Iron functionalized silica as oral phosphate binder to treat hyperphosphatemia

铁功能化二氧化硅作为口服磷结合剂治疗高磷血症

• 批准号: 8251891
• 负责人: Wassana Yantasee
• 金额: $ 29.97万
• 依托单位: PDX PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-20 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251891
• 关键词: Acute; Address; Adherence; Adverse effects; Aluminum; American; Amines; Animal Model; Animals; Anions; Award; Benign; Binding; Biological Sciences; Biomedical Engineering; Calcium; Caring; Cells; Chemicals; Chronic; Chronic Kidney Failure; Clinical; Collaborations; Cost Analysis; Development; Dialysis patients; Dose; Drug Evaluation; Ethylenediamines; Evaluation; Excision; Feasibility Studies; Foundations; Funding; Gastrointestinal tract structure; Goals; Grant; Health Sciences; Human; IACUC; In Vitro; Institutes; Intellectual Property; Internal Medicine; Intestines; Investigational Drugs; Iron; Kidney; Kidney Failure; Laboratories; Lead; Licensing; Life; Ligands; Liver; Measures; Medical; Metals; Methods; Nanotechnology; Nephrology; No-Observed-Adverse-Effect Level; Oral; Oregon; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Process; Production; Property; Protocols documentation; Rattus; Reference Standards; Relative (related person); Reporting; Reproducibility; Risk; Rodent; Rodent Model; Safety; Silicon Dioxide; Siloxanes; Small Business Technology Transfer Research; Staging; Stomach; Tablets; Technology; Testing; Time; Toxic effect; Toxin; Universities; Work; animal facility; base; calcification; commercialization; compliance behavior; cost; cytotoxicity; design; gastrointestinal; good laboratory practice; high risk; improved; in vivo; innovation; inorganic phosphate; large scale production; medical schools; meetings; mortality; nanoscience; next generation; novel; phase 2 study; pill; professor; research and development; safety practice; safety study; scale up; standard of care; success

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.

描述（由申请人提供）：高磷酸盐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​​，美国总计有 400,000 名患者，全世界有 200 万患者。目前用于治疗高磷血症的口服磷酸盐结合剂仍然存在许多缺点，包括钙化风险高、成本高（每位患者每年 2100-6500 美元）、低至中等疗效、胃肠道不良反应以及高药丸负担（500-800 美元）。毫克片剂，每天 3-12 片）。这些导致服药依从性低，这是患者未能服药的主要原因 控制高磷血症，这可能是致命的。为了满足医疗需求，PDX Pharmaceuticals, LLC 正在申请 STTR 第一阶段拨款，用于开发新型口服磷酸盐结合剂。尽管此类药物 2009 年每年产生约 14 亿美元的收入，但缺乏寻找更好药物的新研发，落后于技术水平。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、提高患者的依从性（通过降低药物负担和胃肠道副作用）并降低药物相关风险。该第一阶段项目将涉及我们的铁功能化二氧化硅 (Fe-SAMMS) 的小规模配制，然后根据护理药物标准在体外和啮齿动物模型中进行功效和安全性评估。我们的初步研究表明，Fe-SAMMS 具有磷酸盐结合能力，不依赖于 pH 值或与胃肠道相关的其他竞争性阴离子，由二氧化硅、铁和乙二胺聚硅氧烷等良性化学物质组成，并且几乎不溶解或不溶解。在肾衰竭大鼠中进行测试时被吸收到体内。 SAMMS 可在现有制造基地内轻松扩大规模，保质期长达 8 年以上，且生产成本低。该项目将是 PDX Pharmaceuticals（OHSU 的一家衍生公司）与 OHSU 之间的合作项目，前者负责材料开发和优化，后者通过利用 OHSU 最先进的动物设施和临床专业知识进行体内功效和安全性评估。 结果将为第二阶段奠定基础，该阶段旨在大规模 GMP 生产 Fe-SAMMS 及其针对 IND 申请的 GLP 安全评估。我们强大的团队由人体金属捕获 SAMMS 的创新者和开发者 (Yantasee) 组成； OHSU 副教授（格鲁伯，医学博士），在动物药物评估和通过 FDA 流程推动药物方面拥有长期记录；美国内科医学委员会肾脏病学前主席（医学博士安德森）；以及巴特尔风险投资公司（沃伦）的合伙人，专门从事巴特尔运营的国家实验室的健康和生命科学技术的商业化。我们得到了 Battelle-PNNL 和 OHSU 的大力支持，他们共同拥有授权给我们的知识产权，以及俄勒冈纳米科学和微技术研究所 (ONAMI)，他们即将为我们这项技术的商业化提供初始缺口资金。因此，我们完全预计该项目成功的机会很大。 公共健康相关性：我们建议开发一种新型无钙口服磷酸盐结合剂来治疗终末期慢性肾病患者的高磷血症。新药的目标是比现有药物具有更高的疗效、更少的药物负担、更低的成本和更少的副作用，从而提高药物依从性。