A NOVEL PRECISION MEDICINE APPROACH FOR OBESITY: A RANDOMIZED, MULTI-CENTER TRIAL

NOTE: You must submit in Word format, not PDF, for eRA to update all the systems.
Obesity is a chronic, relapsing, and multifactorial disease,[1] with a prevalence of 42%.[2] As with any obesity treatment, the weight loss response with anti-obesity medications (AOMs) is highly variable. For example, semaglutide 2.4 mg, the most effective AOM leads to a mean total body weight loss (TBWL) of 15% in randomized clinical trials[3] and in real-world clinic cohort studies.[4] However, only 50% of participants achieve >15% in one year,[3] whereas 30% lose less than 10% TBWL. In the clinical practice, access to AOMs can be limited by their high cost. Importantly, given the variable weight loss response to AOM, these may not be cost-effective, particularly in poor responders who will not only incur unnecessary high costs, but will also be exposed to possible side effects. Currently, besides identifying responders by trial-and-error,[5, 6] little is known about the predictors of response to AOM, and the heterogeneous response to this type of intervention, remains an important challenge in clinical practice.[1, 7] There is a critical need to identify the predictors of response to AOM to develop individualized weight-loss strategies that enhance weight loss outcomes in people with obesity.[8]
Our team focuses on understanding the heterogeneity of human obesity by identifying predictors of response to weight loss treatments.[9] Phenotyping of 880 adults has demonstrated that there are phenotypic traits that differentially respond to weight loss interventions. One of these phenotypic traits is abnormal postprandial satiety.[10] Patients with abnormal postprandial satiety have increased postprandial hunger, which is associated with accelerated gastric emptying.[11] To date, we have shown that lifestyle interventions, AOMs, and endoscopic devices targeting this underlying phenotypic trait enhance weight loss outcomes in patients with obesity.[10, 12-20] Our data suggest that the phenotype-tailored approach could become a clinical approach for the treatment of obesity, whereby individual patients are matched to treatments directed at the underlying phenotype. However, the current methods used to identify phenotypes are time-consuming, invasive, expensive, limited to a few academic centers, and not generally accessible for most patients.
To address these limitations, an academic-industry partnership was established, and we have developed and validated a novel blood- and saliva-based biomarker test of appetite regulation in obesity that predicts the abnormal postprandial satiety phenotype. The current biomarker, named MyPhenomeTM test, is ready for commercialization in a CLIA-CAP accredited laboratory; and it will be scalable and affordable to support healthcare providers to guide patients to tailored anti-obesity treatments. Our aim is to study, in a multi-center, 24-week, prospective, randomized, double-blind, placebo-controlled trial, the efficacy of subcutaneous semaglutide 2.4 mg in patients with obesity with either a positive or a negative MyPhenome test for abnormal postprandial satiety. This step is essential in the final validation process of this novel biomarker prior to seeking third party reimbursement for its use to guide therapy for obesity.

Grant Number: 5R44DK138619-02
NIH Institute/Center: NIH
Principal Investigator: Mark Bagnall