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%使用血液透析进行肾脏替代治疗。需要一个功能和持久的血管通路，动静脉瘘（AVF）是首选，因为感染率较低，血栓形成和医疗费用。然而，在形成后，由于早期内膜增生和血管舒张不足，约60%的AVF未能成熟。目前，没有有效的疗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。 Endomimetics已经开发了释放一氧化氮（NO）的生物纳米基质凝胶（“AVF凝胶”），其通过抑制内膜增生、增强血管舒张和减少炎症来改善AVF的成熟。通过SBIR I期和II期资助，该AVF凝胶已在小型和大型动物模型（大鼠和猪）中进行了评价，证明了改善的血流和抑制内膜增生。 在本IIB期提案中，我们提出了制备内模拟物以满足FDA I期临床试验要求的目标。这些目标包括：1）与AmbioPharm一起制定大规模肽合成的生产计划，与Bioserv America一起制定配制、灌装和成品、灭菌的生产计划，和包装符合FDA要求，2）根据人用药品技术要求国际协调理事会（ICH）对AVF凝胶进行体外和体内稳定性和生物相容性评价和国际标准化组织（ISO）的指导方针。 我们正在启动FDA的审查程序，并于2020年3月4日与FDA进行了初步对话，就推进I期临床试验所需的未来步骤向FDA进行了咨询。Endomimetics AVF凝胶的商业化可显著改善需要透析的患者的治疗。

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.