Disease Modifying Treatment for Hemolytic Disorders

溶血性疾病的疾病修饰治疗

基本信息

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
项目类别：
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

项目摘要

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的单一疗法 Soliris（Eculizumab）治疗同时阻断经典（CP）和替代疗法。 (AP) 补体途径，用于治疗 PNH、非典型尿毒症综合征 (aHUS)、 FDA 于 2007 年批准了 Soliris 治疗视神经脊髓炎 (NMO) 和重症肌无力 (MG)。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针对脑膜炎等疾病进行了疫苗接种，但仍需要宿主防御，因为没有其他方法。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，不会通过机制阻断 CP。具体到上游AP，Soliris处理过程中存在的两个问题是可以解决的。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。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) 成功完成第一阶段建立了简化的 cGMP 生产流程，保证了稳健的生产。鉴于这种独特的作用机制，我们相信这种药物将会成为治疗的优质材料。为需要特定阻断近端 AP 的疾病提供益处。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了 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，这确保了给药。该药物对患者友好。该 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，以及从未接受过依库珠单抗治疗的 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 周在这项试点研究中，将评估 PNH 患者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、红细胞如果成功，这种 AP 特异性抑制剂将检测裂解、PNH 克隆大小以及贫血的其他临床标志物。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。