Complement Inhibitors for Macular Degeneration

描述（由申请人提供）：根据世界卫生组织（WHO）全球眼病调查，1400万人因老年性黄斑变性AMD而失明或严重视力受损。这种疾病影响65岁以上成年人的中央视力。除部分/完全视力丧失外，黄斑（中央视网膜）的布鲁氏膜和视网膜色素上皮的退行性改变是AMD的标志。据估计，超过25%的AMD患者会因地理萎缩或脉络膜新生血管（CNV）而出现严重的视力丧失，通常被称为湿性AMD。CNV的发展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。在病理性新生血管中发现VEGF水平升高。血管生成的过程是多因素和高度复杂的，既有新生血管的证据，也有炎症。VEGF在生理和病理情况下都被认为是重要的。通过阻断所有VEGF，局部伤口愈合可能会受损，而对于任何眼部手术治疗，手术可能会被推迟甚至完全停止。为了在湿性AMD中达到预期的效果，必须控制新生血管和炎症。一种防止VEGF和炎症介质形成的策略，而不是单独阻断它们中的每一个，可能对阻止疾病的进展很重要。为了实现这一策略，NovelMed开发了一种高亲和力、高选择性的替代途径中和抗体，可阻止补体和细胞激活以及炎症介质的产生。在兔脉络膜新生血管（CNV）模型中，在28天的时间里，每只眼睛15 ug的浓度的药物阻止了CNV病变的形成。该项目的具体目标是：1)为目标2和3生产和纯化人性化NM9405；2)人源化NM9405在兔脉络膜新生（CNV）模型中的疗效和安全性评估；3)人源化NM9405在蟹猴脉络膜新生（CNV）模型中的疗效和安全性——这些研究将解决眼科疗效和毒性研究的问题，为下一步的新药研究（IND）申请、制药合作和投资做好准备。有效性和初步眼安全性的论证将使该项目进入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.