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：
9038429
负责人：
Rekha Bansal
金额：
$ 127.76万
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 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9038429
关键词：
Affect Alternative Complement Pathway Anemia Animals Antibodies Antibody Response 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 Immunologics 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 Modeling Monitor Monkeys Monoclonal Antibodies Nature Organ Organ failure Orphan Oryctolagus cuniculus Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology and Toxicology Phase Phase I Clinical Trials Placebo Control Placebos Play Prevalence Prevention Primates Process Production Properdin Randomized Rare Diseases Recovery Research Design Risk Safety Saline Testing Therapeutic Time TimeLine Tissues Toxicology Transfusion activation product arm base clinical development cohort complement C5b complement pathway complement system cost cross reactivity design dosage drug candidate experience healthy volunteer human study human subject improved in vivo inhibitor/antagonist male meetings nonhuman primate open label outcome forecast phase 1 study phase I trial preclinical evaluation prevent public health relevance rat Piga protein research clinical testing safety study success

项目摘要

DESCRIPTION (provided by applicant): NovelMed has developed an anti-properdin antibody (hNM9405) for the treatment of intra and 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.

描述（由申请人提供）：NovelMed 开发了一种抗备解素抗体 (hNM9405)，用于治疗阵发性睡眠性血红蛋白尿 (PNH) 的血管内和血管外溶解。该抗体的选择基于在兔子和灵长类动物中进行的体外、离体、体内以及 PK/PD 研究获得的阳性结果。这些强有力的积极结果为我们启动一期临床试验奠定了坚实的基础。我们的主打药物候选者被指定患有 PNH（一种“孤儿病”），旨在满足这种破坏性疾病的迫切需求。通过此申请，NovelMed 提议对其主要候选药物进行研究性新药 (IND) 启用研究。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。红细胞裂解会增加循环血液中血红蛋白和乳酸脱氢酶 (LDH) 的水平。这些化合物水平升高会对多个器官造成进一步损害，最终导致一个或多个器官出现完全器官衰竭。该疾病的慢性性质需要一种安全、高效且低成本的治疗方法来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。这种补体系统上游抑制剂可防止 C3b（血管外溶血 (EVH) 的关键分子）和 C5b-9（血管内溶血 (IVH) 的关键分子）的形成。此外，hNM9405 选择性阻断替代途径，而不损害经典途径的全部功能。为了维持最佳的免疫宿主防御，需要经典途径的完整功能。初步的体外、离体和体内研究表明，hNM9405； 1)阻止C3a、C3b、C5a、C5b和C5b-9的形成； 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。该提案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 PNH 领域的主要领导者。该 1 期试验拟在约 30 名健康人类受试者中进行开放标签、单剂量递增 (SAD) 递增研究，以评估 hNM9405 的安全性和药代动力学。这些研究将构成 FDA 监管备案的基础。该提案的两个具体目标是：a）在非人类灵长类动物中进行单剂量和重复剂量毒理学研究的 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 hNM9405 作为药物的安全性和药代动力学。治疗性的。预计 I 期研究的成功完成将导致进一步的试验，最终目标是注册、 FDA 批准和推出 hNM9405 作为 PNH 的新疗法，通过预防 PNH 患者溶血而不慢性敲除宿主防御。