MICROBIOTIX, INC. — Department of Health and Human Services SBIR Phase II: 100

Description

Project Summary/AbstractThe 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.