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

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.