Translational studies to advance Filociclovir to IND submission for the treatment of adenoviral conjunctivitis and acute keratoconjunctivitis

Project Summary/Abstract The long-term goal of this project, to develop filociclovir (FCV) for the safe and effective treatment of human adenovirus (HAdV) ocular infections, especially HAdV-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 8.5 million lost work days and $1.9 billion in lost wages 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, the objective of this R33 proposal is to generate the remaining ocular-specific preclinical (PC) data needed to support an investigational new drug (IND) submission to treat ocular HAdV infections. In this proposal, final formulation work and IND-enabling GLP-toxicology studies will be completed, along with confirmatory efficacy parameters, suitable for IND submission. We will continue to communicate with the FDA to ensure that the correct study designs are in place. The specific aims of this proposal, along with the research design and milestones, are as follows: AIM 1. Finalize eye drop formulation with suitable preservatives, confirm efficacy in the rabbit HAdV infection model and select a device (eye dropper) (year 1). Milestones: Formulation suitable for two species IND-enabling GLP toxicology and advancement into human studies, formulation passes Antimicrobial Effectiveness Testing (AET), efficacy in rabbit eye model and final device selected. AIM 2. Perform IND-enabling GLP ocular toxicology in rabbits and dose range-finding ocular tolerance and GLP ocular toxicology in rats (years 2-3). Milestones: Completion of acute tolerance studies in rats, GLP 14-day ocular toxicology in rabbits and rats to support an IND filing, NOAEL ≥ 0.5% dosed QID. AIM 3. Complete regulatory requirements, including communications with the FDA, IND application and clinical trial design (years 2-3). Milestones: Pre-IND meeting with the FDA (follow-up to the Type C meeting held January 3, 2024), IND application and clinical trial design completed.