Michael Monostra , 2025-06-23 21:10:00
Key takeaways:
- Maridebart cafraglutide is a dual GLP-1/GIP being investigated for the treatment of obesity and diabetes.
- Once-monthly dosing led to significant weight loss in adults with obesity, with or without diabetes.
CHICAGO — Once-monthly maridebart cafraglutide resulted to significant weight loss at 1 year among adults with obesity, regardless of type 2 diabetes status, according to data from a phase 2 trial.
Healio previously reported data from the phase 2 trial in which maridebart cafraglutide (MariTide, Amgen), administered once-monthly via subcutaneous injection, was tied to greater reductions in body weight, systolic blood pressure, LDL cholesterol, triglycerides and high-sensitivity C-reactive protein compared with placebo. Final data from the phase 2 trial were presented at the American Diabetes Association Scientific Sessions and simultaneously published in The New England Journal of Medicine.
Once-monthly maridebart cafraglutide conferred weight loss of up to 16.2% in the treatment policy estimand among adults with obesity and without diabetes. Image: Adobe Stock
MariTide is a bispecific GLP-1 receptor agonist and glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist. Its dual mechanism of action and longer half-life support monthly or less frequent administration, according to the researchers.
Ania M. Jastreboff
“To have something that is once-monthly or less frequent that both addresses their dysglycemia as well as address the root cause of their diabetes, which is obesity, is unique,” Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of the Yale Obesity Research Center, co-director of the Yale Center for Weight Management and medical director of the Yale Stress Center, said during a press conference.
Researchers enrolled 592 adults with obesity or overweight plus one obesity-related complication in the double-blind randomized controlled trial. Two cohorts were assessed: adults with obesity with and without diabetes. Participants with obesity and without diabetes were randomly assigned to receive 140 mg, 280 mg or 420 mg of maridebart cafraglutide every 4 weeks without dose escalation; 420 mg every 8 weeks without dose escalation; 420 mg every 4 weeks with a 4-week dose escalation; 420 mg every 4 weeks with a 12-week dose escalation; or placebo. Participants with obesity and type 2 diabetes were randomly assigned to 140 mg, 280 mg or 420 mg of maridebart cafraglutide every 4 weeks or placebo. Change in body weight from baseline to 1 year was the primary endpoint.
Results: Obesity without diabetes
The trial included 465 adults with obesity but without diabetes (mean age, 47.9 years; 63% women; mean BMI, 37.9 kg/m2).
At 1 year, mean percent change in body weight from baseline ranged from –12.3% to 16.2% in the MariTide group, compared with –2.5% for those assigned placebo in the treatment policy estimand (intention-to-treat approach), according to the results.
In the efficacy estimand, which the researchers said represents the efficacy as if treated participants had adhered to MariTide for the entire study period, mean percent change in body weight at 1 year was even greater, and ranged from –16.3% to –19.9%, compared with –2.6% with placebo. During a presentation, Julio Rosenstock, MD, FACE, senior scientific advisor for Velocity Clinical Research, director of Velocity’s site at Medical City Dallas and clinical professor of medicine at the University of Texas Southwestern Medical Center, said the difference between the treatment policy estimand and efficacy estimand were greater than what has been seen in other obesity trials and added the difference may be due to the study’s discontinuation rate. Of the participants with obesity and without diabetes assigned MariTide, 16.8% discontinued the treatment due to an adverse event.
Adults with obesity and without diabetes also had a decrease in fat mass ranging from –26.2% to –36.8% with maridebart cafraglutide at 1 year compared with –9.1% with placebo. Lean mass was reduced by –8.6% to –11.6% vs. –2.1%, respectively.
Jastreboff said weight loss in all groups had not yet plateaued at 1 year.
“We don’t know the full efficacy of this agent until we look farther out,” Jastreboff said.
Results: Obesity with type 2 diabetes
The trial included 127 adults with obesity and type 2 diabetes included in the trial (mean age, 55.1 years; 42% women; mean BMI, 36.5 kg/m2).
At 1 year, MariTide conferred greater weight loss among adults with obesity plus than placebo. The mean percent change in body weight according to the treatment policy estimand ranged from –8.4% to –12.3%, compared with –1.7% in the placebo group, according to the results. In the efficacy estimand, weight loss with maridebart cafraglutide ranged from –12.1% to –17%, compared with –1.4% in the placebo group, according to the results.
Jastreboff said the magnitude of weight loss in the type 2 diabetes group, particularly those assigned 420 mg MariTide, was impressive.
