Long-acting Stable Glucagons for Treatment of Hyperinsulinism

总结/摘要 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。但是，由于本地的不稳定性， 胰高血糖素使其不适合在HI中长期使用，并且护理人员担心泵和 稳定的胰高血糖素类似物的输注管堵塞会产生给药问题， 潜在的并发症在我们重新定向的第二阶段拨款中，我们成功地发现了长效 适合治疗HI的溶液稳定的胰高血糖素类似物，这将消除这些问题。在 在IIb期项目中，我们的目标是进一步验证HI小鼠模型中的这些先导类似物， 主要候选药物的大规模（克级）GLP生产，以支持必要的毒理学， IND申请的免疫原性和制剂研究。我们还打算追捕孤儿 IND提交前的药物认定（ODD）和罕见儿科疾病认定（RPDD）。

SUMMARY/ABSTRACT 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 native glucagon renders it inappropriate for chronic use in HI, and care-giver concerns about pump and infusion-tube blockage for stable glucagon analogs creates both administration problems and potential complications. In our redirected Phase II grant, we successfully discovered long-acting solution stable glucagon analogs suitable for treating HI, which would eliminate these concerns. In this Phase IIb project, we aim to further validate these lead analogs in HI mouse models, perform large scale (gram level) GLP production of the lead candidates to support the necessary toxicology, immunogenicity and formulation studies for an IND application. We also intend to pursue Orphan Drug Designation (ODD) and Rare Pediatric Disease Designation (RPDD) prior to IND submission.