Chloroquine use in the Treatment of COVID-19: Systems Biology Report of Common Targets of SARS-CoV-2 and Chloroquine.

Abstract

BACKGROUND: Chloroquine use for treatment of COVID-19 patients has been under discussion and recommendations have been shifting from positive to caution or non-conclusive. Variability of clinical outputs requires understanding of mechanisms of the differences. Implementation of a companion diagnostic would allow selecting patients who may benefit from the drug. The first line would be markers already used in clinics. Systems biology opens for an opportunity to identify targets common for chloroquine and SARS-CoV-2. These common targets would be candidates for the companion diagnostic.METHODS: Systemic analysis of molecular mechanisms and markers engaged by chloroquine and SARS-CoV-2 virus was performed. The networks of regulatory mechanisms were explored for an intersection and relevance to clinical markers.RESULTS: Reported here systemic analysis describes the intersection of molecular mechanisms of chloroquine and processes engaged by COVID-19. 266 nodes provide insight into the mechanisms of chloroquine impact on the infection and represent a pool of companion diagnostic markers. As an example, an intersection with the markers of heart arrhythmia retrieved 19 nodes. Thirteen of them were reported in human plasma: levels of albumin, amyloid precursor protein, and endoglin correlate with adverse cardiac effects. CONCLUSIONS: Reported intersection nodes of SARS-CoV-2 and chloroquine are the candidate markers for companion diagnostic of the chloroquine application. Some of these markers are already used in the clinic and their interpretation may contribute to monitoring for adverse effects of chloroquine.

Regulators, Pivotal Clinical Trials, and Drug Regulation in the Age of COVID-19

“…For example, the EMA did not authorize the use of hydroxychloroquine for unapproved indications. 28 Different regulatory instruments within the 3 agencies result in different mechanisms to approve remdesivir “conditionally” (Health Canada) or pre-approval as an emergency use authorization (FDA). 29 Most recently, the FDA took extra due diligence in examining safety data, restarting the Phase III Oxford-Astra Zeneca COVID vaccine clinical trial AZD1222 fully 6 weeks later in the United States (October 23) compared to the United Kingdom (September 14) after it was stopped on September 6 due to an adverse event following immunization.…”