Novel drug confers weight loss of up to 20% at 1 year in phase 2 study
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Key takeaways:
- Maridebart cafraglutide reduced body weight by up to 20% at 1 year in patients with overweight or obesity without a weight loss plateau.
- The drug also improved other cardiometabolic parameters vs. placebo.
Maridebart cafraglutide, a novel injectable GLP-1 receptor agonist/GIP receptor antagonist, reduced body weight by up to approximately 20% at 1 year in patients with overweight or obesity without a weight loss plateau, according to a presentation.
Results from a double-blind, dose-ranging phase 2 study of maridebart cafraglutide (MariTide, Amgen) were presented at the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.
“MariTide is a first-of-its-kind peptide antibody conjugate that activates the GLP-1 receptor and simultaneously antagonizes or blocks the GIP receptor,” Narimon Honarpour, MD, PhD, senior vice president of global development for Amgen, said during a presentation. “This construction portends a long half-life with sustained predictable exposure. It also allows us to appreciate the synergistic effect on these signaling mechanisms initially suggested by preclinical models."
Phase 2 study of weight loss
The study covered two cohorts, the first of which consisted of 465 patients with overweight or obesity but no diabetes (63% women; mean BMI, 38 kg/m2), and the second of which consisted of 127 patients with overweight or obesity and diabetes (42% women; mean BMI, 36 kg/m2).
For the cohort without diabetes, patients were assigned to placebo or one of the following maridebart cafraglutide regimens: 140 mg monthly; 280 mg monthly; 420 mg monthly; 420 mg every other month; a dose escalation strategy of 70 mg administration at baseline and again at 2 weeks followed by 420 mg monthly; and a dose escalation strategy of 70 mg administration at baseline, 140 mg at 4 weeks, 280 mg at 8 weeks followed by 420 mg monthly.
In that cohort, at 1 year, all regimens of maridebart cafraglutide were associated with significant weight loss. The highest average weight loss observed in any treatment arm was approximately 20%, without a weight loss plateau, Honarpour said.
Also at 1 year, systolic blood pressure was reduced by 11 mm Hg in those assigned to the maridebart cafraglutide 420 mg target dose compared with a reduction of 3 mm Hg in the placebo group; LDL cholesterol was reduced by 5% in those assigned maridebart cafraglutide 420 mg compared with an increase of 1% in the placebo group; triglycerides were reduced 19% in those assigned maridebart cafraglutide 420 mg compared with an increase of 1% in the placebo group; and high-sensitivity C-reactive protein was reduced by 53% in those assigned maridebart cafraglutide 420 mg compared with an increase of 1% in the placebo group, Honarpour said.
For the cohort with diabetes, patients were assigned placebo or one of the following maridebart cafraglutide regimens: 140 mg monthly, 280 mg monthly or 420 mg monthly.
At 1 year, maridebart cafraglutide 420 mg monthly was associated with weight loss of approximately 17% without a weight loss plateau, compared with a loss of approximately 10% for the other maridebart cafraglutide groups and virtually no weight loss for the placebo group, according to the researchers.
Maridebart cafraglutide reduced HbA1c by approximately 2.2 percentage points at 1 year compared with an increase of 0.1 percentage points for the placebo group, Honarpour said.
Also at 1 year, systolic BP was reduced by 11 mm Hg in those assigned maridebart cafraglutide 420 mg compared with a reduction of 2 mm Hg in the placebo group; glucose was reduced by 58 mg/dL in those assigned maridebart cafraglutide 420 mg compared with an increase of 22 mg/dL in the placebo group; triglycerides were reduced 28% in those assigned maridebart cafraglutide 420 mg compared with an increase of 21% in the placebo group; and high-sensitivity C-reactive protein was reduced by 72% in those assigned maridebart cafraglutide 420 mg compared with a reduction of 25% in the placebo group, Honarpour said.
Most patients finished the study and of those eligible to participate in part two of the trial, more than 90% agreed to continue for the additional year, he said.
There was no association between maridebart cafraglutide and changes in bone mineral density, and changes in heart rate were consistent with those for other approved weight-loss drugs, he said.
The most common adverse events were gastrointestinal, almost all were mild or moderate, with a majority associated with the first dose of maridebart cafraglutide, he said, noting that dose escalations with lower starting doses improved gastrointestinal tolerability.
Future research
Part two of the study, which includes patients who lost at least 15% of body weight in part one and who will be evaluated for another year, is underway, he said.
“The intention of part two is to understand more about the weight reduction effects of MariTide. For example, how long the weight reduction would last by re-randomizing some patients who were receiving MariTide in part one to placebo,” he said. “We also wanted to understand what doses would be necessary for maintenance, so some patients that received MariTide in part one were re-randomized to a lower dose, and for patients on the 420 mg regimen, to assess how much additional weight reduction could be achieved from part one, some patients continued 420 mg [monthly]. Lastly, some patients receiving 420 mg from part one were re-randomized to 420 mg every quarter.”
Amgen's phase 3 MARITIME clinical program will evaluate maridebart cafraglutide for treatment of patients with overweight or obesity, and potentially type 2 diabetes, kidney disease, cardiovascular disease, heart failure, obstructive sleep apnea and/or other conditions, Honarpour said.
“This is the first obesity treatment being investigated with a monthly or less frequent dosing regimen,” Honarpour said during the presentation. “We saw substantial improvements across a variety of cardiometabolic parameters.”
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Honarpour N. Session 13: A glimpse into the future – What’s in the pipeline? Presented at: World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease; December 12-14, 2024; Los Angeles.
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