Development of the New Synthetic Triterpenoid CDDO-2P-Im for Chemoprevention of the ARDS of COVID-19

PROJECT Abstract: COVID-19 infection is associated with substantial mortality in patients with clinical co-morbidities, includingsmoking, advanced age and diabetes mellitus. In these patients, COVID-19 infection leads to ahyperinflammatory state producing vascular leak, interstitial edema, hyaline membrane formation and ARDS.COVID-19 patients requiring ICU admission have high circulating levels of IL-6, GM-CSF, MCP and MIP1 (CCL2)cytokines compared to those with uncomplicated illnesses. This hyper-inflammation syndrome, (aka "cytokinestorm") is a prodromal feature of ARDS and multi-organ failure. Bronchoalveolar fluids (BALF) from patients withsevere COVID-19 are enriched in CCL2, one of the most potent chemokines driving the recruitment of monocytesinto the lung. Of note, cytokine storm is also associated with extensive lung damage in SARS-CoV and MERS-CoV infections, suggesting that innate hyper-inflammation is common to respiratory zoonoses. There is noeffective treatment currently available that may be deployed as an intervention to either prevent or amelioratethe cytokine storm of COVID-19. To address this need, our research team is actively engaged in the preclinicaldevelopment of an optimized lead agent (CDDO-2P-Im, or '2P-Im'), a highly potent synthetic triterpenoid that isthe most advanced among a class of small molecules recognized as effective modifiers of the host inflammatoryresponse. Our data show that 2P-Im broadly inhibits expression of cytokine networks and pathways underlyinghyper-inflammation. In particular, 2P-Im and its related derivatives are potent suppressors of macrophageactivation, suppressing the production of MIP1 (CCL2) by human macrophages at picomolar concentrations. 2P-Im is an innovative new drug, with a mechanism of action not shared by any other drug currently underinvestigation for in use in treating COVID-19. We envision 2P-Im will be provided to patients as an oral agentdeployed to prevent macrophage activation syndrome and disrupt progression to the ARDS of COVID-19disease in high-risk populations. 2P-Im also has potential for use in the outpatient setting as a chemopreventiveregimen to reduce risk in first responders, residents living in group settings, and other high-risk groups exposedto COVID-19. Preliminary data demonstrate potent cytoprotective effects in assays of efficacy against Influenzavirus A H1N1 and Influenza virus A H3N2. Through partnership between Triterpenoid Therapeutics (TTX) andthe Texas Biomedical Research Institute, we will pursue full-scale, IND-enabling efficacy studies in establishedmouse models of COVID-19. Specifically, we will define the capacity of 2P-Im to prevent the cytopathic effectsof SARS-CoV-2 in established, validated in vitro models of COVID-19 (Aim 1); and demonstrate the in vivoefficacy of 2P-Im against SARS-CoV-2 induced inflammation and capacity to promote survival in the establishedK18-hACE2 mouse model of COVID-19 (Aim 2). The proposed plan will lead to approval of an IND that will allowfor future clinical trials of 2P-Im in patients with COVID-19, which is the ultimate goal of this project.