Mitoquinone/mitoquinol mesylate as oral and safe Postexposure Prophylaxis for Covid-19

PROJECT SUMMARY/ABSTRACT Current oral antivirals used against SARS-CoV-2 infection such as protease inhibitors have limitations such as absence of anti-inflammatory effects and rebound COVID-19 after a 5-day course of outpatient antiviral treatment. Novel antiviral therapies against SARS-CoV-2 are urgently needed that ideally also limit inflammatory responses that contribute to morbidity from COVID-19. Reactive oxygen species (ROS) impair cellular functions and drive pro-inflammatory signaling and pathogenesis of infections with RNA viruses like coronavirus. Mitochondria are the main source of energy and ROS (mito-ROS). Mito-ROS are regulated by the antioxidant Nrf2 pathway that mediates pathogenesis and tissue damage of viral infections. We showed that MitoQ, a mitochondrial antioxidant and Nrf2 agonist, inhibits in vitro and in vivo viral replication of several SARS-CoV-2 variants of concern (VOC) and associated inflammatory response and apoptosis in airway epithelial cells through the Nrf2 pathway. Given that MitoQ is a diet supplement that is safe and immediately available to humans for use as possible therapeutic, we also showed antiviral efficacy of MitoQ in humans in a carefully designed open label clinical trial of post exposure prophylaxis (PEP) of MitoQ, compared to no MitoQ (control group), to prevent development of SARS-CoV-2 infection after high-risk exposure to a person with confirmed SARS-CoV-2 infection. MitoQ was well tolerated. We hypothesize that MitoQ attenuates the SARS- CoV-2-induced aberrant mito-ROS and Nrf2 pathway in epithelial cells and ultimately tissue injury that drives development and progression of severe COVID-19. The goal of this application is to determine if MitoQ can be used as novel oral safe outpatient post-exposure prophylaxis treatment against development of severe COVID-19. We propose the first proof-of concept randomized, double-blind, placebo-controlled Phase II efficacy study (RCT) with oral MitoQ use in adults at high risk for development of COVID-19, to further establish the safety and the efficacy of MitoQ against development of SARS-CoV-2 infection. We will include 2 treatment groups (MitoQ 20 mg daily, placebo) and we aim to recruit a total of 112 participants in total (50 per group accounting for 10% attrition). The primary outcome of efficacy will be the development of SARS- CoV-2 infection after high-risk exposure. The primary outcome of safety will be the proportion of participants exhibiting adverse effects of any grade. Given that attenuation of detrimental host responses that propagate viral replication may impose a higher barrier to generation of resistant viruses, this study will directly test MitoQ as a novel oral, safe, potent therapeutic strategy for COVID-19 against emerging SARS-CoV-2 VOCs. Our proposal will set the foundation of larger clinical trial that will advance use of MitoQ for COVID-19 to supplement existing treatments.