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

用于治疗眼部腺病毒感染和角结膜炎的非洛昔洛韦的开发

• 批准号: 10410533
• 负责人: Terry L. Bowlin
• 金额: $ 71.28万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10410533
• 关键词: Accounting; Acute; Adenovirus Infections; Adenoviruses; Adverse effects; Area; Artificial Tears; Australia; Behavioral; Biodistribution; Biological Assay; Blindness; Canis familiaris; Cardiovascular system; Chemistry; Chronic; Cidofovir; Clinical; Clinical Research; Clinical Trials; Conjunctivitis; Cornea; Cytomegalovirus; Cytomegalovirus Infections; Data; Development; Disease; Dose; Drug Kinetics; Enzymes; Epidemic Keratoconjunctivitis; Excipients; Exhibits; Experimental Designs; Eye; Eye Infections; Eyedrops; FDA approved; Formulation; Frequencies; Gel; Goals; Herpesviridae Infections; Human; In Vitro; India; Infection; Investigational Drugs; Keratitis; Keratoconjunctivitis; Medical; Modeling; Mutation; National Eye Institute; Neurologic; No-Observed-Adverse-Effect Level; Non-Steroidal Anti-Inflammatory Agents; Oryctolagus cuniculus; Pancreatic ribonuclease; Pathology; Patients; Pharmacology; Pharmacology and Toxicology; Pharmacotherapy; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphotransferases; Phototoxicity; Polymerase; Positioning Attribute; Povidone-Iodine; Primary Care Physician; Rattus; Reaction; Regimen; Research Design; Research Methodology; Research Priority; Route; Safety; Schools; Small Business Innovation Research Grant; Solid; Supportive care; Therapeutic; Time; Topical Corticosteroids; Toxic effect; Toxicokinetics; Toxicology; United States; Viral; Viral Load result; Virus Shedding; Visit; Visual; Work; carcinogenicity; conjunctiva; dosage; effective therapy; efficacy study; experimental study; genotoxicity; inhibitor; novel; nucleoside analog; ophthalmic drug; organ transplant recipient; phase 2 study; pre-clinical; preclinical development; preclinical study; ranpirnase; respiratory; safety study; socioeconomics; symptomatic improvement

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.

项目概要/摘要 该项目的长期目标是开发非洛昔洛韦（FCV），用于安全有效地治疗人类 眼腺病毒 (AdV) 感染，特别是与 AdV 相关的流行性角结膜炎 (EKC) 眼科研究所 (NEI) 研究优先。目前尚无针对腺病毒患者的治疗方法 结膜炎，每年导致多达 350 万个上课时间和 850 万个工作日损失 在美国，EKC 是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丧失。由于FCV此前已完成1期临床研究 用于实体器官移植受者巨细胞病毒 (CMV) 感染的全身适应症，是一种有效的方法 人类腺病毒抑制剂，该 SBIR 提案的目标是产生剩余的眼部特异性 支持治疗人眼 AdV 的研究性新药 (IND) 提交所需的临床前 (PC) 数据 感染。在此 II 期 SBIR 中，支持 IND 的 PC 眼药代动力学 (PK)、生物分布和 GLP- 将完成毒理学研究以及验证性功效参数，适合 IND 提交。 此外，我们将确认 FCV 对抗 AdV 的作用机制，并将其与已知的进行比较。 CMV 中的病毒靶标。本提案的具体目标以及研究设计和方法如下： 如下： 目的 1. 使用合适的赋形剂优化滴眼剂配方并确认在兔 AdV 中的功效 感染模型（1-2 年）。里程碑：确定适合 PC 和人类临床眼科的最终配方 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： 配方开发、重复Ad5/NZW兔眼感染模型、同一模型中的剂量优化。 目标 2. 执行支持 IND 的眼部生物分布、全身毒代动力学、局部剂量范围查找 白化兔子和狗的眼耐受性和重复剂量眼毒理学及支持研究 （1-2 年）。里程碑：确定眼部和全身暴露和分布以预测潜在区域 毒性。建立 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 天亚急性眼毒理学和体外光毒性研究支持 IND 申请。实验性的 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。 目标 3. 进行行动机制研究（第 1-2 年）。里程碑：确认病毒和宿主聚合酶以及 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获取 AdV。