Treatment of Complement-Mediated Myelitis

补体介导的脊髓炎的治疗

基本信息

批准号：
10254752
负责人：
Rekha Bansal
金额：
$ 30万
依托单位：
NOVELMED THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10254752
关键词：
Acute Adrenal Cortex Hormones Adult Adverse event Affect African Alternative Complement Pathway Animals Antibodies Antibody Response Azathioprine Bacterial Infections Binding Biological Assay Cell Death Cells Cessation of life Chronic Clinic Clinical Clinical Research Clinical Trials Complement Complement 3a Complement 5a Complement Membrane Attack Complex Control Groups Country Cytolysis Deposition Diagnosis Disease Dose Drug Kinetics Evaluation Exhibits Female Flow Cytometry Food and Drug Administration Drug Approval Future Guidelines Half-Life Headache Hemolysis Host Defense Human Immunoglobulin G Immunologics Immunosuppressive Agents In Vitro Incubated Individual Infection Inflammation Mediators Inflammatory Injury Intravenous Intravenous infusion procedures Label Laboratories Lactate Dehydrogenase Lead Length Macaca mulatta Measurement Mediating Methods Modeling Monitor Monkeys Monoclonal Antibodies Motor Myasthenia Gravis Myelitis Neuromyelitis Optica Optic Nerve Organ Pain Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology and Toxicology Pharmacotherapy Phase Phase I Clinical Trials Plasma Exchange Pleural Empyema Prevalence Primates Production Prognosis Properdin Rare Diseases Recovery Relapse Reporting Research Design Retrospective Studies Rhesus Safety Sampling Secondary to Sensory Serum Spinal Cord Symptoms Syndrome Testing Therapeutic Time Tissues Toxicology United States United States Food and Drug Administration Upper Respiratory Infections Virus Diseases Vision aquaporin 4 biobank brain cell cell type central nervous system demyelinating disorder cost cross reactivity drug candidate drug development follow-up healthy volunteer human tissue in vivo evaluation inhibitor/antagonist male multi-site trial mycophenolate mofetil novel therapeutics open label phase 1 study phase 2 study phase I trial phase II trial prevent rituximab secondary infection seropositive success water channel

项目摘要

ABSTRACT We intend to develop our lead drug candidate as a potent, efficacious, and disease-modifying treatment for the orphan disease, Neuromyelitis Optica Spectrum Disorder (NMOSD), with efficacy anticipated to be far superior to the current monotherapy, Soliris (eculizumab). Soliris is approved for the treatment of NMOSD, atypical uremic syndrome (aHUS), and Myasthenia Gravis (MG). Mechanistically, Soliris blocks both the classical (CP) and the alternative pathways (AP) of complement. In 2019, the FDA approved this broad-spectrum complement blocker for NMOSD, despite its non-selectivity to the alternative pathway (AP), which has been implicated as the sole mechanism for cellular death of the brain cells in the disease. Soliris' mechanistic blockade of the classical pathway (CP) is concerning, given that treatment may render patients vulnerable to secondary bacterial and viral infections. Use of Soliris continues to expand as a sole means of therapy for relief of NMOSD-related pathology. Our clinical drug candidate, NM5072, is a selective inhibitor of the AP and therefore does not impair CP activation. By selectively blocking the AP upstream, the production of the two most critical pro-inflammatory molecules, C3a and C5a, is inhibited. Progress during development of this drug has established numerous benefits, including; a) lack of CP inhibition, b) potency in AP inhibition, c) successful toxicology studies, and d) completion of a successful phase I clinical trial in healthy volunteers. Collectively, these accomplished milestones offer confidence in clinical success as a therapeutic drug for treatment of NMOSD. Collectively, preliminary non-clinical data of our drug in normal human serum and results from the phase I trial in healthy volunteers, replicate our in vitro and ex vivo findings that at a 1mg/kg minimum dose, the drug blocks the AP in a dose-dependent manner, all while sustaining CP activity. Selective blockade of the AP at a 1 mg/kg dose in humans further confirms this drug's superior therapeutic potency over Soliris. Another significant advantage of our new drug is that it does not require a loading dose to reach therapeutic levels, demonstrating that administration of this drug is also patient-friendly. Patients who exhibit positivity to Aquaporin-4 (AQP4)-IgG are officially diagnosed as NMOSD. In this proposal, we outline our strategy in evaluative screenings of NMOSD samples using the flow cytometry methods developed by Dr. Sean Pittock's laboratory to select those individuals who are positive AQP4-IgG. These serum samples will be further characterized using our AP/CP and convertase assays to determine NM5072's selectivity of AP/CP activation and the extent of complement inhibition in vitro. Following this, we aim to conduct tissue cross-reactivity studies using the NMOSD serum to assess tissue binding. Finally, we will follow up with a 3-month 12-weekly repeat-dose toxicology study in rhesus monkeys to enable future multi-dose studies in human. Given the unique mechanism of action of our lead drug candidate and in-human potency for blocking the AP, we believe that our drug will provide exceptional therapeutic benefits for treatment of NMOSD.

