FLUORENONE DRUG FOR TREATMENT OF COMBAT-RELATED TRAUMATIC OPTIC NEUROPATHY

Background: Traumatic optic neuropathy (TON) is a frequent cause of significant visual loss after combat-related frontal head trauma. In TON, the injury of the optic nerve originates from concussive forces to the head. There is no clinically proven therapy for improving visual outcomes in TON patients. Our goal is to conduct studies needed to advance the proposed drug candidate, B-3(+), to clinical development for the TON indication. The proposed study directly addresses the FY18 VRP IIRA Focus Areas defined as 'Eye injury or visual dysfunction as related to a military-relevant traumatic event (blast, blunt, thermal, or chemical trauma).'Objective/Hypothesis: The injury-induced edema of the canalicular portion of the optic nerve leads to neural compression that triggers the development of an intracanalicular compartment syndrome. Reduction of swelling by inhibiting injury-induced edema in the intracanalicular portion of the optic nerve is a sound strategy for the prevention of TON-related loss of vision. B-3(+) is an abandoned fluorenone drug that has demonstrated significant efficacy in preventing mortality in animal models of concussive brain injury. B-3(+) acts as a polypharmacological agent capable of significantly reducing insult-induced astrocyte swelling in a number of experimental systems. Given the efficacy of B-3(+) in animal models of traumatic brain injury and assuming that mechanisms of neuronal damage in the canalicular portion of the optic nerve are likely to be analogues to those of the rest of the CNS, we hypothesize that intravitreally administered B-3(+) may be used as a treatment for traumatic optic neuropathy associated with combat-related traumatic brain injury. Our preliminary data indicates that intravitreally administered B-3(+) confers axonal protection in the guinea pig optic nerve crush model, which is consistent with the desired preclinical efficacy of the drug candidate. The overall objective of the proposed project is to conduct the studies needed to support regulatory filings required for B-3(+) to enter clinical development for TON indication. B-3(+) had been systemically administered to humans in Phase I clinical trials for trauma-induced brain edema indicating that it successfully passed some hurdles of preclinical development. However, B-3(+) has never been approved by the US Food and Drug Administration due to nephrotoxicity of the systemically administered drug. We suggest that intravitreal delivery of relatively small B-3(+) doses would lead to the negligible systemic exposure alleviating the concern for drug nephrotoxicity. Additional studies are required for advancing B-3(+) as a treatment for TON that will be administered through intravitreal injections.Specific Aims: (1) Develop a standard in-vitro ADMET package required to support preclinical and clinical development of the drug candidate(2) Conduct systemic and ocular pharmacokinetic studies in beagle dogs; use blood samples collected in PK studies for assessing drug nephrotoxicity(3) Expand upon existing preclinical efficacy data and develop a robust efficacy package that can convincingly justify compound testing in patients with traumatic optic neuropathyStudy Design: We will perform B-3(+) characterization using a set of ADMET assays and assemble a data package required for advancing B-3(+) as a drug treatment for TON. We will conduct ocular and systemic PK experiments in dogs, project the dosing frequency for intravitreal administration of B-3(+) in TON patients, and correlate systemic exposure after intraocular administration with systemic exposures after IV and PO dosing. We will perform the optic nerve crush studies in guinea pigs and determine the range of efficacious B- 3(+) concentrations in the vitreous.Impact/Military Benefit: Traumatic optic neuropathy represents a devastating ophthalmic complication in Soldiers with closed or penetrating head trauma. There is no clinically proven therapy for improving visual outcomes in TON patients. Identification of a new treatment option for TON will have a significant impact on medical management of this condition thus providing an important military benefit.