Preclinical and Clinical Evaluation of Humanized NM9405

摘要 NovelMed已经开发出一种用于治疗血管内和外溶解的抗备解素抗体(HNM9405) 阵发性睡眠性血红蛋白尿(PNH)。这种抗体的选择是基于阳性结果。 从体外、体外、体内和在兔和灵长类动物的PK/PD研究中获得。这些强有力的积极结果 为启动我们的I期临床试验提供了坚实的基础。我们的主要候选药物显示 PNH是一种“孤儿疾病”，旨在满足这种毁灭性疾病的迫切需求。有了这个 申请，NovelMed提议为其领导进行研究性新药(IND)使能研究 毒品候选人。 在PNH中，红细胞(RBC)受到体内自身补体激活产物的攻击，导致 显著的细胞溶解。红细胞溶解可提高小鼠血中血红蛋白和乳酸脱氢酶(LDH)水平 血液循环。这些化合物水平的升高最终会对多个器官造成进一步的损害 有一个或多个器官发生完全器官衰竭的风险(S)。这种疾病的慢性性质需要一种安全的， 高效、低成本的治疗方法，可防止体内红细胞溶解。 NovelMed的先导疗法hNM9405是另一种补体途径的特异性抑制剂。这 补体系统的上游抑制物阻止C3b的形成，C3b是 血管外溶血(EVH)和C5b-9，血管内溶血(IVH)的关键分子。此外， HNM9405选择性地阻断替代途径，而不损害经典的 路径。为了维持最佳的免疫宿主，需要经典途径的全部功能 防守。初步的体外、体外和体内研究表明，hNM9405；1)可以预防 C3a、C3b、C5a、C5b和C5b-9的形成；2)防止PNH和兔血清的红细胞溶解；3) 抑制乳酸脱氢酶的产生，以及4)在非人类灵长类动物中表现出长时间的PK和AP抑制。这项建议 将评估我们的主要候选药物在人类I期试验中的疗效。 在规划第一阶段临床方案的开发过程中，NovelMed聘请了 PNH字段。第一阶段试验是以开放标签的形式在大约30名健康人体受试者中提出的， 单次递增剂量(SAD)升级研究，以评估hNM9405的安全性和药代动力学。 这些研究将构成FDA监管文件的基础。这项提议的两个具体目标是：a) 在非人类灵长类动物中进行GLP安全性研究，进行单剂量和重复剂量毒理学研究和b) 在人类健康志愿者身上进行I期临床安全性研究，以评估安全性和 治疗药物hNM9405的药代动力学。预计第一阶段的成功完成 研究将导致进一步的试验，最终目标是注册、FDA批准并将hNM9405作为 PNH的新疗法，通过预防PNH患者的溶血，而不是宿主的慢性敲除 防守。

ABSTRACT NovelMed has developed an anti-properdin antibody (hNM9405) for the treatment of intra & extravascular lysis in paroxysmal nocturnal hemoglobinuria (PNH). The selection of this antibody was based on positive results obtained from in vitro, ex vivo, in vivo, and PK/PD studies in rabbits and primates. These strong positive results have provided a firm foundation for initiation of our Phase I clinical trial. Our lead drug candidate is indicated for PNH, an "orphan disease," and aims to fill an urgent need for this devastating condition. With this application, NovelMed is proposing to conduct Investigational New Drug (IND) enabling studies for its lead drug candidate. In PNH, red blood cells (RBCs) are attacked by the body's own complement activation products causing significant cell lysis. RBC lysis increases the levels of hemolglobin and lactate dehydrogenase (LDH) in the circulating blood. Elevated levels of these compounds cause further damage to multiple organs, ultimately risking total organ failure(s) of one or multiple organs. The chronic nature of the disease necessitates a safe, highly effective, and low cost therapeutic which can prevent erythrocyte lysis in vivo. NovelMed's lead therapeutic, hNM9405, is a specific inhibitor of the alternative complement pathway. This upstream inhibitor of the complement system prevents the formation of both C3b, a key molecule for extravascular hemolysis (EVH), and C5b-9, a key molecule for intravascular hemolysis (IVH). Moreover, hNM9405 selectively blocks the alternative pathway without compromising the full functionality of the classical pathway. Full functionality of the classical pathway is required in order to maintain optimal immune host defense. Preliminary in vitro, ex vivo, and in vivo studies have demonstrated that hNM9405; 1) prevents the formation of C3a, C3b, C5a, C5b and C5b-9; 2) prevents the lysis of erythrocytes from PNH and rabbit sera; 3) inhibits the production of LDH, and 4) displays long PK and AP inhibition in non-human primates. This proposal will evaluate efficacy of our lead drug candidate in human Phase I trial. In planning for the development of the Phase 1 clinical protocol, NovelMed has engaged key leaders in the PNH field. The Phase 1 trial is being proposed in approximately 30 healthy human subjects in an Open-Label, Single Ascending Dose (SAD) escalation study to evaluate the safety and pharmacokinetics of hNM9405. These studies will form the basis of regulatory filings for the FDA. The two specific aims of this proposal are: a) perform GLP safety studies in non-human primates with single and repeat dose toxicological studies and b) perform Phase I clinical safety studies in human healthy volunteers to evaluate the safety and pharmacokinetics of hNM9405 as a therapeutic. It is anticipated that successful completion of the Phase I study will lead to further trials with the eventual goal of registration, FDA approval and launch of hNM9405 as a new treatment for PNH, via prevention of hemolysis in PNH patients without the chronic knockout of host defense.