Disease Modifying Treatment for Hemolytic Disorders

溶血性疾病的疾病修饰治疗

• 批准号: 10254750
• 负责人: Rekha Bansal
• 金额: $ 53.32万
• 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: 2021-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10254750
• 关键词: Address; Adult; Adverse event; Affect; Affinity; Alternative Complement Pathway; Anemia; Animals; Bilirubin; Binding; Blood; Blood Transfusion; Blood specimen; Cell Death; Cells; Characteristics; Clinical; Clinical Markers; Clinical Research; Complement; Complement 3a; Complement 3b; Complement 5a; Complement Membrane Attack Complex; Contracts; Control Groups; Cyclic GMP; Cytolysis; Data; Dependence; Deposition; Diagnosis; Disease; Dose; Drug Kinetics; Ensure; Erythrocytes; Exhibits; FDA approved; Fatigue; Female; Guidelines; Half-Life; Hemoglobin; Hemoglobin C; Hemoglobin concentration result; Hemolysis; Host Defense; Human; In Vitro; Infection; Inflammation Mediators; Intravenous; Intravenous infusion procedures; Kidney Failure; Lactate Dehydrogenase; Lead; Length; Liver Failure; Macaca mulatta; Measures; Mediating; Meningitis; Modeling; Monitor; Monkeys; Monoclonal Antibodies; Mutation; Myasthenia Gravis; Neuromyelitis Optica; Nevada; Organ; Pathway interactions; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Pilot Projects; Plasma; Prevalence; Process; Production; Prognosis; Properdin; Property; Proteins; Rare Diseases; Recovery; Reporting; Reticulocyte count; Rhesus; Rivers; Safety; Sampling; Secondary to; Serious Adverse Event; Serum; Syndrome; Testing; Therapeutic; Time; Tissues; Toxicology; Transfusion; Vaccination; Vial device; cGMP production; cell bank; cell type; clinical candidate; cooking; cost; cross reactivity; drug candidate; efficacious treatment; healthy volunteer; human tissue; in vivo evaluation; inhibitor/antagonist; male; manufacturing process; novel therapeutics; open label; overtreatment; paroxysmal nocturnal hemoglobinuria; pathogen; phase 1 study; phase 2 study; phase I trial; phase II trial; phase III trial; prevent; secondary infection; success; treatment group; trial comparing

ABSTRACT Our lead drug candidate is being developed as a disease modifying, potent and efficacious treatment for paroxysmal nocturnal hemoglobinuria (PNH), an “orphan disease”, and is anticipated to be far superior to the current monotherapy Soliris (Eculizumab) treatment. Soliris blocks both the classical (CP) and the alternative (AP) pathways of complement, and is used in treatment of PNH, atypical uremic syndrome (aHUS), neuromyelitis optica (NMO), and myasthenia gravis (MG). The FDA approved Soliris in 2007 despite its possessing two troubling properties: a) uncontrolled extravascular hemolysis (EVH) that causes incurable anemia and b) vulnerability to secondary infections due to blockade of the classical pathway (CP) which is required for host defense, despite vaccination against such ailments as meningitis. Because there is no other treatment for PNH currently approved by the FDA, use of Soliris continues to increase yearly. Our clinical candidate is a selective inhibitor of the AP and does not block the CP. By mechanistically blocking the upstream AP specifically, the two issues deficient during Soliris treatment can be addressed. Our lead drug: a) blocks AP-mediated C3b formation and deposition on erythrocytes and therefore prevents EVH, and b) does not block the CP, which is required for host defense against pathogens and infection. Further to this, potential success of this drug in effectively treating PNH is supported by the following characteristics: a) high affinity binding, b) high potency of AP inhibition, c) inhibition of AP-mediated lactate dehydrogenase (LDH) release, d) lack of CP inhibition, e) successful toxicology studies, and f) completion of a successful phase I clinical. A streamlined cGMP manufacturing process has been established, and guarantees robust production of the quality material for treatment. Given this unique mechanism of action, we believe that this drug will provide benefits in diseases where specific blockade of proximal AP is required. Preliminary data from the recently completed phase I trial in 48 healthy volunteers suggests that the drug candidate completely blocks the AP at 1mg/kg, and does not block the CP at any of the doses tested, confirming the beneficial therapeutic potency of this monoclonal antibody. Furthermore, administration of the lead drug did not require loading doses and was deemed safe in humans with no reported severe adverse events. This ensures that administration of this drug is patient friendly. Results from this phase I trial are supported by multiple in vitro and ex vivo studies on normal human serum and blood, and serum from naïve and Soliris treated PNH patients. This submission outlines a proposed phase II PNH clinical study to examine the effects and benefits of NovelMed's lead drug in PNH naïve patients, compared to use as an add-on to Soliris treated PNH subjects. Dosing of our clinical candidate is proposed at a single dose of 10 mg/kg administered every 4 weeks for 3 months in this pilot study in PNH patients. Plasma samples will be evaluated for pharmacokinetics, AP inhibition, CP inhibition, presence of ADA, LDH release, hemoglobin levels, C3b cellular deposition, erythrocyte lysis, PNH clone size, as well as other clinical markers of anemia. If successful, this AP-specific inhibitor will replace Soliris as a far superior and potent therapy for the complications associated with PNH.

