SUMMARY Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly. Most AMD cases are the nonexudative (or “dry”) form, which affects up to 200 million patients globally and is comprised of intermediate dry AMD, characterized by formation of sub-retinal pigment epithelium (RPE) deposits called drusen, and geographic atrophy (GA), more advanced disease characterized by loss of RPE and photoreceptors. Currently, there are no available treatments for any form of dry AMD. Thus, there is a tremendous unmet need for any effective therapy. Mitochondrial dysfunction at the RPE has been established as a major disease mechanism for dry AMD. While systemically administered mitochondria-targeted drugs have shown promise in preclinical and early-phase clinical studies of dry AMD, they have limitations, including insufficient bioavailability at the retina in some patients. The purpose of this Direct to Phase 2 SBIR grant application is to develop a novel intravitreal extended release mitochondria targeted drug (IVT Mito XR) for the treatment of dry AMD. Eclipse Life Sciences has designed novel mitochondria targeted prodrugs of EY005 (lead and backups). Preliminary studies demonstrate that the lead EY005 prodrug and a pilot formulation of the prodrug in IVT Mito XR has excellent efficacy in both in vitro and in vivo models of mitochondrial dysfunction that are relevant to dry AMD. The proposed project is focused on developing lead and backup formulations of IVT Mito XR using Eclipse’s proprietary extended release drug delivery system (XRDDS), to achieve target product specification of 3 months’ sustained release of EY005 following a single intravitreal injection. Aim 1 will finalize IVT Mito XR formulations of lead and backup prodrugs. Aim 2 will be to perform nonGLP (good laboratory practice) pharmacokinetics, toxicology, and proof of concept efficacy studies of IVT Mito XR in rabbit models. Aim 3 will be to execute GMP (good manufacturing practice) production and preliminary characterization of lead EY005 prodrug. The end deliverable will be submission of a pre-IND package in preparation for scheduling a pre-IND meeting with FDA.