Weight-Loss Drug MariTide Gains Momentum in Phase II Trial

Maridebart cafraglutide (Amgen), also known as MariTide or AMG133, helps patients with obesity—whether or not they also have diabetes—lose substantial amounts of body weight, according to newly reported data from a phase II trial.

The results were published online Monday in the New England Journal of Medicine, with Ania M. Jastreboff, MD, PhD (Yale School of Medicine, New Haven, CT), as lead author, to coincide with their presentation at the American Diabetes Association’s 85^th Scientific Sessions.

Like semaglutide (Wegovy; Novo Nordisk), MariTide is a glucagon-like peptide-1 (GLP-1) agonist, and like tirzepatide (Zepbound; Eli Lilly), it has a second mechanism that relates to glucose-dependent insulinotropic polypeptide (GIP) receptors. While tirzepatide works as a GIP receptor agonist, maridebart cafraglutide works as an antagonist.

What’s most unique here, study co-author Donna H. Ryan, MD (Pennington Biomedical Research Center, New Orleans, LA), told TCTMD, is that MariTide was given as a monthly rather than weekly injection in the trial. Its half-life is 21 days, approximately three times what’s seen with the once-weekly obesity drugs currently on the market.

For weight loss, maridebart cafraglutide is likely to be similar to tirzepatide, but “it appears that the efficacy is more than you get with just GLP-1 [agonism] alone,” she said. It’s possible the newer drug will be even more powerful since weight loss had yet to stall by 52 weeks, added Ryan. “We don’t really have the nadir yet.”

Forthcoming data will clarify how far MariTide doses can be spaced out, Ryan explained. “There is the potential that once patients . . . reach the amount of weight loss they want, maybe we could give this every 2 months or even longer.”

Though the specifics still have to be worked out, she cautioned, longer duration of action is quite appealing. “It’s great not to take a shot every day. It’s wonderful to take it once a week, but it is fantastic to take it once a month,” said Ryan. “And what if we could give this every 6 months?”

Early Signs of Cardiometabolic Benefits

For the phase II, double-blind trial, investigators enrolled two cohorts: patients with obesity but not type 2 diabetes (the obesity cohort) and those who had both conditions (the obesity-diabetes cohort). The primary endpoint in both groups was the percent change in body weight from baseline to week 52.

Patients in the obesity cohort (n = 465; mean age 47.9 years; 63% female; mean body mass index 37.9) were randomized to receive placebo or maridebart cafraglutide at doses of:

• 140, 280, or 420 mg every 4 weeks without dose escalation
• 420 mg every 8 weeks without escalation
• 420 mg every 4 weeks with 4-week escalation
• 420 mg every 4 weeks with 12-week escalation

Patients in the obesity-diabetes cohort (n = 127; mean age 55.1 years; 42% female; mean body mass index 36.5) were randomized to receive maridebart cafraglutide at doses of 140, 280, or 420 mg every 4 weeks (all without dose escalation) or placebo.

In the obesity cohort, the mean percent reduction in body weight from baseline to week 52, calculated as intention-to treat, ranged from 12.3% to 16.2% with MariTide and was 2.5% with placebo. In the obesity-diabetes cohort, weight loss ranged from -8.4% to -12.3% with MariTide and was -1.7% with placebo.

“A weight plateau was not reached at 52 weeks, with weight continuing a downward trajectory; therefore, longer-term trials are needed to assess the full weight efficacy of this agent,” the researchers note. Part 2 of the current trial, an extension study, “will help to determine the weight plateau and nadir and whether weight reduction is maintained with lower doses or less frequent administration.”

Glycated hemoglobin levels also moved in the right direction with maridebart cafraglutide, ranging from -1.2 to -1.6 percentage points, as compared with a 0.1 rise with placebo. Other positive changes were noted with regard to waist circumference, body mass index, systolic and diastolic blood pressure, diastolic blood pressure, high-sensitivity C-reactive protein, lipid levels, and reduction in fat versus lean mass.

More than 90% of patients in each cohort experienced an adverse event, as compared with 68% and 81% of those on placebo in the obesity and obesity-diabetes groups, respectively. Two deaths occurred in the MariTide-treated patients, though both were deemed unrelated to the medication by site investigators. The prevalence of injection-site reactions did not differ between the drug and placebo, nor did the prevalence of depressive disorder or suicidal behavior or ideation.

GI events were common, though less so among patients who were randomized to dose escalation and those who started at a lower dose. These events were mostly mild-to-moderate and included nausea, vomiting, constipation, retching, and diarrhea. Eight percent of study participants assigned to dose escalation in the obesity group discontinued MariTide due to GI adverse events, as compared with 12-27% of patients without dose escalation in the obesity cohort and 6-16% of patients in the obesity-diabetes cohort.

It’s great not to take a shot every day. It’s wonderful to take it once a week, but it is fantastic to take it once a month. Donna H. Ryan

Much is left to be learned about maridebart cafraglutide, said Ryan. For instance, the fact that there are positive effects here with GIP antagonism, and also with tirzepatide’s GIP agonism, isn’t fully understood. “This is an entirely different compound than we’re used to using,” she said in reference to the size of the monoclonal antibody. Also unknown is the duration of efficacy, something that will be looked at in the extension study, which Ryan predicted will release results about 1 year from now.

For clinicians, she said, the message for now is: “Watch this space.” And for patients, too, these developments are good news, said Ryan. “More competition means better drugs and lower prices.”

Amgen, in a press release, highlighted the phase III MARTIME trials of chronic weight management in patients with and without diabetes, which are currently enrolling participants. Later this year, phase III trials are planned to launch in patients with atherosclerotic cardiovascular disease, heart failure, and obstructive sleep apnea.