A once-monthly obesity injection shows double-digit weight loss in key clinical trial

A once-monthly obesity injection shows double-digit weight loss in key clinical trial

A new once-a-month injection helped people with obesity up to 16% of their body weight, offering fresh hope for effective, long-acting treatments. Can this breakthrough change the landscape for obesity care?

A phase 2 randomized controlled trial of Maridbart cafraglutide, a long-acting peptide-antibody conjugate, found that the drug is capable of significantly reducing body weight in obese individuals with or without diabetes, using only one dose every four weeks. One group in the study received the drug every eight weeks. The results of the experiment will be published inThe New England Journal of Medicine.

background

Obesity is a chronic metabolic condition characterized by the excessive accumulation of fat in the body, particularly in the abdominal region. The condition can potentially increase the risk of several other health complications, including type 2 diabetes and cardiovascular disease.

The prevalence of obesity is increasing rapidly worldwide, in part because of unhealthy lifestyle habits. According to the World Health Organization (WHO) 2022 report, around 890 million adults and 160 million children and adolescents worldwide lived with obesity.

Among existing therapeutics, once-weekly hormone receptor modulators such as semaglutide and tirzepatide have shown promising results in reducing body weight and treating obesity-related symptoms. However, access and adherence remain key barriers to treatment. Medications given at less frequent intervals can improve the effectiveness of treatments, a critical factor in achieving optimal results.

This phase 2 study was designed to evaluate the effect of Amgen's Maridbart cafraglutide, also known as Maritid or AMG133, on body weight reduction and blood glucose regulation in obese individuals with or without diabetes.

Maridbart Cafraglutide is a long-acting molecule that combines a glucagon-like peptide-1 (GLP-1) receptor agonist and a glucose-dependent insulinotropic polypeptide receptor receptor antagonist. Genetic evidence supports the reasons for GIP antagonism, as variants associated with reduced GIP signaling are associated with lower BMI.

Experimental design

The study was conducted on 592 adults, including 465 people with obesity and 127 people with obesity and diabetes. The efficacy, safety and side effects of Maridbart cafraglutide were evaluated at different doses with or without dose escalation.

Maridbart cafraglutide was injected subcutaneously into participants every four weeks, with one group receiving injections every eight weeks. The dual mode of action and longer half-life of the intervention molecule supported monthly or less frequent administration.

Participants' body weight, glycated hemoglobin levels (a measure of glycemic control) and various parameters of glucose metabolism were measured after 52 weeks of Maridbart cafaglutide administration.

Key Findings

The trial results showed that once monthly Maridbart cafraglutide caused a reduction in mean body weight from 12.3% to 16.2% in participants with obesity after 52 weeks of treatment. In contrast, participants in the control group who did not receive Maridbart cafraglutide experienced a 2.5% reduction in body weight over the same period. This result is based on a conservative analysis of treatment policy. A separate “efficacy analysis,” which estimates the effect under ideal conditions, showed an even greater mean weight reduction of up to 19.9%.

In obese participants with diabetes, reductions in body weight after 52 weeks of Maridbart cafaglutide treatment were 8.4% to 12.3%. However, control group participants only experienced a 1.7% reduction. The effectiveness analysis for this group showed a mean weight reduction of up to 17.0%.

Regarding obesity-related complications, study results showed that Maridbart carraglutide treatment was associated with greater improvement in glycated hemoglobin levels in obese participants with or without diabetes. However, the reduction in glycated hemoglobin was small in participants without diabetes (−0.3 to −0.4 percentage points) and more pronounced in those with diabetes (−1.2 to −1.6 percentage points).

Among body composition measures, reductions in fat mass and lean mass due to Maridbart cafraglutide treatment in obese participants were 26.2% to 36.8% and 8.6% to 11.6%, respectively. In obese participants with diabetes, fat mass and lean mass reductions were 17.4% to 33.7% and 6.8% to 9.6%, respectively.

Safety and side effects

Almost all participants in the Maridbart cafaglutide treatment group reported at least one adverse event, regardless of causality. The most commonly reported adversities were gastrointestinal symptoms, including nausea, vomiting, constipation, cheaters (dry piles), and diarrhea.

The incidence of gastrointestinal adverse events was higher in the groups without dose escalation and lower in the groups with dose escalation and a lower starting dose. Most adverse events were mild to moderate in intensity, although a small number of serious adverse events were also reported. Two deaths occurred in the treatment groups, both of which were deemed unrelated to the drug. Gallbladder-related events were more common in the Maridbart cafraglutide groups than in the placebo group. No unexpected safety signals emerged during the experimental period.

Meaning

This Phase 2 dose-response study shows that Maridbart cafraglutide, with a once-monthly or less frequent treatment regimen, is able to significantly reduce body weight and improve glycemic control in obese adults with or without diabetes. These results, along with the acceptable safety profile of Maridbart cafraglutide, support progression to a Phase 3 trial.

Existing evidence shows that weight reduction of at least 15% is associated with clear improvements in health outcomes. In this study, approximately 50% of participants experienced at least a weight reduction of at least 15%, with the highest dose of Maridbart cafraglutide based on a conservative analysis. According to the efficacy estimate, three quarters of participants reached this milestone. Furthermore, body weight continued to follow a downward trajectory and did not reach a plateau during the 52-week trial period. These benefits highlight the need for longer-term studies to fully evaluate the weight efficacy of this long-acting peptide-antibody conjugate.

Maridbart cafraglutide consists of two identical GLP-1 peptide analogues conjugated to a single monoclonal antagonist against the GIP receptor. It has a half-life of 21 days, which is three times longer than existing longest-acting, weekly obesity medications. The monoclonal antibody backbone that targets the GIP receptor is responsible for how Maridbart cafraglutide works so long-term, making it a drug of choice for increasing treatment drive and reducing treatment burden. This mechanism is notable given the genetic and pharmacological context, as both GIP antagonism (as with Maridbart cafraglutide) and GIP agonism (as with tirzepatide) were effective in combination with GLP-1 agonism, highlighting an area of ​​active scientific investigation.

In particular, the trial results suggest that the use of dose escalation and lower starting doses is associated with better management of adverse reactions, supporting initiation of Maridbart cafaglutide treatment at a lower starting dose and with more gradual dose escalation. In the ongoing Phase 3 trial of Maridbart cafraglutide, dose escalation is being implemented in all trial groups using a more gradual approach. The authors also acknowledged the limitations of the trial, including the need for longer-term data to determine maximum weight loss, which will be addressed in future studies.

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