrinology Conference at the American Diabetes Association’s 85th Scientific Sessions, findings from a randomized, placebo-controlled phase 2 trial suggest that maridebart cafraglutide may offer clinically meaningful weight loss with a reduced injection frequency compared with existing therapies.
The study enrolled 592 adults—465 with obesity and 127 with both obesity and type 2 diabetes—across multiple international clinical sites. Participants were randomly assigned to receive varying doses of maridebart cafraglutide or placebo over a 52-week treatment period. The once-monthly therapy, also known as MariTide or AMG133, is a long-acting peptide–antibody conjugate that activates glucagon-like peptide-1 (GLP-1) receptors and blocks glucose-dependent insulinotropic polypeptide (GIP) receptors, two hormonal pathways involved in energy balance and metabolism.
Weight Loss Outcomes
Participants in the obesity cohort who received maridebart cafraglutide lost a mean of 12.3% to 16.2% of body weight at 52 weeks, depending on dose and escalation strategy (treatment-policy estimand). In comparison, those receiving placebo lost 2.5%. In the obesity–diabetes cohort, weight loss ranged from 8.4% to 12.3% with active treatment versus 1.7% with placebo.
Investigators assessed weight loss using two statistical approaches. The primary analysis (treatment-policy estimand) included all randomized participants regardless of adherence. A secondary analysis (efficacy estimand), which assumed full adherence, showed even greater reductions—up to 19.9% in the obesity cohort and 17.0% in the obesity–diabetes cohort.
Metabolic Effects
In participants with type 2 diabetes, mean reductions in glycated hemoglobin (HbA1c) ranged from 1.2 to 1.6 percentage points in the maridebart cafraglutide groups, while the placebo group experienced a slight increase of 0.1 percentage points. Participants without diabetes demonstrated modest but consistent metabolic improvements, including reductions in fasting plasma glucose, fasting insulin, and body mass index.
Body Composition Analysis
In a substudy involving 191 participants with obesity and 46 with both obesity and diabetes, dual-energy X-ray absorptiometry (DXA) revealed that the majority of weight loss came from reductions in fat mass. Among the obesity cohort, fat mass declined by 26.2% to 36.8%, while lean mass declined by 8.6% to 11.6%. In the diabetes cohort, fat mass declined by 17.4% to 33.7%, and lean mass by 6.8% to 9.6%.
Safety and Tolerability
Adverse events occurred in up to 99% of treated participants but were predominantly mild to moderate and gastrointestinal in nature. These included nausea, vomiting, constipation, and diarrhea. Dose-escalation protocols—either 4-week or 12-week—significantly reduced both the frequency and severity of these events. For example, the incidence of treatment discontinuation due to gastrointestinal events was 8% in the dose-escalation groups versus 12% to 27% in the no–dose-escalation groups.
Two deaths occurred among participants receiving maridebart cafraglutide; both were deemed unrelated to the study drug by investigators.
Additional adverse events of interest included mild to moderate hypersensitivity reactions, injection-site reactions, and gallbladder events. No cases of pancreatitis, diabetic retinopathy, or C-cell hyperplasia were reported.
Pharmacokinetics and Future Research
The agent’s half-life—approximately 21 days—is about three times longer than currently approved once-weekly GLP-1–based agents, supporting monthly or potentially less frequent dosing. A separate pharmacokinetics study (PK-LDI) indicated that lower starting doses were associated with fewer early gastrointestinal events and informed the design of the ongoing phase 3 trials.
Part 2 of the phase 2 trial is underway to assess long-term weight maintenance and the optimal dosing strategy. Investigators continue to evaluate maridebart cafraglutide as a potential long-term therapeutic option for chronic weight management.
The trial was funded by Amgen and registered under ClinicalTrials.gov identifier NCT05669599. Full disclosures are available in the published article.
