A new once-a-month injection helped people with obesity shed up to 16% of their body weight, offering fresh hope for effective, long-acting treatments. Can this breakthrough change the landscape for obesity care?
Study: Once-Monthly Maridebart Cafraglutide for the Treatment of Obesity — A Phase 2 Trial. Image Credit: 279photo Studio / Shutterstock
A phase 2 randomized controlled trial of maridebart cafraglutide, a long-acting peptide-antibody conjugate, revealed that the drug is capable of significantly reducing body weight in obese individuals with or without diabetes, with just one dose every four weeks. One group in the trial received the drug every eight weeks. The findings of the trial are published in The 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 rapidly increasing worldwide, partly because of unhealthy lifestyle habits. According to the 2022 World Health Organization (WHO) report, approximately 890 million adults and 160 million children and adolescents were living with obesity worldwide.
Among existing therapeutics, once-weekly hormone receptor modulators, such as semaglutide and tirzepatide, have shown promising outcomes in terms of body weight reduction and management of obesity-related complications. However, access and adherence remain the major barriers to treatment. Medication administered at less frequent intervals may enhance treatment adherence, a crucial factor for achieving optimal outcomes.
This Phase 2 trial was designed to evaluate the effect of maridebart cafraglutide, also known as MariTide or AMG133, from Amgen, on body weight reduction and blood glucose regulation in obese individuals with or without diabetes.
Maridebart cafraglutide is a long-acting molecule that combines a glucagon-like peptide-1 (GLP-1) receptor agonist and a glucose-dependent insulinotropic polypeptide (GIP) receptor antagonist. Genetic evidence supports the rationale for GIP antagonism, as variants linked to reduced GIP signaling are associated with lower BMI.
Trial design
The trial was conducted on 592 adult individuals, including 465 individuals with obesity and 127 individuals with obesity and diabetes. The efficacy, safety, and side effects of maridebart cafraglutide were assessed at various doses, with or without dose escalation.
Maridebart cafraglutide was injected subcutaneously to the participants once 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.
Body weight, glycated hemoglobin level (a measure of glycemic control), and various glucose metabolism parameters of participants were measured after 52 weeks of maridebart cafraglutide administration.
Key findings
The trial findings indicated that once-monthly maridebart cafraglutide caused a 12.3% to 16.2% reduction in mean body weight among participants with obesity following 52 weeks of treatment. In contrast, the control group participants who did not receive maridebart cafraglutide experienced a 2.5% reduction in body weight during the same period. This result is based on a conservative 'treatment policy' analysis; 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, the reduction in body weight was 8.4% to 12.3% following the 52-week maridebart cafraglutide treatment. The control group participants, however, experienced only a 1.7% reduction. The efficacy analysis for this group showed a mean weight reduction of up to 17.0%.
Regarding obesity-related complications, the trial findings revealed that the maridebart cafraglutide treatment was associated with greater improvements in glycated hemoglobin levels in obese participants with or without diabetes. However, the reductions in glycated hemoglobin were small (–0.3 to –0.4 percentage points) in participants without diabetes, and more pronounced (–1.2 to –1.6 percentage points) in those with diabetes.
Among body composition measures, reductions in fat mass and lean mass due to maridebart cafraglutide treatment were 26.2% to 36.8% and 8.6% to 11.6%, respectively, among obese participants. 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 maridebart cafraglutide treatment group reported at least one adverse event, irrespective of causality. The most commonly reported adversities were gastrointestinal symptoms, including nausea, vomiting, constipation, retching (dry heaves), and diarrhea.
The incidence of gastrointestinal adverse events was higher in the groups with no 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 assessed as unrelated to the drug. Gallbladder-related events were more frequent in the maridebart cafraglutide groups than in the placebo group. No unexpected safety signals emerged during the trial period.
Significance
This Phase 2 dose-ranging trial demonstrates that maridebart cafraglutide, with a once-monthly or less frequent treatment regimen, is capable of significantly reducing body weight and improving glycemic control in obese adults with or without diabetes. These findings, together with the acceptable safety profile of maridebart cafraglutide, support advancement to a phase 3 trial.
Existing evidence indicates that a weight reduction of at least 15% is associated with clear improvements in health outcomes. In this trial, approximately 50% of participants experienced at least a 15% weight reduction with the highest dose of maridebart cafraglutide, based on a conservative analysis. Under the efficacy estimand, three-quarters of participants achieved 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 underscore the need for longer-term trials to fully assess the weight efficacy of this long-acting peptide–antibody conjugate.
Maridebart cafraglutide is composed of two identical GLP-1 peptide analogues conjugated to a single monoclonal antibody antagonist to the GIP receptor. It has a half-life of 21 days, which is 3 times greater than the existing longest-acting once-weekly obesity medications. The monoclonal antibody backbone targeting the GIP receptor is responsible for such long-term functioning of maridebart cafraglutide, making it a medication of choice for increasing treatment adherence and mitigating treatment burden. This mechanism is notable given the genetic and pharmacological context, as both GIP antagonism (as in maridebart cafraglutide) and GIP agonism (as in tirzepatide) have been effective when combined with GLP-1 agonism, highlighting an area of active scientific investigation.
Notably, the trial findings suggest that the use of dose escalation and lower starting doses is associated with better management of side-effects, supporting the initiation of maridebart cafraglutide treatment at a lower starting dose and with more gradual dose escalation. In the ongoing phase 3 trial of maridebart cafraglutide, dose escalation is being implemented in all the trial groups with a more gradual approach. The authors also acknowledged the trial's limitations, including the need for longer-term data to determine maximum weight loss, which will be addressed in future studies.