2'-Fluorophosphophloretin (2FP)in the Treatment of Chronic Renal Failure

描述（由申请人提供）：CKD（慢性肾脏疾病）是一种进行性疾病，据报道影响全球5%的人口。终末期肾病（ESRD）是CKD的第五阶段，也是最后阶段。2013年，ESRD将影响全球220万人，超过50万美国人，仅在美国就造成超过350亿美元的损失。血清磷（Pi）升高是刺激CKD进展和患者预后不良的主要因素。NKF（国家肾脏基金会）推荐血清Pi的目标范围在3.5 mg/dL和5.5 mg/dL之间。在目前的治疗下，不到30%的ESRD患者达到了这一目标。为了解决这一现代流行病，DuoPhos开发了一种肠道蛋白抑制剂，该蛋白负责50%至70%的膳食磷吸收，即肠道Na+/磷酸盐共转运蛋白（NaPi 2b）。2′-氟磷脂（2FP）是一种NaPi 2b的小分子抑制剂，已被证明在动物模型中，每日剂量5 ？G /kg体重，2-12周研究。初步毒理学研究表明，2FP在浓度为有效剂量的10,000倍的情况下，在长达4周的时间内没有毒性。该提案的长期目标是将2FP以药丸形式提供给CKD阶段

DESCRIPTION (provided by applicant): 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.