Preclinical and Clinical Evaluation of Humanized NM9405

摘要 NovelMed开发了一种抗备解素抗体（hNM 9405），用于治疗血管内和血管外溶解 阵发性睡眠性血红蛋白尿症（PNH）。该抗体的选择是基于阳性结果 从兔和灵长类动物的体外、离体、体内和PK/PD研究中获得。这些强有力的积极结果 为我们的I期临床试验的启动提供了坚实的基础。我们的候选药物 PNH是一种“孤儿病”，旨在满足对这种毁灭性疾病的迫切需求。与此 申请，NovelMed建议进行试验性新药（IND）使其能够研究的领导 候选药物 在PNH中，红细胞（RBC）被身体自身的补体激活产物攻击， 显著的细胞溶解。红细胞溶解增加血红蛋白和乳酸脱氢酶（LDH）的水平， 循环血液这些化合物的水平升高会对多个器官造成进一步损害， 有一个或多个器官完全衰竭的风险。这种疾病的慢性性质需要一种安全， 高效、低成本治疗剂，可防止体内红细胞溶解。 NovelMed的主要治疗药物hNM 9405是一种特异性补体旁路抑制剂。这 补体系统的上游抑制剂阻止了C3 b的形成，C3 b是补体系统的关键分子。 血管外溶血（EVH）和C5 b-9，血管内溶血（IVH）的关键分子。此外，委员会认为， hNM 9405选择性地阻断旁路途径，而不损害经典的 通路为了维持最佳的免疫宿主，需要经典途径的全部功能 防御初步的体外、离体和体内研究已经证明，hNM 9405; 1）阻止细胞凋亡， C3 a、C3 b、C5 a、C5 b和C5 b-9的形成; 2）防止PNH和兔血清中的红细胞溶解; 3） 抑制LDH的产生，和4）在非人灵长类动物中显示长PK和AP抑制。这项建议 将评估我们的先导候选药物在人体I期试验中的疗效。 在规划1期临床方案的开发过程中，NovelMed聘请了 PNH字段。该I期试验拟在约30名健康人类受试者中进行开放标签试验， 评估hNM 9405的安全性和药代动力学的单次递增剂量（SAD）递增研究。 这些研究将构成FDA监管文件的基础。这项建议的两个具体目标是： 在非人灵长类动物中进行GLP安全性研究，包括单次和重复给药毒理学研究，和B） 在人类健康志愿者中进行I期临床安全性研究，以评价安全性和 图10显示了作为治疗剂的hNM 9405的药代动力学。预计第一阶段的成功完成 这项研究将导致进一步的试验，最终目标是注册，FDA批准和推出hNM 9405作为一种 PNH的新治疗方法，通过预防PNH患者的溶血，而不需要慢性敲除宿主 防御

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.