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开发了一种用于治疗阵发性夜间血红蛋白尿（PNH）中血管内和血管外裂解治疗的抗胃类抗体（HNM9405）。该抗体的选择是基于从体外，体内，体内和PK/PD研究中获得的阳性结果。这些强大的积极结果为启动我们的I期临床试验奠定了基础。我们的铅毒品候选人是针对“孤儿疾病” PNH的，旨在满足对这种毁灭性疾病的迫切需求。通过这种应用，Novelmed提议为其主要候选药物进行研究新药（IND）促进研究。在PNH中，红细胞（RBC）受到人体自身的补体激活产物的攻击，导致明显的细胞裂解。 RBC裂解增加了循环血液中血凝蛋白和乳酸脱氢酶（LDH）的水平。这些化合物的水平升高会对多个器官产生进一步的损害，最终冒着一个或多个器官的总器官衰竭的风险。该疾病的慢性性质需要一种安全，高效且成本低的治疗性，这可以防止体内红细胞裂解。 Novelmed的铅治疗HNM9405是替代补体途径的特定抑制剂。补体系统的这种上游抑制剂可防止C3B的形成，即血管外溶血（EVH）的关键分子和C5B-9，这是血管内溶血（IVH）的关键分子。此外，HNM9405选择性地阻止了替代途径，而不会损害经典途径的完整功能。为了保持最佳免疫宿主防御，需要经典途径的全部功能。初步体外，体内和体内研究表明HNM9405; 1）防止C3A，C3B，C5A，C5B和C5B-9的形成； 2）防止PNH和兔血清的红细胞裂解； 3）抑制LDH的产生，4）在非人类灵长类动物中显示长的PK和AP抑制作用。该提案将评估我们在人类I期试验中候选药物的疗效。在计划开发第一阶段临床方案时，Novelmed吸引了PNH领域的主要领导者。在大约30名健康的人类受试者中提出了第1阶段试验，该受试者在开放标签的单个上升剂量（SAD）升级研究中，以评估HNM9405的安全性和药代动力学。这些研究将构成FDA监管申请的基础。该提案的两个具体目的是：a）在非人类灵长类动物中进行单一和重复剂量毒理学研究和b）在人类健康志愿者中进行I期临床安全研究，以评估HNM9405的安全性和药代动力学。预计成功完成I期研究将导致进一步的试验，最终通过预防PNH患者的PNH患者进行注册，FDA批准和启动HNM9405作为PNH的新方法，而无需进行宿主防御的长期敲除。