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Long-acting Stable Glucagons for Treatment of Hyperinsulinism

长效稳定胰高血糖素治疗高胰岛素血症

基本信息

批准号：
10611746
负责人：
Pawel Fludzinski
金额：
$ 128.77万
依托单位：
AMIDEBIO, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-18 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10611746
关键词：
Animals Birth Blindness COVID-19 pandemic Canis familiaris Caregivers Cerebral Palsy Cessation of life Child Childhood Chronic Clinic Clinical Clinical Research Clinical Trials Complement Continuous Infusion Contracts DNA Sequence Alteration Defect Diabetes Mellitus Diffuse Disease Dose Effectiveness Epilepsy Equipment Event Failure Family Feedback Fermentation Formulation Glucagon Glucose Glucose Plasma Concentration Goals Grant Hyperinsulinism Hypoglycemia In Vitro Incidence Infusion Pumps Infusion procedures Investigational Drugs Investigational New Drug Application Lead Learning Disabilities Letters Life Medical Methods Mind Modeling Newborn Infant Operative Surgical Procedures Orphan Drugs Pancreatectomy Patient-Focused Outcomes Patients Persistent Hyperinsulinemia Hypoglycemia of Infancy Phase Phase II Clinical Trials Physiological Production Property Protocols documentation Pump Rattus Reporting Research Series Technology Testing Toxicology Tube United States United States National Institutes of Health Validation Work analog bariatric surgery base blood glucose regulation care costs cost design effective therapy immunogenicity in vitro Model in vitro activity in vivo in vivo evaluation insulin regulation insulin secretion large scale production lead candidate milligram mouse model novel patient population pharmacokinetics and pharmacodynamics phase 2 study phase II trial preference prevent primary endpoint programs rare condition scale up subcutaneous

项目摘要

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.

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）。