Preclinical and Clinical Evaluation of Humanized NM9405

人源化NM9405的临床前和临床评价

• 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
• 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

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properdin抗体（hNM9405），用于治疗突发性夜间血红蛋白尿（PNH）的血管内和血管外溶解。该抗体的选择基于兔和灵长类动物的体外、离体、体内和PK/PD研究的阳性结果。这些强有力的积极结果为我们I期临床试验的启动提供了坚实的基础。我们的先导药物