Clinical development of a colon-targeted butyrate tablet to evaluate effects on cholesterol and trimethyl amine oxide in subjects at risk for cardiovascular disease

PROJECT SUMMARY Cardiometabolic disease (CMD), which includes cardiovascular disease, type 2 diabetes (T2D), and stroke, is the number-one cause of death in the world. Drugs currently used to treat CMDs by lowering LDL-C, such as statins and proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, are either not completely effective, have numerous side effects, are very expensive, or are delivered by injection. In addition, these drugs do not reduce the incidence of T2D and insulin resistance. Thus, there is a critical need for new therapies that treat the various conditions of CMD and that address the shortcomings of current treatments. Secretion of gut hormones in response to nutrient ingestion is critical for the proper management of lipids, glucose, and appetite; however, gut hormone responses are impaired in patients with hyperlipidemia, diabetes, and obesity. BioKier is developing the first orally administered therapeutic, BKR-017, that restores gut hormone secretion in the colon of patients with CMD. The active ingredient is butyrate, one of the most important natural activators of gut hormone release. BioKier’s approach is to improve the delivery of butyrate to the active site of gut hormone secretion, the colon, and thus improve gut hormone secretion in conditions of CMD. This approach is a significant advance on the use of other formulations of butyrate that do not specifically target the colon and on injectable GLP-1 analogs that have efficacy but also have dose-limiting side effects. BKR-017 is designed to address deficiencies in gut hormone secretion, improve cardiometabolic conditions, and, due to its novel mechanism of action, complement the actions of existing therapies. The overall aim of this Phase I project is to demonstrate the safety of BKR-017 in a Phase 1 clinical trial. Safety in Phase 1 is the first step in the clinical development of novel drugs under an IND. Successful completion of this Phase I SBIR project will position BKR-017 for a Phase II SBIR application in which we plan to propose a Phase 2 clinical trial to investigate the efficacy of BKR-017 in lowering LDL-C levels in subjects with elevated LDL-C and the associated risk of cardiovascular events. Pilot studies by BioKier indicated that BKR-017 significantly reduced total cholesterol, LDL-C, non-HDL-C, apolipoproteins, trimethylamine N-oxide (TMOA), and fatty liver biomarkers, which are all indicators of increased cardiovascular risk. However, these studies were conducted in subjects selected for T2D but not for hyperlipidemia. These results suggest that BKR-017 will have even more significant effects in hypercholesterolemia patients, many of whom cannot lower their LDL-C to safe levels with statin use alone. Development of BKR-017 along the path of prescription drug approval will significantly increase the value of the drug and its appeal to large corporate partners who have the capacity to commercialize it. BioKier has commissioned a market analysis that indicates that there is a large and growing market for new drugs that are effective in patients who are resistant to, or unwilling to use, statins. Other options are not widely accepted because of cost, inconvenient administration, and/or side effects.