Investigational monthly obesity drug led to durable weight loss in phase 1 trial
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Key takeaways:
- Maridebart cafraglutide induced dose-dependent weight loss for adults with obesity in a phase 1 trial.
- Nausea and vomiting were the most common adverse events reported.
Adults with obesity who received an injectable GIP receptor antagonist/GLP-1 receptor agonist every 4 weeks had a decrease in body weight that was maintained for up to 150 days, according to study findings published in Nature Metabolism.
In a phase 1 randomized placebo-controlled trial, adults aged 18 to 65 years with obesity and without diabetes were randomly assigned to maridebart cafraglutide (formerly AMG 133, Amgen) or placebo. Adults receiving maridebart cafraglutide were placed in one of six single-ascending dose groups or one of three multiple-ascending dose groups. All of the maridebart cafraglutide groups achieved a body weight reduction in the study and most adverse events were gastrointestinal-related and mild.
“The safety and tolerability profiles, the longer half-life of AMG 133 allowing for extended dosing intervals and the magnitude and durability of weight loss support continued evaluation of AMG 133 in a phase 2 setting,” Murielle M. Véniant, PhD, executive director of research and development at Amgen, and colleagues wrote.
In the single-dose portion of the phase 1 trial, 49 adults were randomly assigned to one dose of 21 mg, 70 mg, 140 mg, 280 mg, 560 mg or 840 mg maridebart cafraglutide or placebo and were followed for up to 150 days. For the multiple-ascending dose portion of the trial, 26 adults were randomly assigned to 140 mg, 280 mg or 420 mg maridebart cafraglutide or placebo and were followed for up to 207 days. Participants in the multiple-ascending dose groups received maridebart cafraglutide or placebo every 4 weeks. The trial’s primary endpoints were treatment-emergent adverse events, changes in laboratory safety events, vital signs and 12-lead ECGs. Exploratory endpoints included changes in body weight, waist circumference, BMI, fasting glucose, insulin, C-peptide, glucagon, free fatty acids, lipids and HbA1c.
Adults receiving maridebart cafraglutide had decreases in body weight that varied depending on dose. From baseline, those in the 21 mg group had a decrease in body weight of 2.4% at 29 days, and those receiving the 840 mg lost 8.2% of their body weight at 92 days. The single-ascending dose placebo group had a 1.7% body weight increase at 92 days.
For adults receiving multiple doses, the 140 mg group lost 7.4% of their body weight at 78 days and the 420 mg group lost 14.5% of their body weight at day 85. The multiple-dose placebo group gained 1.5% of their body weight at 85 days. The 420 mg group maintained a body weight reduction of 11.2% at 150 days after the final dose of the medication.
The multiple-dose groups had a decrease in fasting glucose from baseline to day 85. Fasting glucagon decreased in all groups, but normalized within the 280 mg and 420 mg groups at day 169. Adults receiving maridebart cafraglutide had greater increases in free fatty acids compared with placebo.
“The overall changes observed in weight and metabolic parameters for both preclinical and clinical studies suggest strong incretin-related effects,” the researchers wrote. “Further investigation is still needed to optimize the dosing regimen of AMG 133 for weight loss and other metabolic effects.”
The most common treatment-emergent adverse events were gastrointestinal symptoms such as nausea and vomiting. Symptoms were mostly mild and resolved 48 hours after receiving maridebart cafraglutide. No severe or serious adverse events leading to discontinuation of the drug were reported, and there were no cases of hypoglycemia related to treatment. There were no clinically meaningful changes in blood pressure after maridebart cafraglutide administration, and heart rate changes remained in the normal range.
“The safety profile of AMG 133 was similar to that of GLP-1 receptor agonists, including unimolecular GLP-1/GIP receptor agonist peptides,” the researchers wrote.
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