Disease Modifying Biologics for Rheumatoid Arthritis

描述(由申请人提供)： 美国有近7000万人患有与关节炎相关的疾病[1，2]。其中，类风湿性关节炎(RA)病例约占300万。类风湿关节炎是一种慢性全身性炎症性疾病，主要导致关节的侵蚀性破坏，并伴有不同的关节外影响。不断增长的老年人口以及RA在老年年龄组(高达三分之一的病例)中的流行，突显了在未来几十年内开发有效的治疗方案以减轻美国的医疗负担的迫切需要。NovelMed已经开发出一种有效的抗关节炎药物YalcioMab，它专门阻止替代补体途径的激活。该化合物可防止单核细胞产生肿瘤坏死因子-1，有效地抑制类风湿性关节炎动物模型的炎症和关节破坏，并在初步研究中表现出良好的安全性。这项Fast Track应用建议通过1)评估其在预防和治疗兔抗原性关节炎(AIA)模型中的有效性；2)鉴定其嵌合版本c-YalcioMab的特性并进行体内测试；以及3)其人源化版本h-YalcioMab的生产、鉴定、体内和毒理学评估，从而进一步将YalcioMab开发为一种有效的抗关节炎药物。NovelMed预计，在这项重要的研究之后，h-YalcioMab将准备好作为临床前IND(研究新药)工作的产品。根据到目前为止获得的初步结果，NovelMed预计h-YalcioMab的治疗将比目前的药物英夫利昔单抗(RemicadeTM)和Enbrel更具特异性，这两种药物也针对人体内的基础水平的肿瘤坏死因子-1。NovelMed已经提交了保护YalcioMab及其类似物的专利申请，并拥有新生物的独家权利。NovelMed得到了美国国立卫生研究院和几个投资者的资金支持，是一家设备齐全的专注于生物制剂的药物发现公司。总体而言，建议的工作是朝着通过调节特定补体介导的炎症反应来预防类风湿关节炎患者关节破坏的成本效益、有效和安全的治疗剂的方向。 公共卫生相关性： 类风湿性关节炎(RA)在美国影响着近300万人，但目前还没有有效和安全的治疗方法。目前主要针对炎症的类风湿性关节炎(RA)治疗方法并不是对所有患者都有效。NovelMed已经开发出一种有效的抗关节炎药物，在有限的动物模型研究中显示出出色的结果。NovelMed的治疗剂防止中性粒细胞、单核细胞和血小板的激活，这些细胞共同推动炎症和与RA相关的关节破坏。这项申请建议通过体外和体内研究开发该药剂，以便在不久的将来向FDA提交IND申请。

DESCRIPTION (provided by applicant): Nearly 70 million people in the US suffer from arthritis related conditions[1, 2]. Of these, rheumatoid arthritis (RA) cases constitute approximately 3 million. RA is a chronic systemic inflammatory disease that primarily results in erosive destruction of articular joints with additional variable extra-articular effects. The growing elderly population coupled with the prevalence of RA in the elderly age group (up to a third of cases) highlights the critical need to develop effective treatment options to reduce the health care burden of the US in the coming couple of decades. NovelMed has developed a potent anti-arthritic pharmaceutical agent YalcioMab that specifically blocks the activation of the alternative complement pathway. This compound prevents TNF-1 (tumor necrosis factor 1) production by monocytes; effectively inhibits inflammation and joint destruction in an animal model of RA; and exhibits a good safety profile in initial studies. This Fast Track application proposes to further develop YalcioMab as a potent anti-arthritic agent through 1) evaluation of its efficacy in prophylactic and therapeutic models of rabbit models of antigen-induced arthritis (AIA); 2) characterization and in vivo testing of its chimeric version c-YalcioMab; and 3) production, characterization, in vivo and toxicological evaluation of its humanized version h-YalcioMab. NovelMed expects that following this important research, h-YalcioMab will be ready as a product for pre-clinical IND (investigational new drug) work. Based on the preliminary results obtained so far, NovelMed projects that h-YalcioMab treatment will be more specific than current drugs, infliximab (RemicadeTM) and Enbrel, which also target basal levels of TNF-1 in the human body. NovelMed has filed patent applications protecting YalcioMab and its analogs and has exclusive rights on the new biologic. NovelMed is supported by funds from the NIH and a couple of investors, and is a fully equipped drug discovery company focusing on biological agents. Overall, the proposed work is in the direction of a cost-effective, efficacious and safe therapeutic agent for preventing joint destruction in RA patients through regulation of a specific complement- mediated inflammatory response. PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) affects nearly 3 million individuals in the US, yet no effective and safe treatment is available. Current therapies for rheumatoid arthritis (RA), which primarily target inflammation, are not effective in all patients. NovelMed has developed a potent anti-arthritic pharmaceutical agent that shows excellent results in limited animal model studies. NovelMed's therapeutic agent prevents activation of neutrophils, monocytes and platelets, which together drive inflammation and joint destruction associated with RA. This application proposes to develop the pharmaceutical agent through in vitro and in vivo studies so as to file an IND application with the FDA in the near future.