CKD (chronic kidney disease) is a progressive disease which is reported to affect 5% of the world's population. End-stage renal disease (ESRD) is the fifth and final stage of CKD. ESRD will affect 2.2 million people worldwide in 2013 and more than 500,000 Americans at a cost of more than $35 billion in the U.S. alone. Elevated serum phosphorus (Pi) is the major factor stimulating CKD progression and poor patient outcomes. The NKF (National Kidney Foundation) recommended a target range for serum Pi of between 3.5 mg/dL and 5.5 mg/dL. Less than 30% of ESRD patients attain this goal under current treatments. To address this modern epidemic DuoPhos developed an inhibitor of the intestinal protein responsible for 50% to 70% of dietary phosphorus absorption, the intestinal Na+/phosphate cotransporter (NaPi 2b). 2'-Fluorophosphophloretin (2FP) is a small molecule inhibitor of NaPi 2b which has been demonstrated to reduce serum Pi 40% to 55% in animal models at daily doses of 5 ?g/kg body wt. over 2-12 week studies. Preliminary toxicology studies indicate that 2FP shows no toxicity for up to 4 weeks at concentrations 10,000X the efficacious dose. The long term goal of this proposal is to deliver 2FP in a pill form to CKD stage 4 and stage 5 patients. The goal of this proposal is to complete the toxicology studies required to complete the IND and begin human trials.
The specific aims are: 1. Synthesize kilogram quantities of 2FP that is GMP (good manufacturing procedures) quality suitable for clinical trials. 2. Assay the safety pharmacology of 2FP. 3. Determine the chronic toxicity of 2FP in rabbits. 4. Examine the chronic toxicity of 2FP in rats. Completion of specific aim 1 will accelerate human trials by providing a source and formulation (pill form) of 2FP for human trials. GMP certified 2FP is required by the FDA for clinical trials.
Specific aims 2 -4 will complete the toxicology studies required by the FDA and complete the IND packet. Completion of the IND will allow DuoPhos to either start Phase 1 human trials or partner with a large pharmaceutical company to collaborate on the human trials and upon their completion take 2FP to market.