Long-acting Stable Glucagons for Treatment of Hyperinsulinism

摘要/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，原生生物的不稳定性 胰高血糖素使其不适合在HI中长期使用，护理人员担心泵和 稳定的胰升糖素类似物输液管堵塞会造成给药问题和 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 适用于治疗HI的溶液稳定的胰升糖素类似物，这将消除这些担忧。在……里面 这个IIb阶段的项目，我们的目标是在HI小鼠模型中进一步验证这些铅类似物，执行 大规模(克级)生产候选铅，以支持必要的毒理学； IND应用的免疫原性和配方研究。我们还打算追查孤儿 IND提交前的药物指定(ODD)和罕见儿科疾病指定(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.