RJX is an Intravenous (IV) formulation of known physiologically compatible compounds that is being developed for more effective supportive therapy of patients with sepsis, including COVID-19 patients with viral sepsis and Acute Respiratory Distress Syndrome (ARDS). The RJX formulation is a solution of buffered acid products, electrolyte components, and vitamins, including ascorbic acid, cyanocobalamin, thiamine hydrochloride, riboflavin 5' phosphate, niacinamide, pyridoxine hydrochloride, and calcium d-pantothenate, and magnesium sulfate heptahydrate, a mineral with a negative oxidation-reduction potential. The components of RJX exhibited promising activity in clinical studies involving ARDS patients and/or non-clinical studies in animal models of ARDS. The published data from these clinical and non-clinical studies provided the medical-scientific rationale for our clinical development strategy for RJX and a clinical study in COVID-19 patients.
Severe viral sepsis of coronavirus disease 2019 (COVID-19) is associated with a Cytokine Release Syndrome (CRS) and a high case fatality rate due to the development of Acute Respiratory Distress Syndrome (ARDS) and multi-organ failure in high-risk COVID-19 patients, including cancer patients undergoing chemotherapy. Here, we demonstrate that our COVID-19 drug candidate Rejuveinix (RJX) exhibits potent protective anti-inflammatory activity in the LPS-GalN mouse model of fatal sepsis and multi-organ failure at a dose level >10x lower than its maximum tolerated dose (MTD) for human subjects. In BALB/c mice challenged with an otherwise invariably fatal dose of LPS-GalN, prophylactic administration of 0.7 mL/kg RJX (Human equivalent dose=0.057 mL/ kg), corresponding to 7.5% of its clinical Maximum Tolerated Dose (MTD), prevented the cytokine storm, mitigated the oxidative stress and inflammatory tissue injury in lungs, liver, and heart, and significantly improved the survival outcome. Furthermore, RJX increased the levels of antioxidant enzymes SOD, CAT, and GSH-Px, and reduced oxidative stress in the brain. These results indicate that RJX has clinical potential as a prophylactic anti-inflammatory agent against severe sepsis, including viral sepsis in COVID-19 patients.
Background. New treatment platforms that can prevent acute respiratory distress syndrome (ARDS) or reduce its mortality rate in high-risk 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 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 (GCP) 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 lipopolysaccharide (LPS)-Galactosamine (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 from the study. In the non-clinical study, RJX exhibited potent and dose-dependent protective activity, decreased the inflammatory cytokine responses (IL-6, TNF-, TGF-), and improved survival in the LPS-GalN mouse model of 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 show potential to favorably affect the clinical course of high-risk COVID-19 by preventing ARDS and its complications.
Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX), have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P (RJX PPP.18.1051) or RJX-B (RJX-B200702-CLN) similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats (p < 0.0001). There was no statistically significant difference between tissue SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B (p > 0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels. Furthermore, both formulations showed profound protective activity in a mouse model of sepsis. In agreement with the PD evaluations in rats and their proposed mechanism of action, both RJX-P and RJX-B exhibited near-identical potent and dose-dependent anti-oxidant and anti-inflammatory activity in the LPS-GalN model of ARDS and multi-organ failure in mice.
Abstract Here, we demonstrate that the two distinct formulations of our anti-sepsis drug candidate Rejuveinix (RJX) have a very favorable safety profile in Wistar Albino rats at dose levels comparable to the projected clinical dose levels. 14-day treatment with RJX-P or RJX-B similarly elevated the day 15 tissue levels of the antioxidant enzyme superoxide dismutase (SOD) as well as ascorbic acid in both the lungs and liver in a dose-dependent fashion. The activity of SOD and ascorbic acid levels were significantly higher in tissues of RJX-P or RJX-B treated rats than vehicle-treated control rats ( p <0.0001). There was no statistically significant difference between tissues SOD activity or ascorbic acid levels of rats treated with RJX-P vs. rats treated with RJX-B ( p >0.05). The observed elevations of the SOD and ascorbic acid levels were transient and were no longer detectable on day 28 following a 14-day recovery period. These results demonstrate that RJX-P and RJX-B are bioequivalent relative to their pharmacodynamic effects on tissue SOD and ascorbic acid levels.
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