Stable Glucagon for Treatment of Hyperinsulinism

在严重的持续性高胰岛素血症（HI）中，反复的低血糖发作可最终导致 永久性癫痫、学习障碍、脑瘫、失明甚至死亡。临床 研究已经证明了短期和长期治疗的有效性， 胰高血糖素用于严重形式的HI和胰高血糖素的连续皮下给药已经被广泛接受。 推荐的原因是患者结局的潜在改善和 手术干预，然后是长期的年度护理费用。然而，胰高血糖素的不稳定性， 这种解决方案由于输液管而产生了给药问题和潜在的并发症 堵塞。这些不稳定性问题限制了胰高血糖素在重度持续性HI中的应用。到 为了克服这个问题，在我们成功的第一阶段赠款中，我们开发了一系列解决方案， 胰高血糖素类似物，并证明了它们的有效性， 和体内。当在常规无菌稀释剂中配制时，这些类似物不仅保持了 在4ºC下2年储存期内的标准95%效价要求，但更重要的是 在40ºC下提供至少3个月的延长“使用”稳定期。这些类似物是相容的 在泵系统中实施，用于长期管理严重持续HI， 由于胰高血糖素不稳定和泵堵塞问题引起的并发症的担忧。此外，这样一个 该产品将适用于导致超过20万例 住院一年。最后，所得到的产品可以在双激素人工 T1和T2型糖尿病的胰腺。在这个二期项目中，我们的目标是开发大规模（克级） 主要候选药物的GLP生产，完整的毒理学、免疫原性和制剂研究， 并准备一个适合提交IND的监管包，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.