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

项目摘要/摘要 SARS-CoV-2(NCoV2)已被确定为新冠肺炎大流行的病毒病原体 呼吸道疾病，没有有效的治疗方法，发病率和死亡率不断上升。一个 最近发表在《自然》杂志上的开创性研究1显示了三个主要发现 涉及nCoV2。首先，金等人。使主要的蛋白水解酶(MPRO)结晶，这是一种负责 用于病毒复制。其次，他们确定了潜在的药理制剂或抑制的药物 MPRO，利用基于结构的虚拟筛选10,000种化合物，包括批准的和 研究药物。Ebselen对MPRO活性有明显的抑制作用(最低IC50)。第三, Ebselen在体外基于细胞的试验中显示出显著的病毒载量降低(最低EC50)。MPRO 可能是第一个被发现的特异性nCoV2药物靶点，当被抑制时，可以降低病毒载量 或毒性，并有可能减轻新冠肺炎的毁灭性进程。 依布硒是一种新型的有机硒化合物，具有抗炎、细胞保护和抗肿瘤等作用。 神经保护特性。Ebselen模拟谷胱甘肽过氧化物酶(GPX)活性，并在 氧化还原应激可通过依赖Nrf2转录激活细胞和组织中的GPX1 2，3 ebselen的机制已经在多种急性肺和肾损伤的动物模型中进行了测试。 并已被证明可以逆转由多种细胞因子引起的细胞因子风暴和细胞损伤 包括抗生素、化疗和呼吸道病毒在内的对人类有致病作用的药物。 Ebselen是一种正在进行研究的新药，正在五种不同的神经病学和 神经精神病学适应症，4，5，并已获得FDA的快速通道指定 梅尼埃病的治疗。Ebselen的安全性已经在成年人(18-75岁)中进行了评估 潜在的医疗条件，需要大量的伴随治疗。超过6个随机对照试验 (&gt；400名患者)已经完成，主要涉及口服剂量400至1200毫克/天 21~28天，未发生与研究药物相关的严重不良反应。作为一种消炎药， Ebselen不会引起胃肠道不适，不会延长出血时间，不会延长QTC间期，或者 负性免疫抑制，许多其他抗炎治疗的局限性。因此， 依贝塞林可以很容易地重新定位为新冠肺炎患者的潜在治疗方法。 这些数据表明ebselen是一种可以抑制病毒复制的独特的研究药物。 以及减轻机体对nCoV2的反应，从而逆转或限制发病 新冠肺炎，尤其是在肺和肾。根据以下规定，已允许两个阶段的RCT IND 150553测试Spi-1005在预防和治疗新冠肺炎患者中的作用。

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.