摘要 我们的主要候选药物正在开发作为一种疾病修饰，有力和有效的治疗， 阵发性睡眠性血红蛋白尿症（PNH），一种“孤儿病”，预计其治疗效果远上级 目前的单一疗法Soliris（依库珠单抗）治疗。Soliris阻止经典（CP）和替代 (AP)补体途径，并用于治疗PNH，非典型尿毒症综合征（阿胡斯）， 视神经肌无力（NMO）和重症肌无力（MG）。FDA在2007年批准了Soliris， 具有两个令人不安的特性：a）不受控制的血管外溶血（EVH）， 贫血和B）由于经典途径（CP）的阻断而易受继发性感染， 尽管接种了预防脑膜炎等疾病的疫苗，但它们仍然是宿主防御所必需的。因为没有其他 作为目前FDA批准的PNH治疗方法，Soliris的使用每年都在增加。 我们的临床候选药物是AP的选择性抑制剂，并且不阻断CP。通过机械地阻止 上游AP，特别是Soliris处理过程中的两个不足问题可以得到解决。我们的首席 药物：a）阻断AP介导的C3 b形成和在红细胞上的沉积，从而预防EVH，和 B）不阻断CP，这是宿主防御病原体和感染所必需的。除此之外， 这种药物在有效治疗PNH中的潜在成功由以下特征支持： 亲和力结合，B）AP抑制的高效力，c）AP介导的乳酸脱氢酶（LDH）的抑制 释放，d）缺乏CP抑制，e）成功的毒理学研究，和f）成功完成I期研究 临床。已经建立了简化的cGMP生产工艺，并保证了稳健的生产 优质材料进行治疗。鉴于这种独特的作用机制，我们相信这种药物将 在需要特异性阻断近端AP的疾病中提供益处。的初步数据 最近在48名健康志愿者中完成的I期试验表明， 在1 mg/kg的AP，并没有阻止CP在任何测试剂量，证实了有益的治疗 这种单克隆抗体的效力。此外，给予先导药物不需要负荷剂量 并且被认为在人体中是安全的，没有报道严重的不良事件。这就保证了行政 这种药对病人无害。这项I期试验的结果得到了多项体外和离体研究的支持 正常人血清和血液，以及来自初治和Soliris治疗的PNH患者的血清。 本申请概述了一项拟议的II期PNH临床研究，以检查 NovelMed的先导药物在PNH初治患者中的应用，与作为Soliris治疗的PNH受试者的添加药物相比。 我们的临床候选药物的给药建议为每4周一次给予10 mg/kg的单次剂量，持续3 在PNH患者中进行了为期3个月的初步研究。将评价血浆样本的药代动力学、AP 抑制、CP抑制、ADA存在、LDH释放、血红蛋白水平、C3 b细胞沉积、红细胞 裂解、PNH克隆大小以及贫血的其他临床标志物。如果成功，这种AP特异性抑制剂将 替代Soliris作为PNH相关并发症的更优越上级和有效的治疗方法。