Soluble, solution-stable phospho-glucagon for hypoglycemic rescue

项目摘要 低血糖，即血糖水平下降，是3000万美国人的常见现象， 糖尿病在严重的低血糖中，个体处于糖尿病昏迷甚至死亡的风险中。虽然这些 事件可以使用胰高血糖素应急试剂盒进行管理，目前的试剂盒需要多步骤程序，其中 冻干的胰高血糖素被重构并作为注射剂施用。应急包与一个 用户错误率高且经常未使用。此外，当需要时，试剂盒通常不可用， 糖尿病患者发现它们很麻烦，并且依赖于急诊室就诊来治疗严重的低血糖症。的 胰高血糖素应急药盒的误用和利用不足可追溯到胰高血糖素的溶解度和稳定性有限， 胰高血糖素胰高血糖素在试剂盒中以粉末形式提供，因为它在溶液中不稳定，快速形成淀粉样蛋白 纤维此外，胰高血糖素在中性pH下具有有限的溶解度，并且在试剂盒中在酸性pH下溶解。 莫农生物公司正在开发具有增强的稳定性和溶解性的胰高血糖素衍生物， 多功能和用户友好的产品。莫农生物风险公司的方法包括使用可逆磷酸化 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， 称为磷酸胰高血糖素。初步的努力已经鉴定出具有改善的溶解度的磷酸胰高血糖素 和稳定性，并且显示出与天然胰高血糖素（在大鼠中）相当的血糖增加。这些数据 通过快速通道计划支持磷酸化胰高血糖素先导药物的持续开发， 目的是产生鼻内和自我注射肌内磷酸化的靶向产物谱（TPP）， 胰高血糖素制剂。这一总体目标将通过实现以下目标来实现： 第一阶段的具体目标是：1）进行铅的配方研究和结构修饰 磷酸-胰高血糖素以改善氧化稳定性。2)开发和验证分析方法， 血浆中的磷酸胰高血糖素。成功推进到第二阶段的措施是：1）确定至少 在中性pH的溶液中配制的具有所需稳定性（<10%）的两种候选磷酸-胰高血糖素 在30 ℃下氧化3个月，没有可检测到的纤维化），溶解度（>1 mg/mL）和功能性（增加血液 葡萄糖，速率和程度与天然胰高血糖素相似）;和2）经验证的生物分析方法，限度为 检测50 ng/mL或更低。 II期具体目的是：1）确定磷酸-胰高血糖素铅制剂的长期稳定性。 评估磷酸胰高血糖素制剂的PK/药效学（PD）特性。3)完成网站 磷酸-胰高血糖素先导制剂的初步安全性和免疫原性特征。这项措施 第二阶段成功的关键是完成关键的药理学和安全性评估，以构建TPP。

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.