Novel GIP receptor antagonist/GLP-1 receptor agonist for obesity safe in phase 1 trial
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A novel bispecific GIP receptor antagonist and GLP-1 receptor agonist induced weight loss of up to 14.5% in adults with obesity with no safety concerns, according to data from a phase 1 trial.
In findings presented at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease, nearly all treatment-emergent adverse events reported among adults with obesity receiving either single or multiple doses of AMG 133 (Amgen) were mild in nature. The agent also induced significantly greater weight loss in participants receiving a single dose and multiple doses compared with those receiving placebo.
“The safety, tolerability and pharmacokinetic profile, as well as the magnitude, rapidity and durability of weight loss support further clinical development of AMG 133,” Jane Parnes, MD, executive medical director of medical sciences at Amgen, said during a presentation. “We’re looking forward to starting our phase 2 trial early next year.”
Researchers conducted a randomized, double-blind placebo-controlled trial enrolling adults with a BMI between 30 and 40 kg/m2 but no diabetes or other medical conditions. The study included two cohorts, with the first cohort receiving a single dose of 21 mg, 70 mg, 140 mg, 280 mg, 560 mg or 840 mg of AMG 133, or placebo (n = 49). The second cohort was a multiple-dose group where participants received either 140 mg, 280 mg or 420 mg of AMG 133 in three-week intervals, with each dose given four times per week (n = 26), or placebo. Participants in both cohorts were randomly assigned, 3:1, to subcutaneous AMG 133 or placebo. The primary endpoints were the incidence of treatment-emergent adverse events and changes in vital signs, electrocardiograms and laboratory safety tests. Body weight change was measured as a pharmacodynamic secondary endpoint.
In the single-dose cohort, all participants receiving AMG 133 had greater weight loss compared with placebo at 30 days. The weight loss persisted among some participants for up to 120 days. In the multiple-dose cohort, all three AMG 133 groups had a significantly greater weight loss compared with placebo at 90 days. The greatest mean weight loss was 14.5% at 90 days in the 420 mg group. The weight loss in the multiple-dose group was maintained up to 150 days after the final dose of the agent, particularly in the 280-mg group and the 420-mg group, Parnes said.
Among the single dose cohort, treatment-emergent adverse events were reported in most participants receiving 140 mg of AMG 133 or higher. Two adverse events were moderate, with the rest being labeled as mild. In the multiple dose cohort, all AMG 133 participants reported adverse events, with all events reported as mild.
“The majority of the treatment-emergent adverse events were gastrointestinal-related, which is what we expected from the GLP-1 agonism, with the most common being nausea and vomiting,” Parnes said. “Among all subjects, most were mild and resolved within 48 hours.”
Parnes also noted that among participants in the multiple-dose group, more than 90% of the gastrointestinal adverse events were after the first dose and less than 6% occurred after the second or third dose.
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Parnes J. Session 21: Late breaking: A phase 1 study of AMG 133 in subjects with obesity. Presented at: World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease; Dec. 1-3, 2022; Universal City, California (hybrid meeting).
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