Preclinical and Clinical Evaluation of Humanized NM9405

人源化NM9405的临床前和临床评价

基本信息

批准号：
8647587
负责人：
Rekha Bansal
金额：
$ 46.78万
依托单位：
NOVELMED THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8647587
关键词：
Affect Alternative Complement Pathway Anemia Animals Antibodies Antibody Formation Binding Blood Blood specimen Businesses Cells Cessation of life Chronic Clinical Clinical Protocols Complement Complement 3a Complement 3b Complement 5a Complement Activation Complement Inactivators Complement Membrane Attack Complex Contractor Control Groups Cytolysis Development Development Plans Diagnosis Disease Dose Double-Blind Method Drug Kinetics Erythrocytes FDA approved Female Foundations Functional disorder Goals Half-Life Health Hemolysis Host Defense Hour Human Immune In Vitro Individual Inflammation Mediators Intravenous Intravenous infusion procedures Investigational Drugs Investigational New Drug Application Kidney Kidney Failure Knock-out Lactate Dehydrogenase Lead Left Liver Failure Macaca mulatta Monitor Monkeys Monoclonal Antibodies Nature Organ Organ failure Orphan Oryctolagus cuniculus Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Phase I Clinical Trials Placebo Control Placebos Play Prevalence Prevention Primates Process Production Properdin Randomized Rare Diseases Recovery Research Design Risk Safety Saline Serum Testing Therapeutic Time TimeLine Tissues Transfusion Work activation product arm base cohort complement C5b complement pathway complement system cost cross reactivity design dosage drug candidate experience healthy volunteer human study human subject improved in vitro Model in vivo inhibitor/antagonist male meetings nonhuman primate open label outcome forecast phase 1 study preclinical evaluation prevent public health relevance rat Piga protein research clinical testing safety study success

项目摘要

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.

抽象的 NovelMed 开发了一种抗备解素抗体 (hNM9405)，用于治疗血管内和血管外裂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子和灵长类动物的体外、离体、体内和 PK/PD 研究中获得。这些强有力的积极成果为我们的I期临床试验的启动提供了坚实的基础。我们的主要候选药物已被指定 PNH 是一种“孤儿病”，旨在满足这种破坏性疾病的迫切需求。有了这个申请中，NovelMed 提议对其先导药物进行研究性新药 (IND) 启用研究候选药物。在 PNH 中，红细胞 (RBC) 受到人体自身补体激活产物的攻击，导致显着的细胞裂解。红细胞裂解会增加血红蛋白和乳酸脱氢酶 (LDH) 的水平循环血液。这些化合物水平升高最终会对多个器官造成进一步损害存在一个或多个器官完全器官衰竭的风险。该疾病的慢性性质需要安全、高效、低成本的治疗方法，可防止体内红细胞溶解。 NovelMed 的主要治疗药物 hNM9405 是补体旁路途径的特异性抑制剂。这补体系统上游抑制剂可阻止 C3b 的形成，C3b 是补体系统的关键分子血管外溶血 (EVH) 和 C5b-9，血管内溶血 (IVH) 的关键分子。而且， hNM9405 选择性地阻断替代途径，而不损害经典的全部功能途径。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、离体和体内研究表明，hNM9405； 1) 防止形成C3a、C3b、C5a、C5b和C5b-9； 2) 防止PNH和兔血清中红细胞的裂解； 3）抑制 LDH 的产生，4) 在非人类灵长类动物中表现出长期的 PK 和 AP 抑制作用。这个提议将评估我们的主要候选药物在人体 I 期试验中的功效。在规划 1 期临床方案的开发过程中，NovelMed 聘请了该领域的主要领导者 PNH 领域。拟在开放标签中对大约 30 名健康人类受试者进行第一阶段试验，单次剂量递增（SAD）递增研究评估 hNM9405 的安全性和药代动力学。这些研究将构成 FDA 监管备案的基础。该提案的两个具体目标是：a) 通过单剂量和重复剂量毒理学研究对非人类灵长类动物进行 GLP 安全性研究；b) 在人类健康志愿者中进行 I 期临床安全性研究，以评估安全性和 hNM9405 作为治疗剂的药代动力学。预计一期工程顺利竣工研究将导致进一步的试验，最终目标是 hNM9405 注册、获得 FDA 批准并作为药物上市 PNH 的新疗法，通过预防 PNH 患者溶血而无需慢性敲除宿主防御。