SmartInsulin ADME and IND-enabling Preclinical Studies

描述（由申请人提供）：SmartCells正在开发SmartInsulin？这是一种每天一次的自我调节胰岛素注射剂，用于治疗I型糖尿病。它是为美国400万使用胰岛素的糖尿病患者设计的“一次性”替代产品。SmartInsulin旨在为胰岛素依赖型糖尿病患者提供显著的益处，包括更少的注射，更少的血糖监测，降低低血糖水平的发生率，以及单剂量控制空腹和用餐时血糖水平。SmartInsulin是一种纳米结构材料，由两种生物分子构建块自组装：糖基化胰岛素-聚合物偶联物（IPC）和多价葡萄糖结合分子（GBM）。本报告所涉及的工作建立在为期两年的NIH SBIR第一阶段拨款、NIH SBIR第二阶段拨款的成功结果，以及国防部拨款关于SmartInsulin在大型动物模型中的安全性和有效性的初步结果的基础上。这些结果表明，SmartInsulin已经达到了其“概念验证”的技术目标，但是为了将SmartInsulin推向临床，还必须进行IND支持研究。这需要非常详细和昂贵的GLP毒性/ADME研究和GMP制造过程。该项目旨在为SmartInsulin的GLP临床前研究提供一条清晰的路径。在此资助申请中，SmartCells旨在确定和验证必要的药理学分析，进行glp药理学，毒性和药代动力学/ADME研究，从而向FDA提交IND申请。这一项目可能对公众健康产生重大影响。血糖控制不良已被证明会导致一系列糖尿病并发症，每年造成超过540亿美元的医疗费用。具有里程碑意义的糖尿病控制和并发症试验（DCCT）和英国前瞻性糖尿病研究（UKPDS）临床证明，通过降低糖化血红蛋白A1c （HbA1c）水平来衡量，更严格的血糖控制可显著降低这些并发症的发生率。SmartInsulin旨在提供更严格的血糖控制，降低HbA1c水平，从而减少糖尿病并发症的发生率。

DESCRIPTION (provided by applicant): SmartCells is developing SmartInsulin?,which is intended to be a once-a-day, self- regulating insulin injection for the treatment of Type I diabetes. It is designed as a "drop- in" replacement product for the 4 million insulin-using diabetics in the United States. SmartInsulin is designed to provide significant benefits to insulin-dependent diabetics including fewer injections, less frequent blood sugar monitoring, reduced incidence of low blood sugar levels and single-dose control of both fasting and mealtime blood sugar levels. SmartInsulin is a nanostructured material that self-assembles from two biomolecular building blocks: a glycosylated insulin-polymer conjugate (IPC) and a multivalent glucose-binding molecule (GBM). The work covered in this submission is built on the successful results of a two-year NIH SBIR Phase 1 grant, an NIH SBIR Phase 2 grant, and preliminary results from a DOD grant regarding the safety and efficacy of SmartInsulin in large animal models. These results show that SmartInsulin has met its "proof-of-concept" technical goals, but IND- enabling studies must be conducted in order to bring SmartInsulin to the clinic. This requires very detailed and expensive GLP toxicity/ADME studies and a GMP manufacturing process. This project is intended to provide a clear path to IND-enabling GLP preclinical studies for SmartInsulin. In this grant application, SmartCells aims to qualify and validate the necessary pharmacology assays, conduct GLP-pharmacology, toxicity, and pharmacokinetic/ADME studies, leading to an IND submission with the FDA. The impacts to public health as a result of this project are potentially significant. Poor glycemic control has been shown to cause a host of diabetic complications which result in over $54 billion annually in medical costs. The landmark Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS) have clinically proven that tighter glycemic control, as measured by lower glycosylated hemoglobin A1c (HbA1c) levels, significantly reduces the incidence of these complications. SmartInsulin is designed to provide tighter glycemic control, lowered HbA1c levels, and thus decreased incidence of diabetic complications.