Nitric oxide releasing bionanomatrix to enhance dialysis fistula maturation

超过725,000名患者患有终末期肾病，其中近90%的患者使用血液透析进行肾脏替代治疗。需要功能正常和耐用的血管通路，动静脉瘘(AVF)是首选，因为感染、血栓形成和医疗费用较低。然而，大约60%的动静脉动静脉瘘在形成后，由于早期的内膜增生和血管扩张不足而未能成熟。目前，尚无有效的治疗方法来促进血管通路成熟。每年治疗血管通路功能障碍的费用总计超过10亿美元。 内生学已经开发出一种释放一氧化氮(NO)的生物瘤基质凝胶(AVF Gel)，通过抑制内膜增生、增强血管扩张和减轻炎症来促进动静脉瘘的成熟。通过SBIR第一阶段和第二阶段的赠款资助，这种AVF凝胶已经在小动物和大动物模型(大鼠和猪)中进行了评估，显示出改善了血流和抑制了内膜增生。 在这个IIB阶段的提案中，我们建议的AIMS将准备Endomimtics，以满足FDA对I期临床试验的要求。这些目标包括：1)根据国际人用药品技术要求协调委员会(ICH)和国际标准化组织(ISO)的指南，与AmBioPharm公司和美国Bioserv公司共同制定符合FDA要求的配方、填充和整理、灭菌和包装的生产计划；2)根据国际人用药品技术要求协调理事会(ICH)和国际标准化组织(ISO)的指导方针，在体外和体内对AVF凝胶进行稳定性和生物兼容性评估。 我们正在开始FDA的审查过程，并于2020年3月4日与FDA进行了初步对话，在对话中，就推进到I期临床试验所需的未来步骤咨询了FDA。Endomimtics AVF Gel的商业化可能会在需要透析的患者的治疗方面提供重大改进。

Over 725,000 patients have end stage renal disease, with nearly 90% utilizing hemodialysis for renal replacement therapy. A functioning and durable vascular access is required, and an arteriovenous fistula (AVF) is preferred due to a lower rate of infections, thrombosis, and healthcare expenditures. However, after formation, approximately 60% of AVFs fail to mature, due to early intimal hyperplasia and inadequate vasodilation. At present, there are no effective therapies to promote vascular access maturation. The annual cost of treating vascular access dysfunction totals over $1 billion US dollars. Endomimetics has developed a nitric oxide (NO) releasing bionanomatrix gel (“AVF Gel”) that improves the maturation of AVFs by inhibiting intimal hyperplasia, enhancing vasodilation, and reducing inflammation. Through SBIR Phase I and II grant funding, this AVF Gel has been evaluated in both small and large animal models (rat and pig), demonstrating improved blood flow and inhibition of intimal hyperplasia. In this Phase IIB proposal, we propose Aims that will prepare Endomimetics to meet FDA requirements for Phase I clinical trials. These Aims include 1) Development of a manufacturing plan with AmbioPharm for large scale peptide synthesis and with Bioserv America for formulation, fill and finish, sterilization, and packaging that is consistent with FDA requirements and 2) Perform stability and biocompatibility evaluations of the AVF Gel in vitro and in vivo based on The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and International Organization for Standardization (ISO) guidelines. We are beginning the FDA review process, and an initial conversation with the FDA occurred on March 4, 2020, in which the FDA was consulted on future steps necessary to advance to Phase I clinical trials. Commercialization of the Endomimetics AVF Gel may provide significant improvement in the treatment of patients requiring dialysis.