Soluble, solution-stable phospho-glucagon for hypoglycemic rescue

用于低血糖救援的可溶性、溶液稳定的磷酸胰高血糖素

• 批准号: 10065976
• 负责人: Mark Louis Heiman
• 金额: $ 49.51万
• 依托单位: MONON BIOVENTURES, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-05 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065976
• 关键词: Address; Adverse event; American; Amyloid Fibrils; Antibodies; Antibody Response; Artificial Pancreas; Biological Assay; Blood Glucose; Cessation of life; Charge; Cleaved cell; Complex; Data; Detection; Development; Diabetes Mellitus; Diabetic Coma; Dose; Drops; Drug Kinetics; Effectiveness; Emergency Situation; Emergency department visit; Ensure; Enzymes; Event; Formulation; Freeze Drying; Glucagon; Goals; Histologic; Hypoglycemia; Individual; Inflammation; Injectable; Injections; Intervention; Intramuscular; Kinetics; Lead; Life; Measures; Methionine; Methods; Modification; Patient-Focused Outcomes; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Plasma; Powder dose form; Procedures; Prodrugs; Property; Protocols documentation; Rattus; Regimen; Risk; Safety; Savings; Site; Solubility; Structure; Temperature; Therapeutic; Time; amyloid fibril formation; analytical method; commercialization; cost; diabetic; experience; immunogenicity; improved; in vivo; inorganic phosphate; neutralizing antibody; novel; oxidation; prevent; programs; reconstitution; safety assessment; success; user-friendly

PROJECT SUMMARY Hypoglycemia, a decrease in blood sugar levels, is a common occurrence for the 30 million Americans with diabetes. In severe hypoglycemia, the individual is at risk for diabetic coma and even death. Although these events can be managed using a glucagon emergency kit, current kits require a multi-step procedure in which lyophilized glucagon is reconstituted and administered as an injection. Emergency kits are associated with a high rate of user error and frequently go unused. Additionally, kits are often not available when needed, as diabetic individuals find them cumbersome and rely on emergency room visits to treat severe hypoglycemia. The misuse and underutilization of glucagon emergency kits can be traced to the limited solubility and stability of glucagon. Glucagon is supplied as a powder in the kits because it is unstable in solution, rapidly forming amyloid fibrils. Additionally, glucagon has limited solubility at neutral pH and is solubilized in acidic pH in the kits. Monon Bioventures is developing glucagon derivatives with enhanced stability and solubility to provide a more versatile and user-friendly product. Monon Bioventures’ approach involves using reversible phosphorylation of glucagon to prevent the formation of amyloid fibrils, thus creating a solution-stable glucagon derivative, known as phospho-glucagon. Preliminary efforts have identified phospho-glucagons with improved solubility and stability and have shown increases in blood glucose comparable to native glucagon (in rats). These data support the continued development of lead phospho-glucagons through a Fast-Track program that is geared toward generating target product profiles (TPPs) for intranasal and self-injectable intramuscular phospho- glucagon formulations. This overall goal will be met through the execution of the following aims: Phase I Specific Aims are: 1) To execute formulation studies and structural modifications of lead phospho-glucagons to improve oxidative stability. 2) To develop and validate analytical methods for phospho-glucagon in plasma. The measures of success to advance to Phase II are 1) identification of at least two candidate phospho-glucagons formulated in solution at a neutral pH that have desired stability (<10% oxidation at 30oC for 3 months, no detectable fibrillation), solubility (>1 mg/mL), and functionality (increases blood glucose at rate and extent similar to native glucagon); and 2) a validated bioanalytical method with a limit of detection of 50 ng/mL or less. Phase II Specific Aims are: 1) To determine long-term stability of lead phospho-glucagon formulations. To assess the PK/pharmacodynamic (PD) properties of phospho-glucagon formulations. 3) To generate preliminary safety and immunogenicity profiles of the lead phospho-glucagon formulations. The measure of success for Phase II is to complete key pharmacological and safety assessments to construct the TPP.

项目总结 低血糖是血糖水平的下降，对3000万患有糖尿病的美国人来说是一种常见的情况 糖尿病。在严重低血糖的情况下，个体面临糖尿病昏迷甚至死亡的风险。尽管这些 可以使用胰高血糖素应急试剂盒来管理事件，目前的试剂盒需要一个多步骤的程序，其中 冷冻干燥的胰升糖素是重组的，并作为注射使用。应急工具包与 用户错误率高，经常不使用。此外，套件通常在需要时不可用，因为 糖尿病患者发现它们很麻烦，并依赖急诊室就诊来治疗严重的低血糖。这个 误用和未充分利用胰高血糖素急救箱可以追溯到有限的溶解和稳定性 高血糖素。高血糖素在试剂盒中以粉末的形式提供，因为它在溶液中不稳定，迅速形成淀粉样蛋白。 纤维。此外，胰高血糖素在中性pH下的溶解度有限，在酸性pH中可溶解。 Monon BioVentures正在开发具有增强稳定性和溶解性的胰高血糖素衍生物，以提供更多 多功能和用户友好的产品。Monon BioVentures的方法涉及到使用可逆磷酸化 以防止淀粉样纤维的形成，从而产生溶液稳定的胰高血糖素衍生物， 被称为磷酸胰高血糖素。初步工作已确定具有更好的溶解性的磷酸-胰高血糖素 和稳定性，并已显示血糖上升相当于天然胰高血糖素(在大鼠)。这些数据 通过一个快速通道方案支持铅-磷酸-高血糖素的持续发展 为鼻腔内和自身肌肉内注射的磷酸盐生成目标产物轮廓(TPP) 高血糖素配方。这一总体目标将通过执行以下目标来实现： 第一阶段的具体目标是：1)进行铅的配方研究和结构修改 磷酸-胰高血糖素，以提高氧化稳定性。2)开发和验证以下分析方法 血浆中的磷酸高血糖素。成功晋级第二阶段的衡量标准是1)至少确定 在中性pH溶液中配制的两种候选磷酸-胰高血糖素，具有理想的稳定性(&lt；10% 在30oC下氧化3个月，没有检测到纤颤)、溶解度(&gt；1毫克/毫升)和功能性(增加血液 葡萄糖的速率和程度与天然高血糖素相似)；以及2)经过验证的生物分析方法，其限制为 检测浓度为50 ng/mL或更低。 第二阶段的具体目标是：1)确定铅磷酸高血糖素制剂的长期稳定性。 目的：评价磷酸高血糖素制剂的PK/药效学(PD)特性。3)生成 磷酸高血糖素铅制剂的初步安全性和免疫原性概况。这项措施 第二阶段的成功之处在于完成关键的药理和安全性评估，以构建TPP。