The Development of BSN272 From Prevention of Diet-Induced Hyperlipidemia in Mice to a Potential Therapy For Prader-Willi Syndrome in Humans

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

While type 2 diabetes mellitus (T2DM) is distinguished as a disorder of blood glucose homeostasis, the vast majority of patients afflicted with this disease in the US present with the entire complement of the metabolic syndrome: abdominal obesity, hypertriglyceridemia, low HDL levels, elevated blood pressure, and elevated fasting plasma glucose. Current guidelines aim to treat each of these disorders, but do so individually even though they are manifestations of common pathologies. In other words, a patient will be prescribed different medications for diabetes, blood pressure, CVD prevention, etc., while the only single treatment aimed at the myriad of disorders together is changes to dietary and exercise habits. Diet and exercise, when executed properly, has been shown consistently to be the most effective treatment for T2DM. The rate of type 2 diabetes in the US is close to 10%, but the rate of type 2 diabetes is even higher in patients with Prader-Willi Syndrome (a genetic disease that causes excessive weight gain from overeating, resulting in approximately double the risk of diabetes). BSN272 is a combination of 2 molecules (D-tagatose and trans-polydatin) that have shown benefits in treating individual manifestations of the metabolic syndrome presentation as monotherapy and have proved synergistic when taken together to treat the entire complement of the disorders. Previous research in our lab with D-tagatose included safety studies in animal models and humans for use as a dietary ingredient which culminated with the generally recognized as safe (GRAS) designation by the FDA and EU for use in foods. Based on these exposures to determine safety, an IND was granted to evaluate the safety and efficacy of D-tagatose in treating hyperglycemia in T2DM. Phase 2 and 3 global clinical trials were completed showing D-tagatose to be highly safe and moderately effective. The decision was made to search for a molecular complement to D-tagatose that could more completely treat T2DM. Dihydromyricetin and trans-polydatin were identified through literature searches as potentially synergistic with D-tagatose. Both molecules were tested in combination with D-tagatose for their ability to prevent diet-induced elevations in cholesterol markers in ApoE-/- mice. Dihydromyricetin appeared to be additively effective with D-tagatose for lipids, but transpolydatin showed synergy in prevention of cholesterol elevations as results were greater for the combination than were the additive benefits of either as monotherapy. Trans-polydatin also showed this property in a hyperlipidemic hamster model and a LDLr-/- mouse model. Following safety and efficacy results in three animal models for BSN272, an exploratory Phase 1 PK microdose study was submitted to the FDA in an IND filing to investigate whether the presence of D-tagatose has any effects on the kinetics of trans-polydatin when administered in concert compared to trans-polydatin alone. The indication sought for the IND is Prader-Willi Syndrome (PWS) due to the added potential of D-tagatose to impart satiety and reduce weight gain. PWS is a genetic disorder in which patients develop insatiable hunger that leads to obesity and often diabetes while in childhood. There is currently only symptomatic treatment of the disease and none of the medications in treatment guidelines for adult type 2 diabetes are approved for pediatric use.