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.
Public Health Relevance Statement: PROJECT NARRATIVE The goal of this project is to develop a novel eye injection treatment for dry age-related macular degeneration (AMD). In dry AMD, vision loss occurs due to formation of abnormal deposits of fat and proteins under the retina (drusen) and atrophy of retinal tissue over time. There are no approved therapies for dry AMD. One major cause of AMD is damage to mitochondria, the energy factories within our cells. This project will develop a new drug designed to repair damaged mitochondria, which in turn, may slow disease worsening and improve vision in patients suffering from dry AMD.
Project Terms: Affect; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Elderly; Alcohol Chemical Class; Alcohols; Biological Availability; Bioavailability; Physiologic Availability; Biological Sciences; Biologic Sciences; Bioscience; Life Sciences; Biological Response Modifier Therapy; Biological Therapy; biological therapeutic; biological treatment; biologically based therapeutics; biotherapeutics; biotherapy; Cells; Cell Body; Clinical Research; Clinical Study; Clinical Trials; Disease; Disorder; Drug Design; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Investigational Drugs; Investigational New Drugs; Esters; Eye; Eyeball; Fatty acid glycerol esters; Fats; Goals; Growth; Generalized Growth; Tissue Growth; ontogeny; In Vitro; Lead; Pb element; heavy metal Pb; heavy metal lead; Lipids; Macular degeneration; Macular degenerative disease; Mitochondria; mitochondrial; Organelles; Patients; Drug Kinetics; Pharmacokinetics; Photoreceptors; Photoreceptor Cell; Photosensitive Cell; Visual Receptor; Prodrugs; Drug Precursors; Pro-Drugs; Production; Proteins; Oryctolagus cuniculus; Domestic Rabbit; Rabbits; Rabbits Mammals; Reading; Research; Retina; Superoxides; Superoxide Anion; Superoxide Radical; Time; Tissues; Body Tissues; Toxicology; Vision; Sight; visual function; Visual Acuity; polyarginine; poly(L-arginine); Drug Delivery; Drug Delivery Systems; Schedule; improved; Penetration; repair; repaired; Specified; Specific qualifier value; Phase; Biochemical; Link; function luminance; luminance; Age-Related Maculopathy; age related macular dystrophy; senile macular disease; Age related macular degeneration; Atrophic AMD; Atrophic age-related macular degeneration; Dry AMD; Non-exudative age-related macular degeneration; dry age-related macular degeneration; Nonexudative age-related macular degeneration; Therapeutic; Deposition; Deposit; Atrophic; Atrophy; subcutaneous; subdermal; Blindness; vision loss; visual loss; advanced disease; advanced illness; novel; Modeling; response; Druse; Drusen; small molecule; Address; Dose; Bolus Infusion; Bolus; Dryness; Applications Grants; Grant Proposals; Pre-Clinical Model; Preclinical Models; in vivo; in vivo Model; Pigment Epithelium; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Preparation; preparations; Modification; geographic atrophy; intravitreal injection; open label; open label study; pre-clinical; preclinical; designing; design; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; mitochondrial dysfunction; effective treatment; effective therapy; good laboratory practice; Drug Targeting; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; Formulation; efficacy study; Injections; off-patent; pre-Investigational New Drug meeting; Pre IND FDA meeting; Pre-IND mtg; pre-IND consultation; pre-IND discussion; pre-IND meeting; Good Manufacturing Process; Good manufacturing practice; manufacture
