The supernucleophilic cobalt compound, cob(I)alamin, has been kinetically characterized with respect to its ability to bring about transalkylation of adducts to DNA phosphates (phosphotriesters). The reactivity of cob(I)alamin toward different phosphotriesters (model compounds and methylated DNA), as well as its specificity toward DNA-phosphate adducts, has been investigated. Through nucleophilic displacement on the alkyl by cob(I)alamin, the alkyl groups (methyl and ethyl) were transferred from phosphotriesters within minutes at room temperature. In contrast, methylated nucleosides (base adducts) were stable in the presence of cob(I)alamin.

Vascular oxidative stress is an important factor in hypertension-associated vascular damage and is mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. The C242T polymorphism at the p22PHOX gene affects binding of p22PHOX to heme, leading to variants of NADPH oxidase that produce different levels of reactive oxygen species (ROS). Specific variations in ROS are associated with an altered risk of developing cardiovascular disease. In the present study, 140 permanent Kashmiri-resident individuals were recruited (75 with essential systemic hypertension and 65 normotensive controls). Endothelial function was assessed non-invasively using high-resolution ultrasonography of the brachial artery. Endothelium-dependent vasoreactivity was expressed in terms of flow-mediated dilation. The TT genotype was identified in 2% of hypertensive and 7% of normotensive individuals. Frequency of the T-allele was not observed as significantly different between hypertensive and normotensive individuals (P=0.24; OR=0.4; 95% CI, 0.07-2.2). Blood pressure or the prevalence of hypertension did not vary between C242T p22PHOX genotypes or in the presence or absence of the T-allele.

Rationale: Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. Objectives: To evaluate the effect of opaganib on supplemental oxygen requirements, time to hospital discharge and its safety in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods: This Phase 2a, randomized, double-blind, placebo-controlled study, was conducted between July and December 2020 in eight sites in the USA. Forty-two enrolled patients received opaganib (n=23) or placebo (n=19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of investigational product. Main Results: By Day 14, 50.0% of patients in the opaganib and 22.2% in the placebo group no longer required supplemental oxygen for at least 24 hours, while 86.4% and 55.6%, respectively, were discharged from hospital. The relative decrease in total supplemental oxygen requirement from baseline to Day 14 was 61.6% in the opaganib versus 46.7% in the placebo arms. The incidence of ≥ Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. Conclusions: In this proof-of-concept study, patients receiving oral opaganib required less supplemental oxygen, resulting in earlier hospital discharge, with no safety concerns arising. These findings support further evaluation of opaganib in this population.

Background Opaganib, an oral sphingosine kinase-2 inhibitor with antiviral and anti-inflammatory properties, was shown to inhibit SARS-CoV-2 replication in vitro. We thus considered that opaganib could be beneficial for moderate to severe COVID-19 pneumonia. The objective of the study was to evaluate the safety of opaganib and its effect on supplemental oxygen requirements and time to hospital discharge in COVID-19 pneumonia hospitalized patients requiring supplemental oxygen. Methods This Phase 2a, randomized, double-blind, placebo-controlled study was conducted between July and December 2020 in eight sites in the USA. Forty-two enrolled patients received opaganib (n = 23) or placebo (n = 19) added to standard of care for up to 14 days and were followed up for 28 days after their last dose of opaganib/placebo. Results There were no safety concerns arising in this study. The incidence of ≥ Grade 3 treatment-emergent adverse events was 17.4% and 33.3% in the opaganib and placebo groups, respectively. Three deaths occurred in each group. A numerical advantage for opaganib over placebo was observed in in this non-powered study reflected by total supplemental oxygen requirement from baseline to Day 14, the requirement for supplemental oxygen for at least 24 hours by Day 14, and hospital discharge. Conclusions In this proof-of-concept study, hypoxic, hospitalized patients receiving oral opaganib had a similar safety profile to placebo-treated patients, with preliminary evidence of benefit for opaganib as measured by supplementary oxygen requirement and earlier hospital discharge. These findings support further evaluation of opaganib in this population.