Itraconazole for COVID-19: preclinical studies and a proof-of-concept randomized clinical trial

Abstract

Background: The antifungal drug itraconazole exerts in vitro activity against SARS-CoV-2 in Vero and human Caco-2 cells. Preclinical and clinical studies are required to investigate if itraconazole is effective for the treatment and/or prevention of COVID-19. Methods: Due to the initial absence of preclinical models, the effect of itraconazole was explored in a clinical, proof-of-concept, open-label, single-center study, in which hospitalized COVID-19 patients were randomly assigned to standard of care with or without itraconazole. Primary outcome was the cumulative score of the clinical status until day 15 based on the 7-point ordinal scale of the World Health Organization. In parallel, itraconazole was evaluated in a newly established hamster model of acute SARS-CoV-2 infection and transmission, as soon as the model was validated. Findings: In the hamster acute infection model, itraconazole did not reduce viral load in lungs, stools or ileum, despite adequate plasma and lung drug concentrations. In the transmission model, itraconazole failed to

Identification of COVID-19 prognostic markers and therapeutic targets through meta-analysis and validation of Omics data from nasopharyngeal samples

“…Viral RNA load in lung tissue specimens was detected by qRT-PCR. Sample size for hamster experiments were chosen based on previous studies [ 34 , 35 ].…”

Azithromycin for treatment of hospitalised COVID-19 patients: a randomised, multicentre, open-label clinical trial (DAWn-AZITHRO)

“…There may be several reasons why azithromycin fails to benefit COVID-19 patients. First, the in vitro antiviral activity is weak, compared with direct-acting antivirals like remdesivir [ 1 ], and azithromycin has not shown to aid viral clearance in vivo [ 20 ]. Second, the incidence of bacterial superinfection in COVID-19 is low [ 21 ], and, contrary to what is seen in influenza [ 7 , 8 , 22 ], a prophylactic effect against post-viral pneumococcal and atypical pneumonia is thus absent.…”

“…The high disease burden and the rapid spread of the SARS-CoV-2 pandemic immediately directed the search for disease-modifying agents towards the repurposing of existing molecules. The Belgian Direct Antivirals Working against the novel Coronavirus studies were a parallel series of proof-of-concept trials, assessing several treatment strategies for hospitalised patients with COVID-19: itraconazole [ 1 ], azithromycin [ 2 ], anakinra combined with intensified anticoagulation [ 3 ], and convalescent plasma [ 4 ].…”

Strategies for drug repurposing against coronavirus targets

“…However, few NSP13 inhibitors progress past the preclinical stage due to the inhibition of host ATPases and kinases by helicase inhibitors which target the NSP13 ATPase activity ( Elshabrawy, 2020 ). However, promising mfScores do not guarantee efficacious preclinical activity, as seen with itraconazole, a drug with one of the best mfScores, failing to reduce viral load and prevent transmission in a SARS-CoV-2 hamster model ( Liesenborghs et al, 2021 ).…”