Evaluation of novel small molecule targeting lipid and energy homeostasis for treating obesity

ABSTRACT: The goal of the project is to develop a safe and efficacious small molecule therapeutic to address obesity and concomitant metabolic disorders, such as diabetes or insulin resistance, dyslipidemia, fatty liver disease, and risk of cardiovascular disease events. To date, there are no approved therapies that can reliably reduce multiple conditions associated with metabolic diseases over the long-term. Whilst recent milestone approvals for anti-obesity (e.g., incretin analogs) therapeutics have provided new treatment options for patients, they are limited and with shortcomings. ReRx-001 is an orally bioavailable small molecule therapeutic that acts upon clinically validated targets involved in lipid homeostasis and energy metabolism and that has promising effects in addressing obesity and associated metabolic disorders. Characterization of ReRx-001 activity by target screens, benchmark studies, and combination studies demonstrate that the mechanism of action of ReRx-001 is distinct from current therapeutic approaches targeting energy intake (e.g., appetite regulation). Our preliminary proof-of-principle studies in various diet-induced obesity and metabolic dysfunction-associated fatty liver disease mouse models have found that ReRx-001 treatment effectively addresses metabolic, inflammatory, and fibrotic disease markers with no apparent adverse side effect profiles. In this Phase II application, we will investigate translational efficacy and define treatment outcomes in higher species, namely diet-induced obese nonhuman primates, as well as initiate preliminary pharmacokinetic and toxicology studies in rodent species and nonhuman primates. Along with the existing preclinical data, results generated from the proposed studies will culminate in IND-enabling activities and a pre-IND meeting with the FDA for additional clinical guidance and study design.