Project Grant R44EY033267

DEVELOPMENT OF A SELECTIVE INHIBITOR OF NAV1.7 FOR THE TREATMENT OF OCULAR PAIN - PROJECT SUMMARY THE ABSENCE OF SAFE AND EFFECTIVE STRATEGIES FOR THE MANAGEMENT OF OCULAR PAIN IS MOTIVATING THE DEVELOPMENT OF A NOVEL TOPICAL DRUG SUITABLE FOR PATIENT SELF-ADMINISTRATION. CONVENTIONAL LOCAL ANESTHETICS, SUCH AS PROPARACAINE, INHIBIT VOLTAGE-GATED SODIUM CHANNELS (NAV) AND ARE HIGHLY EFFECTIVE FOR THE MANAGEMENT OF OCULAR PAIN IN ACUTE, IN-OFFICE SETTINGS. HOWEVER, THESE ANESTHETIC AGENTS BLOCK PROTECTIVE OCULAR REFLEXES AND ARE TOXIC TO THE CORNEAL SURFACE, WHICH LIMITS THEIR USE TO A FEW IN-OFFICE ADMINISTRATIONS. OTHER AGENTS, SUCH AS TOPICAL NSAIDS, ARE RELATIVELY INEFFECTIVE AT RELIEVING OCULAR DISCOMFORT, OR HAVE SIDE EFFECTS THAT LIMIT THEIR USE. SITEONE THERAPEUTICS HAS DISCOVERED A NOVEL CHEMICAL SERIES OF EXQUISITELY SELECTIVE INHIBITORS OF HUMAN NAV1.7, A VOLTAGE-GATED SODIUM CHANNEL SUBTYPE IMPLICATED IN THE TRANSMISSION OF PAIN SIGNALS BY HUMAN GENETICS. THESE COMPOUNDS EXHIBIT EXCELLENT DOSE-DEPENDENT ANALGESIC EFFECTS IN MULTIPLE ANIMAL MODELS OF ACUTE AND CHRONIC PAIN INCLUDING A RAT DRY EYE MODEL. IN PRECLINICAL SAFETY AND EFFICACY STUDIES, TOPICAL OCULAR ADMINISTRATION IS EFFECTIVE, SAFE, WELL TOLERATED, AND LEADS TO GOOD INTRAOCULAR EXPOSURE. THE GOAL OF THIS PHASE 2 SBIR PROPOSAL IS TO ADVANCE IND-ENABLING DEVELOPMENT OF A TOPICAL OCULAR ANALGESIC PRODUCT. THE SPECIFIC AIMS ARE TO COMPLETE GLP NONCLINICAL SAFETY STUDIES, DRUG PRODUCT DEVELOPMENT, AND TO PREPARE THE FIRST GMP BATCH IN ORDER TO INITIATE CLINICAL STUDIES TO DETERMINE IF THE NEW TOPICAL DRUG HAS AN ADEQUATE SAFETY AND EFFICACY PROFILE TO JUSTIFY FURTHER CLINICAL DEVELOPMENT FOR THE TREATMENT OF OCULAR PAIN.