Iron functionalized silica as oral phosphate binder to treat hyperphosphatemia

描述（由申请人提供）：高磷血症普遍存在于终末期慢性肾病患者和大多数透析患者中，美国总计40万例，全球200万例。目前用于治疗高磷血症的口服磷酸盐结合剂仍然具有许多缺点，包括高钙化风险、高成本（每名患者每年2100 - 6500美元）、低至中等疗效、胃肠道不良反应和高药丸负担（500-800 mg片剂，每天3-12片）。这些导致低药丸依从性，一个主要原因，为什么病人不能 控制他们的高磷血症这可能是致命的为了满足医疗需求，PDX Pharmaceuticals，LLC正在申请STTR I期资助，用于开发新型口服磷酸盐结合剂。虽然这类药物在2009年的收入中每年产生约14亿美元，但缺乏寻找更好药物的新研发，落后于技术状况。该项目的创新在于利用我们的纳米技术和配体设计专业知识来彻底改变口服磷酸盐结合剂。我们的目标是开发下一代药物，降低成本，增加患者的依从性（通过降低药丸负担和胃肠道副作用），并降低药物相关风险。该I期项目将涉及我们的铁功能化二氧化硅（Fe-SAMMS）的实验室规模配制，然后在体外和啮齿动物模型中对标准护理药物进行疗效和安全性评价。我们的初步研究表明，Fe-SAMMS具有磷酸盐结合能力，其不依赖于pH或与胃肠道相关的其他竞争性阴离子，由良性化学物质组成，包括二氧化硅、铁和乙二胺-聚硅氧烷，并且当在肾衰竭大鼠中测试时，几乎不溶于或吸收到体内。SAMMS很容易在现有的生产基地内扩大规模，具有超过8年的长保质期和低生产成本。该项目将是PDX Pharmaceuticals（OHSU分拆公司）与OHSU之间的合作，通过利用OHSU最先进的动物设施和临床专业知识进行体内疗效和安全性评价。 研究结果将为Fe-SAMMS的II期大规模GMP生产及其IND申报的GLP安全性评价奠定基础。我们强大的团队由用于人体金属捕获的SAMMS的创新者和开发者组成（Yantasee）; OHSU副教授（Gruber，医学博士），他在动物药物评估和通过FDA程序转移药物方面有着长期的记录;美国内科委员会肾脏病学前主席（安德森，医学博士）;和巴特尔风险投资公司的合伙人（沃伦），谁专门从事商业化的健康和生命科学技术出来的巴特尔的经营国家实验室。我们得到了Battelle-PNNL和OHSU的大力支持，他们共同拥有许可给我们的知识产权，以及俄勒冈州纳米科学和微技术研究所（ONAMI），他们即将为我们提供用于该技术商业化的初始缺口资金。因此，我们完全预期该项目的成功机会很高。 公共卫生相关性：我们建议开发一种新型的无钙口服磷酸盐结合剂，用于治疗终末期慢性肾脏病患者的高磷血症。这种新药的目标是具有更高的疗效，更少的药丸负担，更低的成本和更少的副作用，从而比目前的药物更高的药丸依从性。

DESCRIPTION (provided by applicant): Hyperphosphatemia is universal to end stage chronic kidney disease patients and a majority of dialysis patients totaling of 400,000 in the US and 2 million worldwide. Current oral phosphate binders to treat hyperphosphatemia still have many drawbacks, including a high risk of calcification, high costs ($2100-$6500 per patient a year), low-to-moderate efficacy, gastrointestinal adverse effects, and high pill burdens (500-800 mg tablet, 3-12 tablets a day). These lead to low pill compliance, a major reason why patients fail to manage their hyperphosphatemia, which can be fatal. To address the medical need, PDX Pharmaceuticals, LLC is applying for an STTR Phase I grant for the development of a novel oral phosphate binder. Although this class of drugs generates ~ 1.4 billion USD a year in 2009 revenues, new R&D in search for the better drugs is lacking, lagging behind the state of technology. Innovation in this project lies in the utilization of our nanotechnology and ligand design expertise to revolutionize oral phosphate binders. Our goal is to develop a next generation drug with reduced costs, increased patients' compliance (by lowering pill burden and gastrointestinal side effects), and reduced drug associated risks. This Phase I project will involve bench-scale formulating of our iron functionalized silica (Fe-SAMMS), followed by efficacy and safety evaluations both in vitro and in rodent models against the standard of care drugs. Our preliminary studies show that Fe-SAMMS has a phosphate binding ability that is not dependent on pH or other competing anions relevant to gastrointestinal tract, is composed of benign chemicals including silica, iron, and, ethylenediamine- polysiloxane, and is virtually not soluble or absorbed to the body when tested in renal failure rats. SAMMS is readily scaled up within an existing manufacturing base, has a long shelf-life of over 8 years, and low production costs. This project will be a collaborative work between PDX Pharmaceuticals (an OHSU spin-off company) for material development and optimization, and OHSU for in vivo efficacy and safety evaluations by exploiting state of the art animal facilities and clinical expertise at OHSU. Results will lay a foundation for Phase II, intended for large-scale GMP production of the Fe-SAMMS, and its GLP safety evaluation toward the IND filing. Our strong team consists of the innovator and developer of SAMMS for metal capture in humans (Yantasee); an Associate Professor of OHSU (Gruber, MD), who has a long track record of drug evaluations in animals and moving drugs through the FDA processes; the former Chair of the Nephrology of the American Board of Internal Medicine (Anderson, MD); and a partner at Battelle Ventures (Warren), who specializes in commercialization of health & life science technologies coming out of Battelle's operated National Laboratories. We enjoy strong support from Battelle-PNNL and OHSU who co-own the IP right to be licensed to us, and the Oregon Nanoscience and Microtechnologies Institute (ONAMI), who is about to grant us initial gap funding for commercialization of this technology. Therefore, we fully anticipate a high chance of success for this project. PUBLIC HEALTH RELEVANCE: We propose to develop a novel calcium-free oral phosphate binder to treat hyperphosphatemia in end stage chronic kidney disease patients. The new drug is aimed to have higher efficacy, less pill burden, lower costs, and less adverse effects, resultin in higher pill adherence than the current drugs.