Development of Filociclovir for the Treatment of Ocular Adenoviral Infections and Keratoconjunctivitis

项目概要/摘要 该项目的长期目标是开发安全有效的治疗人类非昔洛韦（FCV）， 眼腺病毒（AdV）感染，特别是AdV相关的流行性角膜结膜炎（EKC）， 眼科研究所（NEI）研究优先。目前没有治疗患有腺病毒感染的患者的方法。 结膜炎，每年造成多达350万个上学日和850万个工作日的损失 在美国，或EKC，最严重的眼部腺病毒感染形式，通常会导致长期视力下降， 后遗症，如慢性角膜炎和视力下降。由于FCV此前已完成I期临床研究， 用于实体器官移植受者中巨细胞病毒（CMV）感染的全身适应症， 人腺病毒的抑制剂，这个SBIR建议的目的是产生剩余的眼部特异性 临床前（PC）数据，用于支持治疗人眼AdV的研究性新药（IND）申请 感染.在这项II期SBIR中，IND使能PC眼部药代动力学（PK）、生物分布和GLP- 将完成毒理学研究，沿着确证性有效性参数，适用于IND提交。 此外，我们将确认FCV对AdV的作用机制，并将其与已知的 CMV中的病毒靶点。本提案的具体目标，连同研究设计和方法，沿着如下 如下所示： AIM 1.使用合适的辅料优化滴眼液处方，并确认在兔AdV中的有效性 感染模型（1-2年）。关键：确定适用于PC和人类临床眼部的最终制剂 安全性和有效性研究。选择最有利的剂量水平、频率和持续时间。实验设计： 制剂开发、重复Ad 5/NZW兔眼感染模型、在相同模型中剂量优化。 AIM 2.进行IND启用眼部生物分布、全身毒代动力学、局部剂量范围确定 白化病兔和犬的眼部耐受性和重复给药眼部毒理学及支持性研究 （1-2年级）。Milestone：确定眼部和全身暴露和分布，以预测潜在的区域 毒性确定NOAEL以确定人体临床起始剂量。完成急性局部耐受性研究， GLP 28天亚急性眼部毒理学和体外光毒性研究，以支持IND申报。实验 设计：完成眼部途径的剩余临床前研究，以支持眼科产品的IND。 AIM 3.开展作用机制研究（1-2年级）。里程碑：确认病毒和宿主聚合酶， 激酶靶点。实验设计：确定确定CMV的作用机制是否相同 进行突变实验。

Project Summary/Abstract The long-term goal of this project, to develop filociclovir (FCV) for the safe and effective treatment of human ocular adenovirus (AdV) infections, especially AdV-related epidemic keratoconjunctivitis (EKC), a stated National Eye Institute (NEI) research priority. There are currently no treatments for patients suffering from adenoviral conjunctivitis, which is responsible for up to 3.5 million lost school days and 8.5 million lost work days every year in the U.S., or EKC, the most severe form of ocular adenoviral infection, which often causes long-term visual sequelae, such as chronic keratitis and vision loss. As FCV has previously completed Phase 1 clinical studies for a systemic indication of cytomegalovirus (CMV) infection in solid organ transplant recipients and is a potent inhibitor of human adenoviruses, the objective of this SBIR proposal is to generate the remaining ocular-specific preclinical (PC) data needed to support an investigational new drug (IND) submission to treat human ocular AdV infections. In this Phase II SBIR, IND-enabling PC ocular pharmacokinetics (PK), biodistribution and GLP- toxicology studies will be completed, along with confirmatory efficacy parameters, suitable for IND submission. Additionally, we will confirm the mechanism of action of FCV against AdV and compare it with what is known for the viral targets in CMV. The specific aims of this proposal, along with the research design and methods, are as follows: AIM 1. Optimize eye drop formulation with suitable excipients and confirm efficacy in the rabbit AdV infection model (years 1-2). Milestones: Identify final formulation suitable for PC and human clinical ocular safety and efficacy studies. Select most favorable dose level, frequency and duration. Experimental design: formulation development, repeat Ad5/NZW rabbit eye infection model, dosage optimization in the same model. AIM 2. Perform IND-enabling ocular biodistribution, systemic toxicokinetics, local dose range finding ocular tolerance and repeat-dose ocular toxicology and supporting studies in albino rabbits and dogs (years 1-2). Milestones: Determine ocular and systemic exposure and distribution to predict areas of potential toxicity. Establish NOAEL to determine human clinical starting dose. Completion of acute local tolerance studies, GLP 28-day subacute ocular toxicology and in vitro phototoxicity studies to support an IND filing. Experimental design: complete remaining preclinical studies for the ocular route to support IND for ophthalmic product. AIM 3. Conduct mechanism of action studies (years 1-2). Milestones: Confirm viral and host polymerase and kinase targets. Experimental design: determine whether the mechanism of action identified for CMV is the same for AdV by performing mutation experiments.