Stable Glucagon for Treatment of Hyperinsulinism

在严重的持续性高胰岛素血症(HI)中，反复的低血糖发作最终可能导致 永久性癫痫、学习障碍、脑瘫、失明甚至死亡。临床 研究表明，无论是短期治疗还是长期治疗， 治疗严重形式HI的高血糖素和持续皮下注射高血糖素 推荐既是因为患者预后的潜在改善，也是因为 手术干预之后是长期的年度护理费用。然而，胰高血糖素在体内的不稳定性 解决方案既造成了管理问题，也造成了输液管的潜在并发症 堵塞。这些不稳定的问题限制了胰高血糖素在严重持续性HI中的使用。至 克服这一问题，在我们成功的第一阶段授予我们开发了一系列稳定的解决方案 用一种新的设计方法设计并证明了它们的体外有效性 在活体内。当这些类似物在常规无菌稀释剂中配制时，不仅保持 标准的95%效力要求，在4℃的2年储存期内，但更重要的是 在40°C下提供至少3个月的延长的使用中稳定期。 在泵系统中实施，用于严重持续性HI的长期管理 担心因胰升糖素不稳定和泵堵塞问题而引起的并发症。此外，这样的一个 该产品将适用于导致超过200,000的紧急低血糖事件 每年住院治疗一次。最后，合成的产品可以在双激素人工制品中实现。 T1和T2糖尿病患者的胰腺。在这个第二阶段的项目中，我们的目标是开发大规模(克级) 候选铅的GLP生产，完整的毒理学、免疫原性和配方研究， 并准备一份适合提交IND的监管方案，为临床试验做准备。

In severe persistent hyperinsulinism (HI), repeated hypoglycemic episodes can ultimately lead to permanent seizure disorders, learning disabilities, cerebral palsy, blindness and even death. Clinical studies have demonstrated the effectiveness of both short-term and long-term treatment with glucagon for severe forms of HI and continuous subcutaneous administration of glucagon has been recommended both because of the potential improvement in patient outcome and high costs of surgical intervention followed by long-term annual care costs. However, the instability of glucagon in solution creates both administration problems and potential complications due to infusion tube blockage. These instability problems have limited the use of glucagon for severe persistent HI. To overcome this problem, in our successful Phase I grant we developed a series of solution stable glucagon analogs using a novel design approach and demonstrated their effectiveness both in vitro and in vivo. These analogs when formulated in a conventional sterile diluent maintain not only the standard 95% potency requirement throughout a 2 year storage period at 4ºC but more importantly offer an extended “in use” stability period of at least 3 months at 40ºC. Such analogs are compatible with implementation in a pump system for the long-term management of severe persistent HI without concern for complications due to glucagon instability and pump clogging issues. In addition, such a product will be suitable for emergency hypoglycemic incidences which result in over 200,000 hospitalizations a year. Finally, the resultant product could be implemented in a bi-hormonal artificial pancreas for T1 and T2 diabetes. In this Phase II project, we aim to develop large scale (gram level) GLP production of the lead candidates, complete toxicology, immunogenicity and formulation studies, and prepare a regulatory package suitable for filing an IND in preparation for clinical trials.