Abbreviations
Absolute neutrophil count (ANC), adverse drug reaction (ADR), adverse events (AEs), alanine aminotransferase (ALT), angiotensin receptor blocker (ARB), antibody-dependent enhancement (ADE), AP2-associated protein kinase 1 (AAK1), antigen-dependent enhancement (ADE), aspartate transaminase (AST), chronic obstructive pulmonary disease (COPD), cluster of differentiation 73 (CD73), cytochrome P450 (CYP), deep vein thrombosis (DVT), disease-modifying anti-rheumatic drug (DMARD), drug-drug interaction (DDI), drug-induced liver injury (DILI), Early Access to Medicines Scheme (EAMS), exoribonuclease (ExoN), favipiravir-ribofuranosyl-5′-triphosphate (favipiravir-RTP), human coronavirus (HCoV), human immunodeficiency virus (HIV), intensive care unit (ICU), interferon stimulated response element (ISRE), interferon regulatory factor (IRF), main protease (Mpro), maximum serum concentration (Cmax), Medicines and Healthcare products Regulatory Agency (MHRA), Middle East respiratory syndrome coronavirus (MERS-CoV), monocyte chemoattractant protein 1 (MCP1), Multicentric Castleman’s disease (MCD), multiple sclerosis (MS), non-steroidal anti-inflammatory drugs (NSAIDS), non-structural protein 14 (nsp14), P-glycoprotein (P-gp), pharmacokinetic (PK), phosphate (P), RNA-dependent RNA polymerase (RdRp), secondary haemophagocytic lymphohistiocytosis (sHLH), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), signal transducer and activator of transcription proteins (STAT), sulfobutylether β-cyclodextrin sodium (SBECD), thrombotic microangiopathy (TMA), tumour necrosis factor (TNF), upper limit of normal (ULN), World Health Organization (WHO).
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly pathogenic beta-coronavirus that emerged in Wuhan, Hubei Province, in late December 2019 (X. Yang et al., 2020). SARS-CoV-2 is the seventh human coronavirus (HCoV) to be identified and is the cause of the disease known as COVID-19 which was declared by the World Health Organization (WHO) as a “Public Health Emergency of International Concern” on 30 January 2020 (T. Liu et al., 2020). The symptoms of COVID-19 are non-specific and cover a broad clinical spectrum meaning that clinical diagnosis without a test is challenging. Patients commonly present with fever, cough and anosmia, although many patients are asymptomatic. The virus can be transmitted by asymptomatic patients alongside those in the symptomatic and pre-symptomatic phase of the disease (D. Wu, Wu, Liu, & Yang, 2020; X. Yang et al., 2020). As of 6th June 2020, COVID-19 is responsible for 395,459 deaths worldwide (John Hopkins University and Medicine, 2020). As the number of new cases continues to increase rapidly, many clinical and preclinical studies have been initiated to identify viable treatment options for COVID-19 patients. Many of these potential therapeutic strategies are based upon the re-purposing of approved drugs or the evaluation of those currently in the clinical stages of drug development (figure 1). For this reason, much information already exists on the pharmacology and toxicology of each prospective therapy. In order to examine their potential for efficacy and safety against COVID-19, it is essential to consider all of the available information in this extremely fast-moving and critical research field. Therefore, it is important to assess drug-specific safety parameters in the context of the pathogenesis of the virus and its clinical features in order to begin to evaluate the disease-specific harm-benefit ratio.
Therapeutic strategies for the treatment of COVID-19 span a range of phases including prophylactic administration, through to early infection, through to the more severe disease stage characterised by pulmonary involvement requiring mechanical ventilation and hyperinflammation in some instances (Siddiqi & Mehra, 2020). At the time of writing, over 600 clinical trials have been initiated across the globe, with the majority of these investigating the use of a drug(s) already approved for treatment of another disease (Clinical Trials.gov, 2020b). In addition to their administration as a monotherapy, combination therapy has also been utilised. In addition to repurposed compounds, several candidates in preclinical or clinical development stages are also under-investigation, as well as widely available borderline substances such as ascorbic acid (Clinical Trials.gov, 2020d). However, it is important to note that the number of clinical trials initiated should not be taken as an indicator of the ultimate potential for success.
Our perspective will focus upon selected repurposed therapies which are used in different phases of the disease (figure 1), and can broadly be categorised by their mechanism of action as 1) viral entry inhibitors; 2) disruption of cellular viral processing; 3) modulators of the inflammatory phase and 4) compounds that stimulate the host’s anti-viral response. Selections were based upon agents undergoing the largest clinical trials at the time of writing, 6thJune 2020.