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: 10257718
• 负责人: Terry L. Bowlin
• 金额: $ 74.95万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10257718
• 关键词: Accounting; Acute; Adenovirus Infections; Adenoviruses; Adverse effects; Antiviral Agents; 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; Organ Transplantation; 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; Transplant Recipients; United States; Viral; Viral Load result; Virus Shedding; Visit; Visual; Work; carcinogenicity; conjunctiva; dosage; effective therapy; efficacy study; experimental study; genotoxicity; inhibitor/antagonist; novel; nucleoside analog; ophthalmic drug; 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.

项目摘要/摘要 该项目的长期目标是开发Filociclovir（FCV），以安全有效地治疗人类 眼部腺病毒（ADV）感染，特别是与ADV相关的流行病性角膜结构炎（EKC），一个陈述的国家 眼科研究所（NEI）研究优先级。目前尚无针对患有腺病毒的患者的治疗方法 结膜炎，该炎造成高达350万个损失的上学天，每年850万个损失的工作日 在美国或EKC，是眼科腺病毒感染最严重的形式，通常会引起长期视觉 后遗症，例如慢性角膜炎和视力丧失。由于FCV先前已经完成了1期临床研究 用于系统的巨细胞病毒（CMV）感染的系统性指示，是一种有效的 人类腺病毒的抑制剂，该SBIR提案的目的是生成剩余的眼部特异性 支持研究新药（IND）的临床前（PC）数据来治疗人类眼睛ADV 感染。在此II期SBIR中 毒理学研究将完成，以及确认功效参数，适合于提交。 此外，我们将确认FCV对ADV的作用机理，并将其与已知的 CMV中的病毒靶标。该提案的具体目的以及研究设计和方法是 以下内容： AIM 1。用合适的赋形剂优化眼滴配方，并确认在兔子ADV中的功效 感染模型（1 - 2年）。里程碑：确定适合PC和人类临床眼的最终配方 安全与效力研究。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。执行辅助眼生物分布，全身有毒因素，局部剂量范围查找 眼部兔子和狗的眼部耐受性和重复剂量眼毒理学和支持研究 （1 - 2年）。里程碑：确定眼和全身暴露和分布以预测潜在区域 毒性。建立Noael来确定人类的临床起始剂量。完成急性局部耐受研究， GLP 28天亚急性眼毒理学和体外光毒性研究以支持IND归档。实验 设计：针对眼部途径为眼科产品的IND途径的完整剩余的临床前研究。 目标3。进行行动研究机理（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识别的作用机理是否相同 通过执行突变实验来进行ADV。