Complement Inhibitors for Macular Degeneration

描述（由申请人提供）：根据世界卫生组织（WHO）全球眼科疾病调查，1400万人因年龄相关性黄斑变性AMD而失明或严重视力受损。这种疾病会影响65岁以上成年人的中心视力。除了部分/完全视力丧失之外，黄斑（中央视网膜）中的布鲁赫膜和视网膜色素上皮的退行性变化是AMD的标志。据估计，超过25%的AMD患者将由于地图状萎缩或脉络膜新生血管化（CNV）（通常称为湿性AMD）而发展为严重的视力丧失。CNV的发展来源于炎症和血管生成。因此，必须控制VEGF和炎症介质以防止CNV相关的视力丧失。在病理性新生血管形成中发现VEGF水平升高。血管生成的过程是多因素的，并且高度复杂，有新血管形成和炎症的证据。VEGF被认为在生理和病理情况下都是重要的。通过阻断所有VEGF，局部伤口愈合可能受损，而对于任何眼部手术治疗，该过程可能会被推迟或甚至完全停止。新血管形成和炎症必须得到控制，以实现湿性AMD的预期效益。预防血管内皮生长因子和炎症介质形成的策略，而不是仅仅单独阻断它们中的每一种，对于阻止疾病的进展可能很重要。为了实施这一策略，NovelMed开发了一种高亲和力、高选择性的旁路途径中和抗体，可防止补体和细胞活化以及炎症介质的产生。在脉络膜新生血管（CNV）的兔模型中，该药物以每只眼睛15 μ g的浓度在28天内防止CNV损伤的形成。本项目的具体目标是：1）人源化NM 9405的生产和纯化，用于目标2和3; 2）人源化NM 9405在脉络膜新生血管形成（CNV）的兔模型中的评价和3）人源化NM 9405在脉络膜新生血管形成（CNV）的食蟹猴模型中的功效和安全性-这些研究将解决眼疗效和毒性研究所需的移动到下一个步骤的研究性新药（IND）申请，制药合作和投资。有效性和初步眼部安全性的证明将使该项目进入IND阶段申请。

DESCRIPTION (provided by applicant): According to the World Health Organization (WHO) global eye disease survey, 14 million people are blind or severely visually impaired due to age-related macular degeneration AMD. This disease affects the central vision of adults over the age 65. Degenerative changes of the Bruch's membrane and the retinal pigment epithelium in the macula (central retina) in addition to the partial / complete vision loss is the hallmark of AMD. It is estimated that greater than 25% of AMD patients will develop severe vision loss due to either geographic atrophy or Choroidal NeoVascularization (CNV), commonly known as wet AMD. CNV development derives from both inflammation and angiogenesis. Thus, both VEGF and inflammatory mediators must be controlled to prevent CNV associated vision loss. Elevated levels of VEGF have been found in pathological neovascularization. The process of angiogenesis is multi-factorial and highly complex with evidence of both neovascularization and inflammation. VEGF is considered important in both physiological and pathological situations. By blocking all VEGF, local wound healing could be impaired, whereas for any ocular surgery treatment the procedure may then be postponed or even stopped altogether. Both neovascularization and inflammation must be controlled in order to achieve the desired benefit in Wet AMD. A strategy to prevent the formation of VEGF & inflammatory mediators, as opposed to just blocking each of them individually, could be important in halting the progression of the disease. To implement this strategy, NovelMed has developed a high affinity highly selective neutralizing antibody of the alternative pathway that prevents complement and cellular activation and production of inflammatory mediators. In a rabbit model of choroidal neovascularization (CNV), the drug prevented the formation of CNV lesions at a concentration of 15 ug per eye over a 28 day period. We would like to develop The Specific Aims of the project are: 1) Production and Purification of Humanized NM9405 for Aims 2 and 3; 2) Evaluation of Humanized NM9405 in the Rabbit Model of Choroidal NeoVascularization (CNV) and 3) Efficacy & Safety of the Humanized NM9405 in the Cynomolgus Monkey Model of Choroidal Neovascularization (CNV)- - These studies will address ocular efficacy and toxicity studies required for moving to the next step of Investigational New Drug (IND) filings, pharma-partnering, and investment. The demonstration of efficacy and preliminary ocular safety will move this program to an IND stage application.