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.

抽象的 我们的主要候选药物正在开发为一种改变疾病、强效且有效的治疗方法 阵发性睡眠性血红蛋白尿症 (PNH) 是一种“孤儿病”，预计其发病率远远优于其他疾病 目前单一疗法 Soliris (Eculizumab) 治疗。 Soliris 阻止经典 (CP) 和替代 (AP) 补体途径，用于治疗 PNH、非典型尿毒症综合征 (aHUS)、 视神经脊髓炎（NMO）和重症肌无力（MG）。 FDA 于 2007 年批准了 Soliris，尽管它 具有两个令人不安的特性：a）不受控制的血管外溶血（EVH），导致无法治愈 贫血和 b) 由于经典途径 (CP) 阻断而易受继发感染 尽管接种了针对脑膜炎等疾病的疫苗，但宿主防御仍是必需的。因为没有其他的 目前 FDA 已批准治疗 PNH 的药物，Soliris 的使用量逐年增加。 我们的临床候选药物是 AP 的选择性抑制剂，并且不会阻断 CP。通过机械阻塞 具体到上游AP，可以解决Soliris处理中不足的两个问题。我们的领先 药物：a) 阻断 AP 介导的 C3b 形成和红细胞沉积，从而预防 EVH，并且 b) 不阻断 CP，这是宿主防御病原体和感染所必需的。更进一步说， 该药物在有效治疗 PNH 方面的潜在成功得到以下特征的支持：a) 高 亲和力结合，b) 高效的 AP 抑制，c) 抑制 AP 介导的乳酸脱氢酶 (LDH) 释放，d) 缺乏 CP 抑制，e) 成功的毒理学研究，以及 f) 成功完成第一阶段 临床。建立了精简的cGMP生产流程，保证了稳健的生产 优质的处理材料。鉴于这种独特的作用机制，我们相信该药物将 为需要特定阻断近端 AP 的疾病提供益处。初步数据来自 最近在 48 名健康志愿者中完成的 I 期试验表明，该候选药物完全阻断 1mg/kg 的 AP，并且在任何测试剂量下都不会阻断 CP，证实了有益的治疗 该单克隆抗体的效力。此外，先导药物的给药不需要负荷剂量 并且被认为对人类是安全的，没有报告严重的不良事件。这确保了管理 这种药物对患者友好。该 I 期试验的结果得到多项体外和离体研究的支持 正常人血清和血液，以及来自未接受治疗和依库珠单抗治疗的 PNH 患者的血清。 本提交概述了拟议的 II 期 PNH 临床研究，以检验以下药物的效果和益处： 与作为依库珠单抗治疗的 PNH 受试者的附加药物使用相比，NovelMed 用于治疗 PNH 初治患者的主导药物。 我们的临床候选药物的剂量建议为单剂量 10 mg/kg，每 4 周给药一次，持续 3 周 这项针对 PNH 患者的试点研究进行了数月。将评估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、C3b 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 取代 Soliris，成为治疗 PNH 相关并发症的一种更优越、更有效的疗法。