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

项目摘要/摘要 该项目的长期目标是开发安全有效的人类治疗药物--非环鸟苷 眼部腺病毒(ADV)感染，特别是ADV相关的流行性角膜结膜炎(EKC)，国家规定 眼科研究所(NEI)的研究重点。目前还没有对腺病毒患者的治疗方法。 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，或称EKC，是眼部腺病毒感染最严重的形式，通常会导致长期视力 后遗症，如慢性角膜炎和视力丧失。因为FCV之前已经完成了第一阶段的临床研究 作为实体器官移植受者巨细胞病毒(CMV)感染的系统性指标，是一种有效的 作为人腺病毒的抑制剂，这项SBIR建议的目标是产生剩余的眼部特异性 临床前(PC)数据需要支持治疗人类眼部ADV的研究新药(IND)提交 感染。在这个第二阶段的SBIR中，IND-Enabling PC眼部药物动力学(PK)、生物分布和GLP- 毒理学研究将完成，连同确认的疗效参数，适合IND提交。 此外，我们还将确认FCV对ADV的作用机制，并将其与已知的 巨细胞病毒的病毒靶标。这项建议的具体目标以及研究设计和方法如下 以下是： 目的1.用合适的辅料优化滴眼剂处方并确定其对兔ADV的疗效 感染模型(1-2岁)。里程碑：确定适合PC和人类临床眼睛的最终配方 安全性和有效性研究。选择最适宜的剂量水平、频率和持续时间。实验设计： 处方研制，重复建立Ad5/NZW兔眼感染模型，在相同模型中进行剂量优化。 目的2.执行IND-Enable眼部生物分布、全身毒物动力学、局部剂量范围发现 白化兔和狗的眼耐受性和重复给药眼毒理学及支持性研究 (1-2年级)。里程碑：确定眼睛和全身的暴露和分布，以预测潜在的区域 毒性。建立NOAEL法测定人体临床起始剂量。完成急性局部耐受研究， GLP 28天的亚急性眼毒学和体外光毒性研究，以支持IND申请。实验 设计：完成剩余的眼路临床前研究，以支持眼科产品的IND。 目的3.开展行动机制研究(1-2年级)。里程碑：确认病毒和宿主聚合酶和 激酶靶标。实验设计：确定CMV的作用机制是否相同 通过进行突变实验来检测ADV。

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.