Mitochondrial-Targeted Therapy for Macular Degeneration

摘要 老年性黄斑变性(AMD)是老年人最常见的致盲原因。大多数AMD 病例为非渗出性(或“干性”)型，影响全球多达2亿患者，包括 中度干性AMD，其特征是形成视网膜下色素上皮(RPE)沉积，称为 和地理性萎缩(GA)，这是一种更严重的疾病，其特征是RPE和 光感受器。目前，任何形式的干性AMD都没有可用的治疗方法。因此，有一个 对任何有效治疗的巨大需求尚未得到满足。视网膜色素上皮线粒体功能障碍已被证实 作为干性AMD的主要发病机制。虽然系统地给药线粒体靶向药物 在干性AMD的临床前和早期临床研究中显示出了希望，他们有局限性，包括 一些患者的视网膜生物利用度不足。这项直接到第二阶段SBIR的拨款的目的 应用是开发一种新型的玻璃体内缓释线粒体靶向药物(IVT Mito XR) 干性AMD的治疗。ECLIPSE生命科学公司设计了EY005的新型线粒体靶向前药 (销售线索和备份)。初步研究表明，先导EY005前药和中试制剂 在体外和体内线粒体功能障碍模型中，前药对IVT Mito XR都具有良好的疗效 与干性老年性黄斑变性有关。拟议项目的重点是开发以下物质的主导和后备配方 IVT Mito XR使用Eclipse专有的缓释药物输送系统(XRDDS)，以实现目标 单次玻璃体内注射后EY005缓释3个月的产品规格。目标1将 最终确定先导和后备前药的IVT Mito XR配方。目标2将执行非GLP(好 实验室实践)IVT Mito XR的药代动力学、毒理学和概念验证疗效研究 兔子模型。目标3将执行GMP(良好制造规范)生产和初步 铅EY005前药的表征。最终交付成果将在以下时间提交预制IND包 为安排与FDA的IND前会议做准备。

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.