In the last several years, we have seen weight management medications evolve from once, twice or thrice daily options, to include once weekly options like semaglutide (Wegovy) and tirzepatide (Mounjaro/Zepbound). What if the next generation of medications could produce treatments given even less often, like once a month? Maridebart cafraglutide (MariTide for short) is an injectable (under the skin) GLP1 receptor agonist / GIP receptor antagonist which is being studied with that goal in mind.

(Note: readers who know tirzepatide (Mounjaro/Zepbound) as a GLP1/GIP dual receptor AGONIST (stimulator) may wonder how MariTide as a GIP ANTAGONIST could also cause weight loss? There is evidence that both GIP agonism and antagonism lead to weight reduction, though we still don’t understand exactly how.)

At the recent American Diabetes Association meeting, results from a phase 2 trial of MariTide were presented and simultaneously published in the New England Journal of Medicine.

This 52 week study randomized 592 patients with obesity into one of eleven different treatment arms, with two cohorts, one cohort without diabetes, and one cohort with diabetes. Various doses and dosing regimens of MariTide were tested, some with gradual dose escalation, some without dose escalation, and with placebo comparisons. Most dose regimens were once a month, with one arm receiving doses every 2 months.

Amongst the 465 people in the trial without diabetes, weight loss ranged from -12.3% to -16.2% with MariTide, vs -2.5% with placebo. Amongst the 127 people with diabetes, weight loss ranged from -8.4% to -12.3% with MariTide, vs -1.7% with placebo. Hemoglobin A1c (diabetes report card) improved by -1.2 to -1.6% with MariTide, vs an increase of 0.1% with placebo. There were improvements in metabolic health parameters with MariTide, such as blood pressure, cholesterol, and hsCRP (a marker of inflammation). The study also looked at bone density in a subset of patients, finding no substantial changes in bone density in the spine, and changes in the hip consistent with studies of diet induced weight loss (we know that bone density naturally decreases with weight loss, so it would be great to see a treatment emerge that could preserve bone as body weight goes down).

Gastrointestinal (GI) side effects were most common, but less frequent with lower starting doses and with gradual escalation in dosage. Eight percent of people in the dose escalation cohorts and 6-27% of people in the no-dose-escalation groups stopped treatment because of GI side effects. This study took an interesting approach to evaluate GI side effects – in addition to standard (unsolicited) side effect reporting, they used a modified patient reported outcome tool used in chemotherapy trials to assess nausea, vomiting and retching in some of the treatment arms. Just like in real world clinical practice, I actually think that GI side effects are often ‘solicited’ (purposely asked about) in clinical trials already, because we know they can happen with obesity medications. But I think it’s a really neat idea to ask these questions on a scoring scale in this systematic way in real life and clinical trials, as this could be helpful to manage the dosage accordingly to minimize side effects.

BOTTOM LINE: This phase 2 study of MariTide is promising in its development as an obesity medication, demonstrating robust weight loss and metabolic health improvements. A slow, gentle dose escalation may be just what is needed here to minimize gastrointestinal side effects. I will look forward to phase 3 data exploring MariTide for weight management and improvement in weight-related health conditions.

Disclaimer: I am involved in clinical trials of maritide, semaglutide, and tirzepatide. I receive honoraria as a consultant with the makers of MariTide (Amgen), semaglutide (Novo Nordisk), and tirzepatide (Eli Lilly).

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