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）：高磷酸血症是普遍存在的慢性肾病患者，大多数透析患者在美国和全球占200万。当前的口腔磷酸盐粘合剂以治疗高磷酸血症仍然有许多缺点，包括高钙化风险，高成本（每年$ 2100- $ 6500），低至中度功效，胃肠道不良反应和高药丸负担（500-800）（500-800 MG平板电脑，每天3-12片）。这些导致药丸的依从性低，这是患者无法的主要原因 管理他们的高磷酸血症，这可能是致命的。为了满足医疗需求，PDX Pharmaceuticals，LLC正在申请STTR I期赠款，以开发新型的口服磷酸盐粘合剂。尽管这类药物在2009年的收入中每年产生约14亿美元，但缺乏寻找更好的药物的新研发，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粘合剂。我们的目标是开发一种下一代药物，其成本降​​低，患者的依从性提高（通过降低药丸负担和胃肠道副作用），并降低了与药物相关的风险。该阶段I项目将涉及我们的铁功能化二氧化硅（FE-SAMMS）的台式规模，然后在体外和啮齿动物模型中进行针对护理药物标准的疗效和安全评估。我们的初步研究表明，Fe-Samms具有磷酸结合能力，不依赖于pH或其他与胃肠道相关的竞争性阴离子，由硅质化学物质组成，包括二氧化硅，铁和乙二胺多甲硅烷，并且实际上不是溶解或不溶于或不溶于或不溶于在肾衰竭大鼠中测试时，吸收到体内。 SAMMS在现有的制造基地内很容易扩展，其保质期长8年，而生产成本较低。该项目将是PDX Pharmaceuticals（OHSU衍生公司）进行材料开发和优化之间的合作工作，以及通过利用OHSU的TAR TAR动物设施和临床专业知识来实现​​体内功效和安全评估的OHSU。 结果将为II期奠定基础，该基础旨在用于大规模的GMP生产Fe-SAMM，并将其GLP安全性评估用于IND归档。我们的强大团队由人类金属捕获的SAMMS的创新者和开发商组成（Yantasee）； OHSU（马里兰州Gruber）的副教授，他在动物中的药物评估和通过FDA过程中移动药物有悠久的记录；美国内科医学委员会（MD）肾脏科的前主席；以及Battelle Ventures（Warren）的合作伙伴，他专门研究来自Battelle经营的国家实验室的健康与生命科学技术的商业化。我们享有Battelle-PNNL和OHSU的大力支持，他们共同拥有获得许可的IP的权利，以及俄勒冈州的纳米科学和微观技术研究所（ONAMI），他们即将授予我们最初的差距资金用于该技术的商业化。因此，我们完全预计该项目有很大的成功机会。 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粘合剂，以治疗末期慢性肾脏疾病患者的高磷酸血症。新药的目的是具有更高的疗效，较少的药丸负担，较低的成本和减少的不良影响，从而使药丸依从性高于目前的药物。