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.

项目摘要/摘要 SARS-COV-2（NCOV2）已被确定为Covid-19的病毒病因，这是大流行 没有有效治疗，发病率和死亡率的呼吸道疾病。一个 开创性研究，最近发表在《自然》杂志上，1显示了三个主要发现 涉及NCOV2。首先，Jin等。结晶的主蛋白（MPRO），一种关键酶负责 用于病毒复制。其次，他们确定了抑制的潜在药理学剂或药物 MPRO，使用基于结构的虚拟筛选> 10,000种化合物，包括批准和 研究药物。 Ebelen表现出对MPRO活性的显着抑制作用（最低IC50）。第三， Ebslen在基于体外​​细胞的测定中显示出明显的病毒载荷降低（最低的EC50）。 mpro 可能是第一个识别的特定NCOV2药物靶标，如果被抑制，可能会减少病毒载量 或病毒，并有可能减轻Covid-19的破坏性过程。 Ebelen是一种具有抗炎，细胞保护和 神经保护特性。 ebselen模拟谷胱甘肽过氧化物酶（GPX）活性，下方 氧化还原应力可以通过依赖NRF2转录激活细胞和组织中的GPX1 机制。2,3Ebselen已在多种急性肺和肾脏损伤的动物模型中进行了测试 并已证明可以逆转多种多样的细胞因子风暴和细胞损伤 包括抗生素，化学疗法和呼吸道病毒的药物对人有致病性。 Ebelen是一种在五种不同的神经学和 神经精神疾病的适应症，4,5，它已获得FDA的快速轨道名称 治疗Meniere病。 Ebslen的安全已在成年人（18 - 75年）中进行了评估 需要大量伴随疗法的基本医疗条件。超过6个RCT （> 400名患者）已完成，主要涉及400至1200 mg/天的口服剂量 21-28天，没有与研究药物有关的严重不良事件。作为抗炎药， Ebelen不会引起胃肠道不适，延长出血时间，延长QTC间隔或 负免疫抑制作用，许多其他抗炎治疗的局限性。所以， Ebselen可以很容易地重新定位，以作为Covid-19患者的潜在治疗方法。 这些数据表明Ebselen是一种独特的研究药物，可以抑制病毒复制 以及减轻人体对NCOV2的反应，从而逆转或限制发病机理 covid-19，尤其是在肺和肾脏中。在下 IND 150553在预防和治疗Covid-19患者中测试SPI-1005。