Abstract
Background: New treatment platforms that can prevent acute respiratory distress syndrome (ARDS) or reduce its mortality rate in high-risk coronavirus disease 2019 (COVID-19) patients, such as those with an underlying cancer, are urgently needed. Rejuveinix (RJX) is an intravenous formulation of anti-oxidants and anti-inflammatory agents. Its active ingredients include ascorbic acid, cyanocobalamin, thiamine hydrochloride, riboflavin 5′ phosphate, niacinamide, pyridoxine hydrochloride, and calcium D-pantothenate. RJX is being developed as an anti-inflammatory and anti-oxidant treatment platform for patients with sepsis, including COVID-19 patients with viral sepsis and ARDS. Here, we report its clinical safety profile in a phase 1 clinical study (ClinicalTrials.gov Identifier: NCT03680105) and its potent protective activity in the lipopolysaccharide galactosamine (LPS-GalN) mouse model of ARDS. Methods: A phase 1, double-blind, placebo-controlled, randomized, two-part, ascending dose-escalation study was performed in participating 76 healthy volunteer human subjects in compliance with the ICH (E6) good clinical practice guidelines to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of RJX (Protocol No. RPI003; ClinicalTrials.gov Identifier: NCT03680105). The ability of RJX to prevent fatal shock, ARDS, and multi-organ failure was examined in the well-established LPS-GalN mouse model of sepsis and ARDS. Standard methods were employed for the statistical analysis of data in both studies. Findings: In the phase 1 clinical study, no participant developed serious adverse events (SAEs) or Grade 3-Grade 4 adverse events (AEs) or prematurely discontinued participation in the study. In the non-clinical study, RJX exhibited potent and dose-dependent protective activity, decreased the inflammatory cytokine responses (interleukin-6, tumor necrosis factor alpha, transforming growth factor beta), and improved survival in the LPS-GalN mouse model of sepsis and ARDS. Histopathological examinations showed that RJX attenuated the LPS-GalN induced acute lung injury (ALI) and pulmonary edema as well as liver damage. Conclusion: RJX showed a very favorable safety profile and tolerability in human subjects. It shows potential to favorably affect the clinical course of high-risk COVID-19 by preventing ARDS and its complications.
Highlights
IntroductionA significant minority of patients infected with the new coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), develop viral pneumonia that causes an acute lung injury (ALI) capable of rapid progression to viral sepsis and acute respiratory distress syndrome (ARDS) with a high fatality rate especially if they are older and have comorbidities (Carver and Jones, 2020; Kuderer et al, 2020; Lian et al, 2020; Uckun, 2020a; Uckun, 2020b; Wu et al, 2020; Zheng et al, 2020; Zhou et al, 2020)
In Part 1, no deaths or serious adverse event (SAEs) were reported, none of the 39 RJX-treated subjects experienced Grade 3 or 4 adverse events (AEs), and no AEs led to discontinuation of RJX (Supplementary Table S7A)
The treatmentemergent AEs (TEAEs) in two of the subjects were considered possibly or probably related to RJX. Both patients were in Cohort 2: One patient had a mild infusion site discomfort on day 6 considered possibly related to RJX and another patient had a mild infusion site pain on days 6 and 7 considered probably related to RJX infusion (Supplementary Tables S6, S7)
Summary
A significant minority of patients infected with the new coronavirus, SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), develop viral pneumonia that causes an acute lung injury (ALI) capable of rapid progression to viral sepsis and acute respiratory distress syndrome (ARDS) with a high fatality rate especially if they are older and have comorbidities (Carver and Jones, 2020; Kuderer et al, 2020; Lian et al, 2020; Uckun, 2020a; Uckun, 2020b; Wu et al, 2020; Zheng et al, 2020; Zhou et al, 2020). New treatment platforms that can prevent acute respiratory distress syndrome (ARDS) or reduce its mortality rate in high-risk coronavirus disease 2019 (COVID-19) patients, such as those with an underlying cancer, are urgently needed. We report its clinical safety profile in a phase 1 clinical study (ClinicalTrials.gov Identifier: NCT03680105) and its potent protective activity in the lipopolysaccharide galactosamine (LPS-GalN) mouse model of ARDS
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