Purpose:
Maridebart cafraglutide is a first-in-class, peptide-antibody combination with functional activities that antagonize glucose-dependent insulinotropic polypeptide receptor (GIPR) along with GLP-1 receptor agonism. The antagonist blocks the action of GIP, an incretin hormone, which can lead to weight loss and improved metabolic parameters. Studies have shown that GIPR antagonists, especially when combined with GLP-1 receptor agonists, can induce significant weight loss and improve insulin sensitivity. Due to the expected combined actions on appetite regulation, glucose metabolism, and cardiometabolic risk factors, maridebart cafraglutide has the potential to exceed the weight loss efficacy of GLP-1 RAs alone. Finally, its longer half-life and once monthly dose frequency have the potential to improve compliance, reduce injection burden, and enable prolonged weight loss maintenance.
This is a phase 3, randomized, double-blind, parallel-group, placebo-controlled study comparing maridebart cafraglutide with placebo in addition to standard of care for prevention of heart failure events or cardiovascular death in participants with obesity and with symptomatic heart failure with preserved and mildly reduced ejection fraction. This study will be event-driven and will enroll approximately 5000 participants. Participants will be randomized in a 1:1 ratio to receive a once-a-month injection of maridebart cafraglutide or placebo. Part 1 of the study includes a dose escalation period followed by maintaining the target dose for approximately two years. At the conclusion of Part 1 of the study, participants completed Part 1 will have the opportunity to participate in Part 2 of the study. In this part, all participants who were compliant with the study procedures and had no safety or tolerance issues will be treated with maridebart cafraglutide for approximately 2 years and followed for efficacy and safety outcomes.
Description:
Obesity is a chronic disease resulting in decreased health-related quality of life and reduced life expectancy. It has been identified as a major risk factor for the development of heart failure with preserved ejection fraction (HFpEF), otherwise known as the “stiff heart syndrome”. Patients with the “stiff heart syndrome” will often have symptoms including shortness of breath with normal activities of life, a decrease in the ability to exercise or fatigue and/or have swelling of the lower extremities known as edema. 50% of patients diagnosed with HFpEF are dead within five years of a diagnosis unless treated, nearly 80% of patients with HFpEF are either obese or are overweight. Obesity is associated with systemic inflammation and increased risk of a variety of conditions, including type II diabetes, hypertension, cholesterol disorders, sleep apnea, cardiovascular diseases, and the risk of early death. Recent studies have demonstrated marked improvement in symptoms and functional capacity in patients living with obesity and HFpEF treated with the injectable GLP-1 agonist, including semaglutide and tirzepatide. Maridebart cafraglutide, being evaluated in this study, may serve as a valuable adjunct to lifestyle intervention for individuals with obesity-related HFpEF and HFmrEF in order to achieve and sustain a clinically relevant weight loss, to improve complications, and health-related quality of life.
Key Eligibility Requirements:
(Please note: Additional eligibility requirements may be assessed at the time of study screening evaluation.)
- BMI ≥ 30 kg/m²
- Diagnosed with symptomatic heart failure, NYHA Class II-IV, not related to hypertrophic or infiltrative cardiomyopathies
- Left ventricular ejection fraction > 40%
- Heart failure hospitalization within 12 months or structural heart disease as documented on echo with:
o Average E/é ≥ 15
o Left atrial (LA) enlargement (LA width ≥ 3.8 cm, or LA length ≥ 5.0 cm, or LA area ≥ 20.0 cm², or LA volume ≥ 55 mL, or LA volume index ≥ 34 mL/m²)
o Left ventricular (LV) hypertrophy with septal thickness, or posterior wall thickness ≥ 1.2 cm
o Elevated NT-proBNP > 300 pg/mL for patients in sinus rhythm, or > 600 pg/mL for participants in active atrial fibrillation or flutter
Patients May Be Excluded From Trial Participation If They Have:
- Type 1 diabetes
- A history of chronic pancreatitis
- An estimated Glomerular Filtration Rate (eGFR) < 20 mL/min/1.73 m²
- History of malignancy within the last 5 years before screening (except for the following: non-melanoma skin cancer, breast ductal carcinoma in situ, cervical carcinoma in situ, or prostate cancer in situ)
- Use of any GLP-1 RA, GIP agonists or antagonists, or amylin analogs within 90 days before randomization
- Participants of childbearing potential are unwilling to use the protocol-specified method of contraception during treatment and for an additional 16 weeks after the last dose of the investigational product
The information we are providing includes important background on a variety of important cardiovascular conditions and ongoing clinical trials. We encourage you to use this information in discussions with your health care professional. Since enrollment in clinical trials are limited in time, we can’t guarantee their availability at any given time. However, we have continued access to new clinical trial opportunities and will share them as soon as they are available.