Mitochondrial-Targeted Therapy for Macular Degeneration

总结 视网膜相关性黄斑变性（AMD）是老年人失明的最常见原因。大多数AMD 病例为非渗出性（或“干性”）形式，全球影响多达2亿患者，包括 中度干性AMD，其特征在于形成视网膜下色素上皮（RPE）沉积物，称为 玻璃疣和地图状萎缩（GA），更晚期的疾病特征在于RPE的丧失， 光感受器目前，对于任何形式的干性AMD都没有可用的治疗方法。因此，有一个 对有效治疗的巨大需求。已经确定RPE处的线粒体功能障碍 作为干性AMD的主要发病机制。当全身给予靶向药物时， 在干性AMD的临床前和早期临床研究中显示出前景，但它们有局限性，包括 在某些患者中视网膜的生物利用度不足。此直接至第2阶段SBIR赠款的目的 本申请的目的是开发一种新的玻璃体内缓释线粒体靶向药物（IVT Mito XR），用于治疗 治疗干性AMD。Eclipse Life Sciences设计了EY005的新型线粒体靶向前药 (lead备份）。初步研究表明，先导EY005前药和先导EY005前药的中试制剂具有良好的生物相容性。 IVT Mito XR中的前药在体外和体内线粒体功能障碍模型中均具有优异的疗效 与干性AMD相关的疾病拟议项目的重点是开发下列药物的主要和备用制剂： IVT Mito XR使用Eclipse专有的延长释放药物输送系统（XRDDS），以实现目标 在单次玻璃体内注射后3个月持续释放EY005的产品规格。目标1将 最终确定IVT Mito XR的先导和备用前药制剂。目标2是执行非GLP（良好 实验室实践）IVT Mito XR的药代动力学、毒理学和概念验证功效研究 兔子模型目标3将是执行GMP（良好生产规范）生产和初步 先导EY005前药的表征。最终可交付成果将是提交IND前文件包， 准备安排与FDA的IND前会议。

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.