SAC-COVID: An FDA-approved Phase III clinical trial evaluating the safety and therapeutic efficacy of CD24Fc in severe COVID-19 patients

Summary Although most COVID-19 patients exhibit mild to moderate clinical symptoms, a substantial portion require hospitalization with oxygen support. These patients are classified as having severe COVID-19 and have high risk of progression to an intensive care unit (ICU) with requirement for invasive mechanical ventilation, extracorporeal membrane oxygenation (ECMO), and carry high risk for mortality. The current proposal seeks to repurpose CD24Fc, a first-in-class biological drug in cancer immunotherapy, to accelerate clinical improvement while reducing clinical progression of severe COVID-19 patients. The new drug belongs to the category of immunomodulators, and thus complements antiviral therapeutics that are being developed to inhibit SARS-CoV-2 virus replication. In addition to viral damage of lung epithelial cells, the pathogenesis of COVID- 19 involves inflammation in response to cellular injuries caused by the virus, which is mediated by inflammatory factors referred to as damage-associated molecular patterns (DAMPs). The prototypical DAMPs such as HMGB1 and HSP70/90 are released when cells undergo either stress or necrosis, and trigger inflammation by interacting with TLR4 or RAGE. Over 10 years ago, we showed that the CD24-Siglec 10/G pathway selectively regulates inflammation to DAMPs. Numerous studies have confirmed the role of DAMPs in the pathogenesis of different viral infections. Recent reports from our group in collaboration with others have demonstrated a critical role for CD24 and Siglecs in inflammation caused by human/simian immunodeficiency virus (HIV/SIV). Based on this new understanding, effective treatment of COVID-19 likely requires a combination of both antiviral and non-antiviral-based approaches. Antivirals can limit SARS-CoV-2 replication; while immune modulators can ameliorate inflammation in the lung, protect lung tissue from inflammatory injuries, preserve immune function by preventing T cell lymphopenia and functional T cell exhaustion, and prevent cytokine release syndrome (CRS). Given the biology of the CD24-Siglec pathway in limiting inflammation to DAMPs, we hypothesize that the CD24-Siglec innate-immune-checkpoint can be fortified to treated COVID-19 patients and improve outcomes for patients. CD24Fc is an investigational drug that comprises the non-polymorphic extracellular region of CD24, which we have shown to be an innate checkpoint against the inflammatory response to tissue injuries or DAMPs, attached to the Fc region of human IgG1. Preclinical and clinical studies have demonstrated that CD24Fc effectively addresses the major challenges associated with COVID-19 with excellent safety and therapeutic activity in leukemia patients with high risk of graft vs host diseases due to hematopoietic stem cell transplantation (HCT). Building on these exciting developments, we received FDA approval of a clinical protocol for a Phase III clinical trial testing the therapeutic effect of CD24Fc in protecting COVID-19 patients. The Phase III trial will involve 230 patients randomized into blinded CD24Fc arms and placebo, with time to clinical improvement from severe to mild disease and time to clinical progression as the co-primary endpoints. By showing safety and efficacy of CD24Fc for COVID-19 treatment, our work will provide a new medical countermeasure for the global health crisis and potential new pandemic by emerging strains of SARS virus and influenza virus in the future. The requested funding will cover the first part of the clinical trial that provides clinical proof-of-concept for CD24Fc in COVID-19 patients.Narrative This research program aims to evaluate whether CD24Fc, an agonist of the CD24-Siglec 10 innate-immune- checkpoint, provides a therapeutic benefit for severe COVID-19 patients. We will perform a multi-center, randomized double blind clinical trial. Our work may allow us to develop a new medical countermeasure against COVID-19.