February 24, 2024

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Breakthrough Weight Loss Drug by Amgen: Monthly Injection Leads to Significant Weight Reduction

Breakthrough Weight Loss Drug by Amgen: Monthly Injection Leads to Significant Weight Reduction



Breakthrough Weight Loss Drug by Amgen: Monthly Injection Leads to Significant Weight Reduction

Amgen has unveiled promising clinical data for a breakthrough weight loss drug, with just one injection per month resulting in a reduction of 26 pounds after only three doses, with effects sustained for over five months.

Obesity, recognized as a heterogeneous chronic disease, has emerged as a prevalent public health issue, posing one of the greatest threats to human health and well-being in the 21st century. Complications associated with obesity impose significant burdens on both global patients and healthcare systems, underscoring the urgent need for effective and safe treatments.

Medications targeting intestinal incretin hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been utilized in the treatment of type 2 diabetes and obesity. However, there remains a demand for enhanced efficacy, improved pharmacokinetics to reduce dosing frequency, and minimized side effects.

In a groundbreaking study published in the Nature Metabolism journal titled “A GIPR antagonist conjugated to GLP-1 analogues promotes weight loss with improved metabolic parameters in preclinical and phase 1 settings,” researchers at Amgen introduced a novel dual-specificity molecule, AMG 133. This compound, combining a fully human monoclonal anti-GIPR antibody with two GLP-1 analogues, demonstrated efficacy in reducing weight in obese male mice and rhesus monkeys while improving metabolic health.

Breakthrough Weight Loss Drug by Amgen: Monthly Injection Leads to Significant Weight Reduction

During a phase 1 randomized, double-blind, placebo-controlled clinical trial involving obese participants, AMG 133 exhibited acceptable safety and tolerability, along with a significant dose-dependent reduction in weight. Participants receiving high doses experienced an average weight loss of 14.5% after the third injection (day 85), with the remarkable durability of weight reduction maintained at over 11% even after 150 days post-treatment.

GLP-1 and GIP, intestinal-derived incretins, play crucial roles in weight regulation by enhancing glucose-stimulated insulin secretion and influencing satiety and lipid metabolism regulation, respectively. While several GLP-1 receptor agonists (GLP-1RA) have been approved for treating type 2 diabetes and effectively reducing weight, combining additional pathways could further enhance weight loss efficacy, prolong effects, and improve tolerability.

Human genome-wide association studies (GWAS) have highlighted the role of GIP receptor (GIPR) in weight regulation, with GIPR gene knockout mice demonstrating resistance to diet-induced obesity. Pharmacological inhibition of GIPR with anti-GIPR antibodies prevented weight gain in diet-induced obese mice and obese rhesus monkeys. Moreover, combining GIPR antagonism with GLP-1R stimulation synergistically reduced weight in these models, suggesting the potential of GIPR/GLP-1R dual-specific molecules in enhancing obesity treatment outcomes.

To validate this hypothesis, Amgen developed a series of GLP-1 peptide-conjugated GIPR antagonists (GIPR-Ab) and conducted studies. These dual-specific molecules, antagonizing GIPR while stimulating GLP-1R pathways, resulted in weight reduction and improved metabolic parameters in obese mice and monkeys.

AMG 133, known as maridebart cafraglutide, represents an optimized GIPR/GLP-1R dual-specific molecule formed by linking a fully human GIPR monoclonal antibody with two GLP-1 analogues via amino acid linkers.

In this study, the research team reported the design, preclinical development, and clinical validation of AMG 133 to assess its safety, tolerability, pharmacokinetics, and pharmacodynamics.

The study confirmed the activity of GIPR antagonists and GLP-1R agonists in cellular systems, demonstrating AMG 133’s ability to reduce weight and improve metabolic markers in obese male mice and rhesus monkeys.

In a phase 1 randomized, double-blind, placebo-controlled clinical study (NCT04478708) involving obese patients, AMG 133 exhibited acceptable safety and tolerability, along with a significant dose-dependent reduction in weight. Weight loss was sustained for up to 150 days following multiple escalating doses. These findings support continued clinical evaluation of AMG 133.

Specifically, 49 adult obese participants were enrolled in seven single ascending dose (SAD) cohorts, receiving doses ranging from 21 to 840 milligrams of AMG 133 or placebo, with follow-up for up to 150 days. Twenty-six adult obese participants were enrolled in three multiple ascending dose (MAD) cohorts, receiving 140, 280, or 420 milligrams of AMG 133 or placebo, with follow-up for up to day 207. In MAD cohorts, AMG 133 or placebo was administered intravenously every 4 weeks on days 1, 29, and 57, totaling three doses. Participants in the 140 and 280 milligram AMG 133 MAD cohorts, as well as the placebo cohort, received all three planned doses, while three-quarters of participants in the 420 milligram AMG 133 MAD cohort completed all three doses. The mean baseline body mass index (BMI) was 32.5-34.8 kg/m² for SAD cohorts and 32.5-34.2 kg/m² for MAD cohorts. Participants had no history of diabetes, with mean glycated hemoglobin (HbA1c) levels of 5.4-5.6% for SAD cohorts and 5.5-5.6% for MAD cohorts.

Results demonstrated dose-dependent reductions in weight, BMI, and waist circumference in MAD cohorts, with participants receiving 420 milligrams experiencing an average weight loss of 14.5% by day 85 (average baseline weight: 90.5 kilograms, average loss: 13.1 kilograms). Importantly, AMG 133 exhibited outstanding durability, with participants in the high-dose group maintaining weight loss of over 11% even after 150 days post-treatment.

In terms of safety, AMG 133 showed a safety profile similar to GLP-1 receptor agonists and GLP-1/GIP receptor dual agonists, with the most common adverse events being gastrointestinal-related, including nausea and vomiting, mostly mild in severity. There was no observed increase in the severity of nausea, vomiting, or other treatment-related adverse events with increasing doses of AMG 133.

For further information, please refer to the research paper: Link to the paper.

Breakthrough Weight Loss Drug by Amgen: Monthly Injection Leads to Significant Weight Reduction

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