Stable Glucagon for Treatment of Hyperinsulinism

稳定胰高血糖素治疗高胰岛素血症

• 批准号: 9909030
• 负责人: Pawel Fludzinski
• 金额: $ 74.01万
• 依托单位: AMIDEBIO, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-18 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9909030
• 关键词: Amino Acid Substitution; Amino Acids; Aminoisobutyric Acids; Artificial Pancreas; Biological; Birth; Blindness; Cerebral Palsy; Cessation of life; Child; Clinic; Clinical Research; Clinical Trials; DNA Sequence Alteration; Defect; Diabetes Mellitus; Diffuse; Disease; Dose; Effectiveness; Emergency Situation; Epilepsy; Equipment; Failure; Fermentation; Formulation; Glucagon; Glucose; Glucose Plasma Concentration; Grant; Hormonal; Hospitalization; Hyperinsulinism; Hypoglycemia; Immune response; In Vitro; Incidence; Infusion procedures; Investigational Drugs; Investigational New Drug Application; Lead; Learning Disabilities; Life; Medical; Methods; Miniature Swine; Modeling; Newborn Infant; Operative Surgical Procedures; Pancreatectomy; Patient-Focused Outcomes; Patients; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Phase; Physiological; Preparation; Production; Protocols documentation; Pump; Rattus; Regulation; Risk; Series; Sterility; System; Technology; Testing; Toxicology; Tube; United States; Work; analog; bariatric surgery; base; care costs; cost; design; diabetic; effective therapy; efficacy study; immunogenicity; in vitro Model; in vivo; in vivo evaluation; insulin secretion; large scale production; lead candidate; milligram; non-Native; novel; phase 1 study; physical property; prevent; rare condition; scale up; subcutaneous; unnatural amino acids

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.

在严重的持续性超胰岛素（HI）中，反复的降血糖发作最终会导致 永久性癫痫发作，学习不景气，脑瘫，失明甚至死亡。 研究证明了短期和长期的有效性 严重形式的HI和连续皮下给药的胰高血糖素已经是 推荐既是因为患者结局的潜在改善和成本有所改善 但是，手术干预遵循长期的年度护理费用。 解决方案既会产生给药问题和由于输液管引起的潜在汇编 这些不稳定性问题限制了胰高血糖量的严重持续性HI 克服这个问题，在我们成功的阶段I授予中，我们开发了一系列解决方案稳定 使用无新型设计方法的胰高血糖素类似物，并证明了有效的体外 和体内。 在4ºC的2年存储期间，标准的95％效力要求，但更重要的是 在40ºC时提供至少3个月的“使用”稳定性期。 在泵系统中实施，用于长期管理严重的持久性HI 由于胰高血糖素不稳定性和泵堵塞问题而引起的并发症。 产品适用于紧急降血糖事件，导致超过20万 住院 T1和T2糖尿病的palc夫。 铅候选者的GLP产生，完整的毒理学，免疫原性和制定研究， 并准备适用于临床试验的备案和IND准备的常规包装。