Eli Lilly’s retatrutide - an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1 and glucagon receptor - has a mean weight reduction up to 24.2% at 48 weeks and achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight. The results were presented in a symposium at the American Diabetes Association's 83rd Scientific Sessions and were simultaneously published in The New England Journal of Medicine.
"Obesity is a treatable chronic disease with a complex underlying biology. We are now in the midst of a rapidly expanding therapeutic landscape of potential highly effective treatment options for individuals with obesity," said Dr Ania Jastreboff, Associate Professor of Medicine & Pediatrics, Endocrinology & Metabolism, at Yale School of Medicine; Director, Yale Obesity Research Center (Y-Weight); and co-Director of the Yale Center for Weight Management. "Participants treated with the highest dose of retatrutide achieved a mean weight reduction of 24.2%; this translates to an average absolute weight reduction of about 58 pounds over 11 months of the study. Given that participants had not yet reached a weight plateau at the time the study ended, it appears that full weight reduction efficacy was not yet attained. Longer duration phase 3 trials will enable comprehensive evaluation of efficacy and tolerability of this potential pharmacotherapeutic for the treatment of obesity."
The phase 2 study was a 48-week, randomised, double-blind, placebo-controlled trial evaluating the efficacy, tolerability, and safety of retatrutide at various doses and dose-escalation regimens in people with obesity, or overweight with weight-related conditions, except type 2 diabetes. The trial, conducted in the US, randomised 338 participants in a 2:1:1:1:1:2:2 ratio to receive retatrutide 1 mg, 4 mg (with initial dose of 2 mg), 4 mg (with initial dose of 4 mg), 8 mg (with initial dose of 2 mg), 8 mg (with initial dose of 4 mg), 12 mg (with initial dose of 2 mg) or placebo, administered subcutaneously once weekly for 48 weeks. The primary endpoint was percent change in weight from baseline at 24 weeks.
The outcomes from the phase 2 study showed that at 24 weeks, retatrutide (1 mg, 4 mg, 8 mg or 12 mg) met the primary endpoint for the efficacy estimand in participants living with obesity or overweight without diabetes, demonstrating a mean weight reduction up to 17.5% (41.2 lb. or 18.7 kg). In a secondary endpoint, retatrutide demonstrated a mean weight reduction up to 24.2% (57.8 lb. or 26.2 kg) at the end of the 48-week treatment duration.
The safety profile of retatrutide was similar to other incretin-based therapies. Gastrointestinal side effects were the most commonly reported adverse events, were generally mild-to-moderate in severity, and usually occurred during the dose escalation period.
Treatment with retatrutide was associated with improvements in cardiometabolic measures (exploratory endpoints) including systolic and diastolic blood pressure, triglycerides, LDL-cholesterol, total cholesterol, HbA1c, and fasting glucose and insulin at weeks 24 and 48.
"We believe that combining glucagon receptor agonism with GIP and GLP-1 receptor agonism may be one of the reasons retatrutide showed this level of weight reduction," said Dr Dan Skovronsky, Lilly's chief scientific and medical officer, and president of Lilly Research Laboratories. "These phase 2 data have given us confidence to further explore the potential of retatrutide in phase 3 trials that will look beyond weight reduction and focus on treating obesity and its complications comprehensively."
The TRIUMPH phase 3 development program is evaluating the safety and efficacy of retatrutide for chronic weight management, obstructive sleep apnea (OSA), and knee osteoarthritis (OA) in people with obesity and overweight. The core registration studies include:
The TRIUMPH phase 3 development program is evaluating the safety and efficacy of retatrutide for chronic weight management, obstructive sleep apnea (OSA), and knee osteoarthritis (OA) in people with obesity and overweight. The core registration studies include:
TRIUMPH-1: randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety in participants without type 2 diabetes who have obesity or overweight, including participants with OSA and OA
TRIUMPH-2: randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety in participants with type 2 diabetes who have obesity or overweight including participants with OSA
TRIUMPH-3: randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety in participants with Class II (BMI ≥ 35 kg/m2 and < 40 kg/m2) or Class III (BMI ≥ 40 kg/m2) obesity and established cardiovascular disease
TRIUMPH-4: randomised, double-blind, placebo-controlled trial to investigate the efficacy and safety in participants who have obesity or overweight with OA
To access the abstract of this paper, ‘Triple–Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial’, please click here (login required for full access)
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