“Individuals with type 2 diabetes usually lose less weight than those with obesity [alone],” Jastreboff said. “This was a very good result to see.”
HbA1c also decreased among adults with obesity and diabetes assigned MariTide. In the efficacy estimand, declines in HbA1c ranged from –1.9 to –2.2 percentage points, compared with a 0.1 percentage point increase in the placebo group, according to the results.
Fat mass decreased between –17.4% and –33.7% at 1 year in the MariTide group, while lean mass was reduced by –6.8% to –9.6%. The placebo group had a 4.3% decrease in fat mass and 2.3% decline in lean mass.
Safety data
At least 90% of participants assigned MariTide in both cohorts reported at least one adverse event, compared with 68% of the placebo group with obesity and without diabetes and 81% of those with obesity plus type 2 diabetes assigned placebo. Gastrointestinal adverse events were the most common among adults assigned MariTide. Most GI events were mild to moderate and were more likely to occur among participants who did not receive dose escalation of MariTide, according to the researchers. GI events were the most common reason for treatment discontinuation.
“The efficacy and safety of phase 2 support the investigation of MariTide in phase 3,” Jastreboff said during a presentation.
Improving gastrointestinal tolerability
Researchers also reported results of a phase 1, pharmacokinetics low-dose initiation study, which evaluated lower starting doses, informed by the pharmacokinetics of MariTide.
This included 121 adults who were randomly assigned to a starting dose of 21 mg, 35 mg or 70 mg of MariTide. All three groups had an increase to 70 mg at day 15 and to 350 mg at day 29. Monitored occurred in an inpatient setting the first 7 days after receiving a dose. The primary analysis for this study was performed at 43 days.
Mean plasma concentrations of MariTide were higher during the first 15 days in the higher-dose groups. Mean levels of exposure to the MariTide increased at day 15 and day 29, with a larger increase in the lower-dose groups than the 70 mg starting dose cohort. Donna H. Ryan, MD, professor emerita at Pennington Biomedical Research center, who presented the results, said plasma concentrations of the drug at day 29 were similar between the three groups.
At day 43, GI adverse events occurred in 61% of the 21 mg dose group, 77.5% of the 35 mg group and 92.5% of the 70 mg group.
Donna H. Ryan
Participants completed a Modified Index of Nausea, Vomiting and Retching each day of the study. During the first 15 days, the 21 mg group had the lowest prevalence of GI adverse events. However, after day 15, when all groups increased their dose to 70 mg, GI events were similar in the 21 mg starting dose group compared with 30 mg and 75 mg starting doses.
“We think what’s going on is, when we look back at our pharmacokinetics study, we see that large plasma increase,” Ryan said. “We think that is probably driving the increased events on day 15. This would suggest that an intermediate dose would alleviate some of those problems.”
Based on the pharmacokinetic findings, Ryan said the researchers have a plan for dose escalation in a future phase 3 study. Ryan said participants assigned MariTideg will start at 21 mg at baseline, increase to 35 mg at 2 weeks and then increase again to 70 mg at 4 weeks. At 8 weeks, participants will be randomly assigned to one of three target doses.
“We think this is a great opportunity here and we’re really excited about that long half-life and the potential for monthly or even less frequent dosing,” Ryan said.
Reference:
Sources/Disclosures
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Seeley RJ, et al. Once-monthly MariTide for the treatment of obesity in people with or without type 2 diabetes — A 52-week phase 2 study. Presented at: American Diabetes Association Scientific Sessions; June 20-23, 2025; Chicago.
Disclosures:
Jastreboff reports receiving grant funding from Amgen, Boehringer Ingelheim, Eli Lilly, Novo Nordisk and Rhythm Pharmaceuticals; consulting for Amgen, AstraZeneca, Biohaven Pharmaceutical, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Regeneron, Scholar Rock, Structure Therapeutics, Terns, WW and Zealand; and owning stock options in Intellihealth, State 4 Therapeutics and Syntis Bio. Ryan reports serving as a scientific advisor for AbbVie, Altimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Biohaven, Calibrate, Carmot/Roche, CINRx, Currax, Eli Lilly, eMedd, Epitomee, Fractyl, Gila, Nestle, Novo Nordisk, Pfizer, Regeneron, Scientific Intake, Source Bio, Structure Therapeutics, Tenvie, Wondr Health and Zealand; serving on a speaker’s bureau for Eli Lilly and Novo Nordisk; owning stock options in Calibrate, Epitomee, Roman, Scientific Intake and Xeno Bioscience; and serving on a data safety monitoring board for CINRx, Eli Lilly and IQVIA setmelanotide.
