58. Maritide: Once-a-Month GLP-1 Injection for Weight Loss.

A Phase 2 study shows promising results.

Obesity increasingly influences the landscape of chronic disease management. The utilization of medications for weight reduction has risen, notably following the success of GLP-1 receptor agonists. These agents have demonstrated considerable potential in facilitating weight loss and transforming the treatment approach for metabolic diseases both in the United States and worldwide. Today, we shall focus on the investigational drug, Maritude or Maridebart cafraglutide. This long-acting peptide-antibody conjugate has been shown to significantly decrease body weight in obese individuals, regardless of the presence of diabetes, with a regimen of one dose administered every four to eight weeks. The results of this study have been published in the New England Journal of Medicine.

Obesity is a long-term metabolic condition marked by too much fat storage in the body. It can raise the risk of several other health issues, including type 2 diabetes and heart disease. The global obesity rate is rising fast, partly due to unhealthy lifestyles. According to the World Health Organization's 2022 report, nearly a billion people are obese.

Among available weight loss medications, weekly hormone receptor modulators like semaglutide and tirzepatide have shown encouraging results in reducing body weight and managing obesity-related problems. However, getting treatment and sticking to it can be tough. Giving medications less often may help people stick to their treatment plan, which is key to getting the desired results.

Maridebart cafraglutide is a promising new treatment that combines two powerful approaches to help manage obesity and blood sugar levels. It features two identical GLP-1 peptide analogues attached to a monoclonal antibody that blocks the GIP receptor, giving it a 21-day half-life—three times longer than current weekly medications. This extended duration can make adherence easier and reduce the overall treatment burden. What's exciting is that both GIP antagonism, as in maridebart cafraglutide, and GIP activation, as in tirzepatide, have shown effectiveness when paired with GLP-1 stimulation, making this an exciting area of ongoing research. In clinical trials, gradually increasing the dose from a lower starting point has proven to help with tolerability, and this method is now being used in ongoing Phase 3 studies. While these early results are encouraging, longer-term data will be essential to understand how much weight can ultimately be lost.

A Phase 2 study is the second stage of human clinical trials, designed to assess whether a new drug or treatment is effective for the target condition while continuing to monitor its safety. Unlike Phase 1, which mainly focuses on safety in small groups, Phase 2 involves a larger number of participants, typically ranging from a few dozen to a few hundred, who have the condition being treated. These studies often test different doses to find the best balance between effectiveness and side effects, and they are usually randomized and controlled, comparing the new treatment to a placebo or standard therapy. Phase 2 trials can last several months to a few years, depending on the disease and drug. If the results show that the treatment works and has an acceptable safety profile, the drug moves on to Phase 3, where it will be tested in much larger populations to confirm its benefits and identify rare side effects.

A clinical trial with 592 adult participants, including 465 with obesity and 127 with both obesity and diabetes, explored how effective and safe maridebart cafraglutide is. The study looked at different dosing plans, some with and some without increasing the dose. Participants received injections under the skin either once every four weeks or, in one group, every eight weeks. The drug’s dual action and long-lasting effects made these less frequent doses possible. After 52 weeks, researchers checked body weight, HbA1c levels, and other measures related to blood sugar to see how well the treatment worked.

The trial results showed that once-monthly maridebart cafraglutide helped participants with obesity lose a significant amount of weight, ranging from 12.3% to 16.2% over a year, while the control group saw just a 2.5% decrease. Under ideal conditions, the weight loss was even more impressive, reaching up to 19.9%. For those with obesity and diabetes, the medication led to weight reductions between 8.4% and 12.3%, compared to only 1.7% in the control group, with some cases showing up to 17.0% loss. The treatment also helped improve blood sugar control, with modest decreases in non-diabetic participants (about 0.3 to 0.4 percentage points) and more notable improvements (around 1.2 to 1.6 points) in individuals with diabetes. Furthermore, the analysis of body composition revealed that maridebart cafraglutide significantly decreased both fat and lean mass. Specifically, fat mass among obese participants dropped by 26.2% to 36.8%, and lean mass by 8.6% to 11.6%. Participants with diabetes saw fat mass decrease by 26.2% to 36.8%, and lean mass by 6.8% to 9.6%.

Almost all participants taking maridebart cafraglutide reported at least one side effect, regardless of whether it was directly related to the drug. The most common side effects were gastrointestinal, including nausea, vomiting, constipation, retching, and diarrhea. These symptoms were more likely to occur among participants who received higher initial doses without gradually increasing them. In contrast, those in groups with lower starting doses and dose escalation reported fewer gastrointestinal issues. Most adverse events were considered mild to moderate, although a small number of serious adverse events did happen. Two deaths were reported in the treatment groups, but neither was linked to the drug. Participants taking maridebart cafraglutide also experienced more gallbladder-related events than those in the placebo group. However, no unexpected safety concerns were raised during the trial.

This exciting Phase 2 trial shows that maridebart cafraglutide, which can be administered once a month or even less frequently, offers meaningful help in reducing body weight and enhancing blood sugar control for obese adults, whether they have diabetes or not. The safety profile is quite reassuring, making it a hopeful candidate for upcoming Phase 3 studies. It's especially encouraging that about half of the participants taking the highest dose experienced at least a 15% weight loss in a cautious analysis, with the figure rising to 75% in a more optimistic view. Even more promising is that weight loss persisted beyond 52 weeks, underscoring the importance of long-term research. Many exciting drugs targeting diabetes and metabolic health are on the horizon, building on the success of current GLP1 agonists like Tirzepatide (Mounjaro) and Semaglutide (Ozempic).

Suman Manchireddy MD

Board Certified in Internal Medicine and Obesity Medicine

Reliant MD Group LLC

Leesburg, VA 20176

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References :

1. Monthly Maridebart Cafraglutide Treatment for Obesity: A Phase 2 Study, NEJM 2025

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Disclaimer: This is for purely informational and educational purposes only. Seek medical advice before starting any testing or treatment regimen. The data presented here has been extensively researched and condensed for a broader audience, and it should be viewed for educational purposes only. The blogger or blog has no affiliation with any pharmaceutical company.