抽象的我们打算开发我们的主要候选药物，作为一种强效、有效和缓解疾病的治疗方法孤儿病，视神经脊髓炎谱系障碍 (NMOSD)，预计疗效要好得多目前的单一疗法 Soliris（依库珠单抗）。 Soliris 被批准用于治疗非典型 NMOSD 尿毒症综合征（aHUS）和重症肌无力（MG）。从机制上讲，Soliris 阻止了经典 (CP) 和补体的替代途径（AP）。 2019年，FDA批准了这种广谱药物 NMOSD 的补体阻断剂，尽管它对替代途径 (AP) 没有选择性，被认为是该疾病中脑细胞死亡的唯一机制。 Soliris 的机制经典途径（CP）的阻断令人担忧，因为治疗可能使患者容易受到继发性细菌和病毒感染。 Soliris 作为唯一的缓解治疗手段的使用不断扩大 NMOSD 相关病理学。我们的临床候选药物 NM5072 是 AP 的选择性抑制剂，因此不会损害 CP 激活。通过选择性阻断 AP 上游，两种最关键的促炎物质的产生分子 C3a 和 C5a 被抑制。这种药物的开发过程中取得的进展已经确定了许多福利，包括； a) 缺乏 CP 抑制，b) AP 抑制效力，c) 成功的毒理学研究，以及 d) 在健康志愿者中成功完成一期临床试验。总的来说，这些成就里程碑为作为 NMOSD 治疗药物的临床成功提供了信心。总的来说，我们的药物在正常人血清中的初步非临床数据以及健康人 I 期试验的结果志愿者重复了我们的体外和离体研究结果，即在 1 毫克/千克的最小剂量下，该药物可阻断 AP 以剂量依赖性方式，同时维持 CP 活性。在 1 mg/kg 剂量下选择性阻断 AP 人类进一步证实了该药物比 Soliris 更优越的治疗效力。另一个显着优势我们的新药不需要负荷剂量即可达到治疗水平，这表明这种药物的给药也是对患者友好的。水通道蛋白 4 (AQP4)-IgG 呈阳性的患者被正式诊断为 NMOSD。在这个提案中，我们概述了使用流式细胞术方法对 NMOSD 样本进行评估筛选的策略由 Sean Pittock 博士的实验室开发，用于选择 AQP4-IgG 呈阳性的个体。这些血清样本将使用我们的 AP/CP 和转化酶测定进一步表征，以确定 NM5072 AP/CP 激活的选择性和体外补体抑制的程度。在此之后，我们的目标是使用 NMOSD 血清进行组织交叉反应性研究以评估组织结合。最后我们将跟随在恒河猴中进行为期 3 个月、每周 12 周的重复剂量毒理学研究，以实现未来的多次剂量对人类的研究。鉴于我们的主要候选药物的独特作用机制和人体功效阻断 AP，我们相信我们的药物将为 NMOSD 的治疗提供卓越的治疗效果。