Preclinical and Clinical Evaluation of Humanized NM9405

人源化NM9405的临床前和临床评价

• 批准号: 8925257
• 负责人: Rekha Bansal
• 金额: $ 115.93万
• 依托单位: NOVELMED THERAPEUTICS, INC.
• 依托单位国家: 美国
• 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/8925257
• 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; 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; phase I trial; preclinical evaluation; prevent; rat Piga protein; research clinical testing; safety study; success

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（hNM 9405），用于治疗阵发性睡眠性血红蛋白尿症（PNH）的血管内和血管外溶解。该抗体的选择基于从兔和灵长类动物的体外、离体、体内和PK/PD研究中获得的阳性结果。这些强阳性结果为启动我们的I期临床试验提供了坚实的基础。我们的主要药物 候选人是指PNH，一种“孤儿病”，旨在填补这种毁灭性的条件迫切需要。通过这项申请，NovelMed提议对其主要候选药物进行研究性新药（IND）研究。在PNH中，红细胞（RBC）被身体自身的补体激活产物攻击，引起显著的细胞溶解。RBC溶解增加循环血液中血红蛋白和乳酸脱氢酶（LDH）的水平。这些化合物的水平升高会对多个器官造成进一步损害，最终有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、高效和低成本的治疗方法，其可以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。这种补体系统的上游抑制剂可防止C3 b（血管外溶血（EVH）的关键分子）和C5 b-9（血管内溶血（IVH）的关键分子）的形成。此外，hNM 9405选择性地阻断旁路途径，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，需要经典途径的全部功能。初步的体外、离体和体内研究已经证明，hNM 9405：1）防止C3 a、C3 b、C5 a、C5 b和C5 b-9的形成; 2）防止来自PNH和兔血清的红细胞的裂解; 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。该提案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领域的主要领导人。在开放标签、单次递增剂量（SAD）递增研究中，提出在约30名健康人类受试者中进行1期试验，以评估hNM 9405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。本提案的两个具体目的是：a）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，以及B）在人类健康志愿者中进行I期临床安全性研究，以评价hNM 9405作为治疗剂的安全性和药代动力学。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hNM 9405作为PNH的新治疗，通过预防PNH患者中的溶血而没有宿主防御的慢性敲除。