SBIR-STTR Award

Direct to Phase II

The long-term goal of this project, to develop filociclovir (FCV) for the safe and effective treatment of humanocular adenovirus (AdV) infections, especially AdV-related epidemic keratoconjunctivitis (EKC), a stated NationalEye Institute (NEI) research priority. There are currently no treatments for patients suffering from adenoviralconjunctivitis, which is responsible for up to 3.5 million lost school days and 8.5 million lost work days every yearin the U.S., or EKC, the most severe form of ocular adenoviral infection, which often causes long-term visualsequelae, such as chronic keratitis and vision loss. As FCV has previously completed Phase 1 clinical studiesfor a systemic indication of cytomegalovirus (CMV) infection in solid organ transplant recipients and is a potentinhibitor of human adenoviruses, the objective of this SBIR proposal is to generate the remaining ocular-specificpreclinical (PC) data needed to support an investigational new drug (IND) submission to treat human ocular AdVinfections. 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 forthe viral targets in CMV. The specific aims of this proposal, along with the research design and methods, are asfollows:AIM 1. Optimize eye drop formulation with suitable excipients and confirm efficacy in the rabbit AdVinfection model (years 1-2). Milestones: Identify final formulation suitable for PC and human clinical ocularsafety 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 findingocular 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 potentialtoxicity. 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. Experimentaldesign: 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 andkinase targets. Experimental design: determine whether the mechanism of action identified for CMV is the samefor AdV by performing mutation experiments.

Public Health Relevance Statement:
Project Narrative The overall goal of this project is to develop filociclovir (FCV) as a safe and effective treatment for the most common cause of ocular infections, human adenovirus. There are currently no treatments for patients suffering from: (i) 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 (ii) epidemic keratoconjunctivitis (EKC), the most severe form of ocular adenoviral infection, which often causes long-term visual sequelae, such as chronic keratitis and vision loss. This project will complete FCV's ocular preclinical development and position it for human clinical trials as a first- in-class anti-adenoviral inhibitor.

Project Terms:
Accounting ; Adenoviruses ; Adenoviridae ; Adenovirus Infections ; Adenoviridae Infections ; inhibitor/antagonist ; inhibitor ; Non-Steroidal Anti-Inflammatory Agents ; NSAIDs ; Non Steroidal Antiinflammatory Agents ; Nonsteroidal Anti-Inflammatory Agents ; Nonsteroidal Antiinflammatory Agents ; Nonsteroidal Antiinflammatory Drug ; non-steroidal anti-inflammatory drugs ; non-steroidal antiinflammatory drugs ; nonsteroidal anti-inflammatory drugs ; Antiviral Agents ; Antiviral Drugs ; Antivirals ; anti-viral agents ; anti-viral drugs ; anti-virals ; Artificial Tears ; Australia ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Cardiovascular system ; Cardiovascular ; Cardiovascular Body System ; Cardiovascular Organ System ; Heart Vascular ; circulatory system ; Chemistry ; Clinical Research ; Clinical Study ; Clinical Trials ; conjunctiva ; Conjunctivitis ; Cornea ; corneal ; Cytomegalovirus Infections ; CMV infection ; Cytomegalic Inclusion Disease ; Inclusion Disease ; Salivary Gland Virus Disease ; Cytomegalovirus ; CMV ; HCMV ; Salivary Gland Viruses ; cytomegalovirus group ; Disease ; Disorder ; Canis familiaris ; Canine Species ; Dogs ; Dogs Mammals ; canine ; domestic dog ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Investigational Drugs ; Investigational New Drugs ; Enzymes ; Enzyme Gene ; Epidemic Keratoconjunctivitis ; Excipients ; Exhibits ; Experimental Designs ; Eye ; Eyeball ; Eyedrops ; Eye Drops ; Eye Infections ; Ocular Infections ; Gel ; Goals ; Herpesviridae Infections ; Herpes infection ; Herpesviridae disease ; Herpesvirus Infections ; Human ; Modern Man ; In Vitro ; India ; Infection ; Keratitis ; Keratoconjunctivitis ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Organ Transplantation ; Grafting Procedure ; Organ Transplants ; organ allograft ; organ graft ; organ xenograft ; Pathology ; Patients ; Drug Kinetics ; Pharmacokinetics ; Pharmacology ; Phosphotransferases ; Kinases ; Phosphotransferase Gene ; Transphosphorylases ; Povidone-Iodine ; Betadine ; PVP-I ; PVP-Iodine ; Polyvinylpyrrolidone Iodine ; Primary Care Physician ; Oryctolagus cuniculus ; Domestic Rabbit ; Rabbits ; Rabbits Mammals ; Rattus ; Common Rat Strains ; Rat ; Rats Mammals ; Research Design ; Study Type ; study design ; Pancreatic ribonuclease ; Pancreatic RNase ; RNase A ; RNase I ; Ribonuclease A ; Ribonuclease I ; Safety ; Schools ; Time ; Toxicology ; United States ; Work ; ranpirnase ; P-30 Protein ; P30 ; P30 Protein ; Research Methodology ; Research Methods ; Virus Shedding ; Viral Shedding ; dosage ; Area ; Acute ; Chronic ; Solid ; Clinical ; Phase ; Medical ; Neurologic ; Neurological ; Visual ; Toxicokinetics ; Phase II Clinical Trials ; Phase 2 Clinical Trials ; phase II protocol ; No-Observed-Adverse-Effect Level ; NOAEL ; Cidofovir ; HPMPC ; Therapeutic ; Topical Corticosteroids ; ophthalmic drug ; Supportive Therapy ; Supportive care ; Research Priority ; transplant patient ; Transplant Recipients ; Viral Burden ; Viral Load ; Viral Load result ; Frequencies ; Reaction ; Route ; vision loss ; visual loss ; Blindness ; Viral ; respiratory ; Visit ; nucleoside analog ; genotoxicity ; Toxicities ; Toxic effect ; Pharmacology and Toxicology ; novel ; Position ; Positioning Attribute ; carcinogenicity ; Modeling ; Adverse effects ; Early-Stage Clinical Trials ; Phase 1 Clinical Trials ; phase I protocol ; Phase I Clinical Trials ; Polymerase ; Dose ; Data ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; socioeconomics ; socio-economic ; socio-economically ; socioeconomically ; Development ; developmental ; Phototoxicity ; Behavioral ; safety study ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; National Eye Institute ; Biodistribution ; FDA approved ; symptomatic improvement ; improve symptom ; symptom improvement ; effective therapy ; effective treatment ; phase 2 study ; phase II study ; Regimen ; Formulation ; experimental study ; experiment ; experimental research ; efficacy study ; preclinical development ; pre-clinical development ;