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）是一种进展性疾病，据报道影响世界5%的人口。终末期肾病（ESRD）是CKD的第五个也是最后一个阶段。2013年，ESRD将影响全球220万人，超过50万美国人，仅在美国就花费超过350亿美元。血清磷（Pi）升高是促进CKD进展和患者预后不良的主要因素。NKF（国家肾脏基金会）建议血清Pi的目标范围为3.5 mg/dL至5.5 mg/dL。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，负责50%至70%的膳食磷吸收，肠道Na+/磷酸盐协同转运蛋白（NaPi 2b）。2 '-氟磷根皮素（2FP）是一种小分子的NaPi 2b抑制剂，已被证明在动物模型中，每日剂量为5？g/kg体重2-12周的研究。初步毒理学研究表明，2FP在10，000倍有效剂量的浓度下长达4周没有显示毒性。该提案的长期目标是以药丸形式将2FP递送至CKD阶段 4和5期患者。本提案的目标是完成IND所需的毒理学研究，并开始人体试验。具体目标是：1.合成公斤量的2FP，其是适合临床试验的GMP（良好制造程序）质量。2.对2FP进行安全性药理试验。 3.测定2FP对家兔的慢性毒性。 4.观察2FP对大鼠的慢性毒性。具体目标1的完成将通过为人体试验提供2FP的来源和制剂（丸剂形式）来加速人体试验。FDA要求GMP认证的2FP用于临床试验。具体目标2-4将完成FDA要求的毒理学研究并完成IND数据包。IND的完成将允许DuoPhos开始1期人体试验或与大型制药公司合作进行人体试验，并在完成后将2FP推向市场。

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.