While GLP-1 drugs have exploded in popularity, they don’t work for everyone, and experts say phenotyping based on a greater understanding of the disease is the future of obesity treatment.
Pictured: Visualization of genetic phenotypes over colorful background/Nicole Bean for BioSpace
The past decade has brought about a paradigm shift in the way obesity is viewed and, therefore, treated by the medical community. Once considered a lifestyle disease, it is now recognized as a chronic, multifactorial biological disorder— one that can potentially be treated on a personalized basis.
Over 42% of American adults live with obesity, and therapeutics targeting weight loss are one of pharma’s hottest opportunities, with analysts forecasting a market range of $100 billion to $200 billion by 2030.
The treatment landscape is evolving as endocrinologists and obesity specialists recognize that even with the most successful anti-obesity medicines, there is no “one size fits all” solution.
While glucagon-like peptide 1 agonist (GLP-1) drugs like Novo Nordisk’s Wegovy and Eli Lilly’s Zepbound currently shine in the spotlight, they don’t work for everyone. Some patients simply do not respond to the drug, and others get side effects so severe they have to stop treatment. Side effects for GLP-1 agonists—particularly gastrointestinal—are considered more the rule than the exception.
Possibly in light of this, there is currently a push toward a more personalized approach to treating obesity.
Getting to the Root Cause of Obesity
Andres Acosta’s Precision Medicine for Obesity Lab at the Mayo Clinic is exploring the biological root causes of obesity in order to treat the disease from the inside out. Acosta, along with Mayo gastroenterologist Michael Camilleri, developed obesity phenotyping, utilizing biomarkers and external factors to understand the underlying driver of each person’s disease.
After identifying four categories—hungry brain, hungry gut, emotional hunger and slow burn—they launched Phenomix Sciences to develop a saliva test that can be done at a primary care physician’s office. The approach pairs patients with the right intervention—a therapeutic, medical device or surgery—alongside a diet plan that is best tailored for their obesity phenotype.
“We can now tell you why people have obesity, what’s unique among each person,” Acosta told BioSpace.
Both from clinical studies and real-life patient experiences, it’s clear to obesity experts that each person responds uniquely to different obesity interventions. Understanding why some respond and others don’t is the key to unlocking patient benefit, Acosta said, and big pharma is taking note.
“Almost every pharma person we talk to says the future of obesity medicine is precision medicine,” said Phenomix CEO Mark Bagnall, adding that the future appears to be in polypharmacy or targeted drug treatments.
There is already an anti-obesity medication (AOM) on the market well-suited for patients with the emotional hunger phenotype. Currax Pharmaceuticals’ Contrave is the only AOM on the market targeting the mesolimbic system.
Currax CEO George Hampton told BioSpace the company is working on a once-a-day version of the Contrave—the current regimen is two pills twice a day—and is exploring options to use the drug as a secondary medication or as a less expensive option for patients who have already lost weight on another product.
Precision treatment could also help to address side effects. GLP-1 drugs for weight loss have been found to cause muscle wasting, which leads to a lower metabolic rate. Drugs targeting the biological driver behind each patient’s specific phenotype will maximize treatment potential, Bagnall said, and potentially more than one medicine could be used to tackle the disease from different angles. For example, pairing a GLP-1 drug with a metabolism-boosting therapeutic could counter the lower metabolic rate caused by the former, he said.
Phenotype testing could also be a perfect companion diagnostic to study AOMs in specific patient populations, Bagnall added. Both Bagnall and Acosta alluded to pharma collaborations in the works for clinical study optimization and target development based on obesity phenotypes.
Better Results and Adherence
Scientific evidence is emerging to support the precision medicine approach to treating obesity. In a clinical study led by Acosta, the proportion of patients who lost more than 10% of their weight after 12 months was more than double with a phenotype-guided approach compared to a non-phenotype-guided approach.
A separate study conducted at the Mayo Clinic showed that Phenomix’s Hungry Brain biomarker test could identify high-responders to Qsymia, an FDA-approved AOM. The study showed that patients with an abnormal satiation phenotype—or hungry brain—lost 17.7% of their total body weight in 12 months on Qsymia, compared to an average of only 7.6% for patients without the hungry brain biomarker.
Additionally, studies across multiple disease types show that getting patients on the right drug the first time improves adherence, Acosta said. Novo’s Wegovy has more than three times the adherence rate of older AOMs, according to the journal Obesity. But only 40% of patients are still on the blockbuster drug one year after beginning treatment.
“We have no way of knowing how an individual patient is going to fall on the curve, and it can be very frustrating for patients who are not responding well,” said Michael Glickman, an obesity medicine physician and CEO of Revolution Medicine.
“In clinical practice, it is often a trial-and-error process. If a patient doesn’t respond—typically defined as at least 5% body weight loss—we go back to the drawing board and try another brand,” Glickman told BioSpace.
Ultimately, he said, if the use of biomarkers can help physicians predict which treatments their patients will best respond to, it will “completely revolutionize how we treat obesity.”
Kate Goodwin is a freelance life science writer based in Des Moines, Iowa. She can be reached at kate.goodwin@biospace.com and on LinkedIn.
