In this pilot study BNP is elevated within 24 h after TBI in some patients. However, it does not originate from the brain and increased NT-proBNP concentrations are not consistently associated with hyponatremia or increased urinary sodium loss.

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Background. The identification of effective strategies capable of reducing the case mortality rate of high-risk COVID-19 is an urgent and unmet medical need. We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). Here we report data from a pilot clinical study (RPI-015) which examined the safety, tolerability, and feasibility of using RJX in combination with clinical standard of care (SOC) in hospitalized COVID-19 patients with pneumonia (ClinicalTrials.gov Identifier: NCT04708340). In addition to our early clinical proof of concept (POC) data, we also present non-clinical POC from a mouse model of CRS and ARDS that informed the design of the reported clinical study. Methods. 13 patients, who were hospitalized with COVID-19 pneumonia and abnormally elevated serum inflammatory biomarkers markers ≥3 months prior to the identification of the first confirmed U.S case of the Omicron variant, were treated with IV RJX (daily x 7 days) plus SOC. Non-clinical POC study examined the ability of RJX plus dexamethasone (DEX) to improve the survival outcome in the lipopolysaccharide (LPS)-Galactosamine (GalN) mouse model of fatal cytokine release syndrome (CRS), sepsis and acute respiratory distress syndrome (ARDS). Findings. In the Phase 1 clinical study, none of the 13 patients developed a treatment-related DLT, SAE, or Grade 3-5 AEs. Nine (9) of the 12 evaluable patients, including 3 patients with hypoxemic respiratory failure, showed rapid clinical recovery. In the non-clinical POC study in LPS-GalN challenged mice, the combination of RJX plus DEX was more effective than RJX alone or DEX alone, reversed the CRS as well as inflammatory tissue damage in the lungs and liver, and improved the survival outcome. Taken together, these findings provide the early clinical and non-clinical POC for the development of RJX as an adjunct to the SOC in the multi-modality management of high-risk COVID-19.

MAS825, a bispecific IL-1⍰/IL-18 monoclonal antibody, could improve clinical outcomes in COVID19 pneumonia by reducing inflammasome-mediated inflammation. Hospitalized nonventilated patients with COVID-19 pneumonia (n=138) were randomized (1:1) to receive MAS825 (10 mg/kg single i.v.) or placebo in addition to standard of care (SoC). The primary endpoint was the composite Acute Physiology and Chronic Health Evaluation II (APACHE II) score on Day 15 or on day of discharge (whichever was earlier) with worst case imputation for death. Other study endpoints included safety, Creactive protein (CRP), SARS-CoV2 presence and inflammatory markers. On Day 15, the APACHE II score was 14.5±1.87 and 13.5±1.8 in the MAS825 and placebo groups, respectively (P=0.33). MAS825 + SoC led to 33% relative reduction in intensive care unit (ICU) admissions, ~1 day reduction in ICU stay, reduction in mean duration of oxygen support (13.5 versus 14.3 days) and earlier clearance of virus on Day 15 versus placebo + SoC group. On Day 15, compared with placebo group, patients treated with MAS825 + SoC showed a 51% decrease in CRP levels, 42% lower IL-6 levels, 19% decrease in neutrophil levels and 16% lower interferon-γ levels, indicative of IL-1β and IL-18 pathway engagement. MAS825 + SoC did not improve APACHE II score in hospitalized patients with severe COVID19 pneumonia; however, it inhibited relevant clinical and inflammatory pathway biomarkers and resulted in faster virus clearance versus placebo + SoC. MAS825 used in conjunction with SoC was well tolerated. None of the adverse events (AEs) or serious AEs were treatment-related.

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