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(申请人提供)：NovelMed已经开发出一种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的抗备解素抗体(HNM9405)。该抗体的选择是基于从体外、体外、体内以及在兔和灵长类动物的PK/PD研究中获得的阳性结果。这些强有力的积极结果为我们启动I期临床试验提供了坚实的基础。我们的主药 候选人被指定为PNH，一种“孤儿疾病”，旨在满足这种毁灭性疾病的迫切需求。通过这项申请，NovelMed提议为其主要候选药物进行研究性新药(IND)使能研究。在PNH中，红细胞(RBC)受到体内自身补体激活产物的攻击，导致显著的细胞溶解。红细胞溶解可增加循环血液中的血球蛋白和乳酸脱氢酶(LDH)水平。这些化合物水平的升高会对多个器官造成进一步的损害，最终有可能导致一个或多个器官的全面器官衰竭(S)。这种疾病的慢性性质需要一种安全、高效、低成本的治疗方法，可以防止体内的红细胞溶解。NovelMed的先导疗法hNM9405是另一种补体途径的特异性抑制剂。补体系统的这种上游抑制物可防止C3b和C5b-9的形成，C3b是血管外溶血(EVH)的关键分子，C5b-9是血管内溶血(IVH)的关键分子。此外，hNM9405选择性地阻断替代途径，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，需要经典途径的全部功能。初步的体外、体外和体内研究表明，hNM9405：1)防止C3a、C3b、C5a、C5b和C5b-9的形成；2)防止PNH和兔血清中的红细胞溶解；3)抑制LDH的产生；4)在非人类灵长类动物中表现出长时间的PK和AP抑制。这项建议将评估我们的主要候选药物在人类第一阶段试验中的疗效。在规划第一阶段临床方案的开发过程中，NovelMed聘请了PNH领域的主要领导者。第一阶段试验将在大约30名健康受试者中进行，这是一项开放标签的单次递增剂量(SAD)升级研究，目的是评估hNM9405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。这项建议的两个具体目标是：a)在非人类灵长类动物中进行GLP安全性研究，进行单次和重复剂量毒理学研究；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作为治疗药物的安全性和药代动力学。预计第一阶段研究的成功完成将导致进一步的试验，最终目标是注册、FDA批准并推出hNM9405作为一种治疗PNH的新疗法，通过防止PNH患者的溶血，而不需要慢性敲除宿主防御。