- Obesity is a serious disease with strong biologic and genetic underpinnings that increases the risk of many other serious diseases associated with changes in metabolism, including heart disease, stroke, diabetes and certain cancers.
- Obesity affects individuals in different ways, which suggests treatments should be individualized and outcomes beyond weight loss are also important for patients.
- Based on research that includes human genetic and biological data, Amgen is evaluating the multispecific large molecule AMG 133 as a first-in-class investigational therapy for the treatment of obesity.
When you hear the terms "global pandemic," "massive public health issue" and "huge social and economic costs," you may think of COVID-19. But these terms also apply to obesity, a disease that more than 750 million people are living with worldwide—in the U.S. alone the prevalence of obesity in adults is 41.9%.
While losing weight and maintaining a lower weight are key outcomes tracked when treating obesity, many in the field of drug research and development believe that the more important outcomes are the impact that weight loss has on metabolic issues such as increased blood pressure and blood sugar, excess body fat deposits around the waist and abnormal cholesterol levels. Research shows it's the disruptions in metabolic pathways that lead to the many diseases associated with obesity – from diabetes caused by insulin resistance, to heart disease caused by inflammation.
Amgen is using human data, including genetics, proteomics, metabolomics and imaging to develop drugs that target dysregulated metabolism associated with obesity.
In some ways, obesity is where hypertension was in the 1980s, when it was thought to be related to lifestyle rather than a complex disease requiring long-term management. It took until 2013 for the American Medical Association and 2021 for the European Commission to classify obesity as a chronic disease. And just like hypertension, obesity is not a disease that can be treated with a one-size-fits-all approach.
Individuals respond differently to obesity by developing different conditions. So the goal is to get the right medication to the right patient. For example, not everyone with obesity develops diabetes or heart disease, so medicines specific to each form of obesity need to be developed.
Uncovering the genetics and biology of metabolism
Previously developed obesity drugs, some of which have been pulled from the market, were plagued by disappointing efficacy coupled with multiple safety issues. So the field shied away from the area for many years. But that changed with mounting obesity research on one particular hormone called GLP-1 (Glucagon-Like Peptide 1), a peptide, or piece of a protein, that is involved in insulin signaling, appetite and food intake. GLP-1 interacts with several organs throughout the body, including a part of the brain called the hypothalamus, to reduce appetite and food intake.
Further obesity research at Amgen and Icelandic subsidiary deCODE Genetics began looking at the effects of rare genetic changes, called variants, on Body Mass Index (BMI), a measure of body fat based on height and weight. The Centers for Disease Control and Prevention (CDC) defines obesity as having a BMI of 30 or higher. deCODE looked for variants associated with low BMI in human data accumulated from hundreds of thousands of individuals across biobanks from several countries, with the idea that these could be valuable drug targets.
The deCODE work and other research uncovered variants in the GIPR (Gastric Inhibitory Polypeptide Receptor) gene that were particularly interesting. GIP and its receptor are involved in regulating insulin levels after eating. Individuals with specific variants in this gene that reduced its activity had lower BMIs. Further analysis by Amgen researchers confirmed this finding.
Both GIP and GLP-1 are called incretin hormones, meaning they are secreted by the gut after we eat and help stimulate insulin secretion to break down the sugars in our food and help suppress appetite. So they have the potential to be prime drug targets in a disease characterized by issues with metabolism.
The genetic findings by deCODE and others led Amgen to start working on a first-in-class antibody-based multispecific molecule currently dubbed AMG 133, with a novel mechanism of action that simultaneously activates the GLP-1 receptor and inhibits GIPR. To create AMG 133, researchers started with an antibody that blocks GIPR. To this antibody backbone, they then added two modified GLP-1 peptides that activate the GLP-1 receptor. Preclinical research at Amgen confirmed that this dual action, or bifunctionality that targets these two key metabolic pathways, seemed to have a stronger effect on weight loss than either GLP-1 or GIPR antibodies alone.
Amgen has announced Phase 1 results here.
A Phase 2 trial is being planned for early 2023.