Treatment of Complement-Mediated Myelitis

补体介导的脊髓炎的治疗

• 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
• 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

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.

摘要 我们打算开发我们的主要候选药物，作为一种强效、有效和改善疾病的治疗方法， 孤儿病，视神经肌萎缩性疾病（NMOSD），预期疗效远优于上级 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（阿胡斯）和重症肌无力（MG）。从机械上讲，Soliris阻止了经典（CP） 补体旁路途径（AP）。2019年，FDA批准了这种广谱 NMOSD的补体阻滞剂，尽管其对旁路途径（AP）无选择性， 被认为是该疾病中脑细胞死亡的唯一机制。索利斯机械论 经典途径（CP）的阻断是令人担忧的，因为治疗可能使患者易受 继发性细菌和病毒感染。Soliris的使用继续扩大，作为唯一的缓解治疗手段 NMOSD相关的病理学 我们的临床候选药物NM 5072是AP的选择性抑制剂，因此不会损害CP activation.通过选择性地阻断AP上游，两种最关键的促炎因子的产生 分子C3 a和C5 a被抑制。在开发这种药物的过程中，已经建立了许多 益处，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I期临床试验。总体而言，这些成就 里程碑提供了作为治疗NMOSD的治疗药物的临床成功的信心。总的来说， 我们的药物在正常人血清中的初步非临床数据和健康人I期试验的结果 志愿者，复制我们的体外和离体研究结果，在1 mg/kg的最低剂量下，药物阻断AP， 剂量依赖性的方式，同时维持CP活性。以1 mg/kg剂量选择性阻断AP， 人类进一步证实了这种药物的上级治疗效力超过Soliris。的另一个显著优点 我们的新药是，它不需要负荷剂量达到治疗水平，证明， 这种药物的给药也是患者友好的。 对水通道蛋白-4（AQP 4）-IgG呈阳性的患者被正式诊断为NMOSD。在这一提议中， 我们概述了我们使用流式细胞术方法对NMOSD样本进行评估性筛选的策略 由Sean Pittock博士的实验室开发，用于选择AQP 4-IgG阳性的个体。这些 血清样品将使用我们的AP/CP和转化酶测定法进一步表征，以确定NM 5072的 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 在恒河猴中进行了为期3个月、每周12次的重复给药毒理学研究，以实现未来的多剂量给药 人类的研究。考虑到我们的先导候选药物的独特作用机制和人体内的药效， 阻断AP，我们相信我们的药物将为NMOSD的治疗提供特殊的治疗益处。