Phase 2, Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation studies to Evaluate the Safety and Efficacy of SPI-1005 in Moderate and Severe COVID-19 Patients

评估 SPI-1005 在中度和重度 COVID-19 患者中的安全性和有效性的 2 期、随机、双盲、安慰剂对照、剂量递增研究

• 批准号: 10283500
• 负责人: Jonathan Kil
• 金额: $ 308.28万
• 依托单位: SOUND PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283500
• 关键词: 2019-nCoV; Academic Medical Centers; Acute; Acute Disease; Acute Lung Injury; Adult; Affect; Animal Model; Anti-Inflammatory Agents; Antibiotics; Bacterial Infections; Biological Assay; Biological Markers; Bleeding time procedure; COVID-19; COVID-19 pathogenesis; COVID-19 patient; COVID-19 treatment; Cells; Cellular Immunity; Cellular Membrane; Clinical; Clinical Treatment; Cochlea; Crystallization; Cystic Fibrosis; Data; Disease; Dose; Double-Blind Method; Drug Targeting; Enzymes; Etiology; FDA approved; Genetic Transcription; Goals; Hospitalization; In Vitro; Inflammatory; Injury to Kidney; Intervention Studies; Investigational Drugs; Journals; Kidney; Length; Lung; Lung diseases; Medical; Meniere' s Disease; Morbidity - disease rate; Nature; Oral; Outcome; Oxidation-Reduction; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacology; Phase; Phase II Clinical Trials; Placebos; Prefrontal Cortex; Prevention; Property; Pseudomonas; Publishing; Pulmonary Function Test/Forced Expiratory Volume 1; Randomized; Recurrence; Safety; Serious Adverse Event; Stress; Structure; Testing; Tinnitus; Tissues; Tobramycin; Viral; Viral Load result; Virulence; Virus Diseases; Virus Replication; active method; antineoplastic antibiotics; base; bipolar mania; capsule; cell injury; chronic neurologic disease; cystic fibrosis patients; cytokine release syndrome; cytotoxicity; ebselen; effective therapy; follow-up; gastrointestinal; glutathione peroxidase; hearing impairment; immunosuppressed; improved; man; meetings; mortality; neuropsychiatry; novel; ototoxicity; pandemic disease; pathogenic virus; phase 2 study; phase III trial; pulmonary function; repaired; respiratory; respiratory virus; response; severe COVID-19; treatment duration; virtual screening

Project Summary/Abstract SARS-CoV-2 (nCoV2) has been identified as the viral etiology of COVID-19, a pandemic respiratory disease that has no effective treatment and growing morbidity and mortality. A groundbreaking study, recently published in the journal Nature,1 showed three major findings involving nCoV2. First, Jin et al. crystalized the main protease (Mpro), a critical enzyme responsible for viral replication. Second, they identified potential pharmacologic agents or drugs that inhibit Mpro, utilizing a structure-based virtual screening of >10,000 compounds including approved and investigational drugs. Ebselen showed significant inhibition of Mpro activity (lowest IC50). Third, ebselen showed significant viral load reduction in an in vitro cell-based assay (lowest EC50). Mpro may be the first identified specific nCoV2 drug target that, when inhibited, could reduce viral load or virulence, and potentially mitigate the devastating course of COVID-19. Ebselen is a novel selenorganic compound with anti-inflammatory, cytoprotective, and neuroprotective properties. Ebselen mimics glutathione peroxidase (GPx) activity, and under redox stress can transcriptionally activate GPx1 in cells and tissues through a Nrf2 dependent mechanism.2,3 Ebselen has been tested in multiple animal models of acute lung and kidney injury and has been shown to reverse the cytokine storm and cellular injury induced by a multitude of agents including antibiotics, chemotherapy, and respiratory viruses that are pathogenic to man. Ebselen is an investigational new drug being tested in five different neurotologic and neuropsychiatric indications,4,5 and it has received Fast Track designation by the FDA for the treatment of Meniere’s Disease. Ebselen’s safety has been assessed in adults (18-75 years) with underlying medical conditions that require significant concomitant therapies. More than 6 RCTs (>400 patients) have been completed, primarily involving oral doses of 400 to 1200 mg/day for 21-28 days, with no serious adverse events related to study drug. As an anti-inflammatory, ebselen does not induce gastrointestinal upset, prolong bleeding time, prolong QTc interval, or negatively immunosuppress, limitations of many other anti-inflammatory treatments. Therefore, ebselen can be readily repositioned as a potential treatment for COVID-19 patients. These data indicate that ebselen is a unique investigational drug that could inhibit viral replication as well as mitigate the body’s response to nCoV2, thereby reversing or limiting the pathogenesis of COVID-19 especially in the lungs and kidney. Two Phase 2 RCTs have been allowed under IND 150553 to test SPI-1005 in the prevention and treatment of COVID-19 patients.

项目总结/摘要 SARS-CoV-2（nCoV 2）已被确定为COVID-19的病毒病因， 呼吸道疾病，没有有效的治疗和不断增长的发病率和死亡率。一 最近发表在《自然》杂志上的一项开创性研究1显示了三个主要发现 涉及nCoV 2。首先，Jin等人结晶了主要蛋白酶（Mpro），这是一种关键酶， for viral病毒replication复制.其次，他们确定了潜在的药理学试剂或药物， Mpro，利用基于结构的虚拟筛选> 10，000种化合物，包括已批准和 研究药物。依布硒啉显示出对Mpro活性的显著抑制（最低IC 50）。第三、 依布硒啉在基于细胞的体外测定中显示出显著的病毒载量降低（最低EC 50）。Mpro 可能是第一个确定的特异性nCoV 2药物靶点，当被抑制时，可以降低病毒载量 或毒性，并可能减轻COVID-19的破坏性过程。 依布硒啉是一种新型的硒有机化合物，具有抗炎、细胞保护和 神经保护特性。依布硒啉模拟谷胱甘肽过氧化物酶（GPx）活性，并且在 氧化还原应激可以通过Nrf 2依赖性的转录激活细胞和组织中的GPx 1。 2，3依布硒啉已在急性肺和肾损伤的多种动物模型中进行了测试 并且已经显示出逆转由多种细胞因子诱导的细胞因子风暴和细胞损伤。 包括抗生素、化学疗法和对人致病的呼吸道病毒在内的药剂。 Ebselen是一种正在研究的新药，正在五种不同的神经病学和 神经精神适应症，4，5，并已获得FDA的快速通道指定， 梅尼埃病的治疗Ebselen的安全性已在成人（18-75岁）中进行了评估， 需要显著伴随治疗的基础疾病。超过6项RCT （>400名患者）已经完成，主要涉及口服剂量为400至1200 mg/天， 21-28天，无与研究药物相关的严重不良事件。作为一种消炎药， 依布硒啉不会引起胃肠道不适、延长出血时间、延长QTc间期，或 消极的免疫抑制，许多其他抗炎治疗的局限性。因此，我们认为， 依布硒啉可以很容易地重新定位为COVID-19患者的潜在治疗方法。 这些数据表明，依布硒啉是一种独特的研究药物，可以抑制病毒复制 以及减轻身体对nCoV 2的反应，从而逆转或限制发病机制 尤其是在肺部和肾脏。已允许进行两项II期RCT， IND 150553用于测试SPI-1005在预防和治疗COVID-19患者中的作用。