medwireNews: Monthly injection of the long-acting peptide–antibody conjugate maridebart cafraglutide leads to significant weight loss compared with placebo in people with obesity with or without type 2 diabetes, phase 2 study findings indicate.
Ania Jastreboff (Yale University School of Medicine, New Haven Connecticut, USA) and co-investigators say the findings support a phase 3 trial of maridebart cafraglutide (also known as MariTide), which works by combining glucagon-like peptide-1 receptor agonism and glucose-dependent insulinotropic polypeptide receptor antagonism.
The current study included 465 participants (mean age 48 years, 63% women) with obesity (BMI ≥30 kg/m2, or ≥27 kg/m2 with at least one obesity-related complication) and a glycated hemoglobin (HbA1c) level below 6.5% (46 mmol/mol). They were randomly assigned to receive subcutaneous maridebart cafraglutide at doses of 140 mg, 280 mg, 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.
At baseline, the participants had a mean BMI of 37.9 kg/m2 and mean bodyweight of 107.4 kg. After 52 weeks of treatment, the reduction in bodyweight was significantly greater with all doses of maridebart cafraglutide than with placebo. The mean reduction ranged from 12.3% (420 mg every 8 weeks) to 16.2% (420 mg every 4 weeks with 12-week dose escalation) with maridebart cafraglutide versus 2.5% with placebo.
In addition, mean HbA1c fell by an average 0.3 to 0.4 percentage points during treatment from an overall mean of 5.5% (37 mmol/mol) at baseline, whereas there was no change between baseline and week 52 in the placebo arm.
The study also included a second cohort of 127 participants (mean age 55 years, 42% women) with obesity (BMI ≥27 kg/m2) and type 2 diabetes who were randomly assigned to receive maridebart cafraglutide at fixed doses of 140 mg, 280 mg, or 420 mg every 4 weeks or placebo. The mean baseline BMI was 36.5 kg/m2 in this group while mean bodyweight was 103.9 kg.
Jastreboff and team report that, at week 52, bodyweight had fallen by an average of 8.4% (280 mg every 4 weeks) to 12.3% (420 mg every 4 weeks) with maridebart cafraglutide compared with 1.7% with placebo. The difference between the treatment and placebo groups was again statistically significant.
Furthermore, maridebart cafraglutide use was associated with significantly greater reductions in HbA1c than placebo in the obesity–diabetes cohort. At week 52, mean HbA1c had fallen by 1.2 to 1.6 percentage points in the maridebart cafraglutide groups, from an overall mean of 7.9% (63 mmol/mol) at baseline, whereas there was a 0.1 percentage point increase in the placebo group.
Nearly all (90–99%) participants in the obesity cohort who received maridebart cafraglutide experienced at least one adverse event (AE) compared with 68% of participants given placebo. In the obesity–diabetes cohort, the corresponding proportions were 91–97% and 81%, respectively.
The researchers observed that the most common AEs were gastrointestinal events including nausea, vomiting, diarrhea, constipation, and retching. Of note, these were less common in treatment arms that included dose escalation and had a lower starting dose than in those with no dose escalation and higher starting doses.
In all, 8% of participants given a dose escalation regimen in the obesity cohort discontinued maridebart cafraglutide due to a gastrointestinal AE (most commonly vomiting and nausea) compared with 12–27% of those who had no dose escalation. In the obesity–diabetes cohort, where no participants underwent dose escalation, the discontinuation rate was 6–16%.
Jastreboff and colleagues say that further work is now underway “to determine the weight plateau and nadir and whether weight reduction is maintained with lower doses or less frequent administration.”
The study findings were presented at the 85th ADA Scientific Sessions in Chicago, Illinois, USA and simultaneously published in The New England Journal of Medicine.
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N Engl J Med 2025; doi:10.1056/NEJMoa2504214
ADA 85th Scientific Sessions; Chicago, Illinois, USA: 20–23 June