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Principal Investigator: Michael B Sporn
Organization: TRITERPENOID THERAPEUTICS, INC.
Fiscal Year: 2020
Award: $249,799
Funding agency: National Cancer Institute
PROJECT ABSTRACT
COVID-19 infection is associated with substantial mortality in patients with clinical co-morbidities, including
smoking, advanced age and diabetes mellitus. In these patients, COVID-19 infection leads to a
hyperinflammatory 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 “cytokine
storm”) is a prodromal feature of ARDS and multi-organ failure. Bronchoalveolar fluids (BALF) from patients with
severe COVID-19 are enriched in CCL2, one of the most potent chemokines driving the recruitment of monocytes
into 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 no
effective treatment currently available that may be deployed as an intervention to either prevent or ameliorate
the cytokine storm of COVID-19. To address this need, our research team is actively engaged in the preclinical
development of an optimized lead agent (CDDO-2P-Im, or ‘2P-Im’), a highly potent synthetic triterpenoid that is
the most advanced among a class of small molecules recognized as effective modifiers of the host inflammatory
response. Our data show that 2P-Im broadly inhibits expression of cytokine networks and pathways underlying
hyper-inflammation. In particular, 2P-Im and its related derivatives are potent suppressors of macrophage
activation, 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 under
investigation for in use in treating COVID-19. We envision 2P-Im will be provided to patients as an oral agent
deployed to prevent macrophage activation syndrome and disrupt progression to the ARDS of COVID-19
disease in high-risk populations. 2P-Im also has potential for use in the outpatient setting as a chemopreventive
regimen to reduce risk in first responders, residents living in group settings, and other high-risk groups exposed
to COVID-19. Preliminary data demonstrate potent cytoprotective effects in assays of efficacy against Influenza
virus A H1N1 and Influenza virus A H3N2. Through partnership between Triterpenoid Therapeutics (TTX) and
the Texas Biomedical Research Institute, we will pursue full-scale, IND-enabling efficacy studies in established
mouse models of COVID-19. Specifically, we will define the capacity of 2P-Im to prevent the cytopathic effects
of SARS-CoV-2 in established, validated in vitro models of COVID-19 (Aim 1); and demonstrate the in vivo
efficacy of 2P-Im against SARS-CoV-2 induced inflammation and capacity to promote survival in the established
K18-hACE2 mouse model of COVID-19 (Aim 2). The proposed plan will lead to approval of an IND that will allow
for future clinical trials of 2P-Im in patients with COVID-19, which is the ultimate goal of this project.
Terms: <(TNF)-α><2019 novel coronavirus><2019-nCoV><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Address><Admission><Admission activity><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alveolar Lavage Fluids><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Assay><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Bioassay><Biologic Assays><Biological Assay><Biomedical Research><Blood Vessels><Blood monocyte><Bronchial Lavage Fluid><CCL2><CCL2 gene><COVID-19><COVID19><Cachectin><Cell Body><Cell Culture Techniques><Cells><Chemokine, CC Motif, Ligand 2><Chemoprevention><Chemopreventive><Chemopreventive Agent><Chemotactic Cytokines><Clinical><Clinical Evaluation><Clinical Testing><Clinical Trials><Cytokine Gene><Cytokine Network><Cytokine Network Pathway><DNA Polymerase II><DNA Polymerase epsilon><DNA-Dependent DNA Polymerase II><Da Nang Lung><Data><Development><Diabetes Mellitus><Disease><Disorder><Domestic Rabbit><Dropsy><Drugs><ELISA><ELISPOT><Edema><Elderly><Enzyme-Linked Immunosorbent Assay><Exhibits><Exposure to><Failure><Future><GM-CSF><GS-5734><Gene Expression><Genes><Goals><Granulocyte-Macrophage Colony-Stimulating Factor><H1N1><H1N1 Virus><HPGF><Hepatocyte-Stimulating Factor><Histamine-Producing Cell-Stimulating Factor><Homologous Chemotactic Cytokines><Hour><Human><Hybridoma Growth Factor><Hydrops><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune infiltrates><Immunes><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Influenza A><Influenza A Virus, H1N1 Subtype><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Intercrines><Interleukin-6><Intervention><Intervention Strategies><Investigation><K-18><K-18 conjugate><K18><K18 combination><Laboratories><Liquid substance><Lung><Lung Lavage Fluid><Lung Respiratory System><Lung damage><MCAF><MCP-1><MCP1><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><MGI-2><Macrophage Activation><Macrophage activation syndrome><Macrophage-Derived TNF><Marrow monocyte><Medication><Membrane><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Miscellaneous Antibiotic><Modern Man><Molecular Interaction><Molgramostin><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Myeloid Differentiation-Inducing Protein><Non-Polyadenylated RNA><Oral><Organ><Orthomyxovirus Type A><Oryctolagus cuniculus><Out-patients><Outpatients><Pathogenicity><Patients><Peptides><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacology and Toxicology><Plasmacytoma Growth Factor><Play><Pol II><Population><Production><RNA><RNA Gene Products><Rabbits><Rabbits Mammals><Reader><Regimen><Research><Research Institute><Respiratory Failure><Ribonucleic Acid><Risk><Rivers><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SCYA2><SIS cytokines><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2><Severities><Shock Lung><Small Inducible Cytokine A2><Smoking><Staining method><Stains><Stiff lung><Syndrome><T cell infiltration><T cell tumor trafficking><TC-GM-CSF><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Texas><Therapeutic><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Tumor-Cell Human GM Colony-Stimulating Factor><Tumor-infiltrating immune cells><Type A Influenza><Up-Regulation><Upregulation><Viral><Viral Diseases><Virus Diseases><Virus Replication><Wuhan coronavirus><Zoonoses><Zoonotic><Zoonotic Infection><advanced age><anti-carcinogenic><anticarcinogenic><cell culture><chemoattractant cytokine><chemokine><chemoprevention agent><clinical development><clinical test><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><coronavirus disease 2019><cytokine><cytokine release syndrome><cytokine storm><developmental><diabetes><disease risk><disorder risk><driving><drug/agent><effective therapy><effective treatment><efficacy study><elders><enzyme linked immunospot assay><first responder><fluid><geriatric><granulocyte macrophage colony stimulating factor><high risk group><high risk population><immune cell infiltrate><immune infiltration><in vitro Model><in vivo><industrial partnership><industry partner><industry partnership><inflammatory mediator><innovate><innovation><innovative><interferon beta 2><interstitial><interventional strategy><intratumoral immune cell><late life><later life><lead optimization><liquid><lung injury><macrophage><membrane structure><microbial><monocyte><mortality><mouse model><murine model><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><older adult><older person><oleanane><polyclonal antibody><pre-clinical development><preclinical development><prevent><preventing><pulmonary><pulmonary failure><recruit><remdesivir><research clinical testing><respiratory><respiratory insufficiency/failure><senior citizen><severe acute respiratory syndrome-CoV><small molecule><tumor immune cell><vascular><ventilation><viral infection><viral multiplication><viral replication><virus infection><virus multiplication><virus-induced disease><wet lung>