Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2

Abstract

Summary Effective therapeutics to treat COVID-19 are urgently needed. While many investigational, approved, and repurposed drugs have been suggested, preclinical data from animal models can guide the search for effective treatments by ruling out treatments without in vivo efficacy. Remdesivir (GS-5734) is a nucleotide analog prodrug with broad antiviral activity 1 , 2 , that is currently investigated in COVID-19 clinical trials and recently received Emergency Use Authorization from the US Food and Drug Administration 3 , 4 . In animal models, remdesivir treatment was effective against MERS-CoV and SARS-CoV infection. 2 , 5 , 6 In vitro , remdesivir inhibited replication of SARS-CoV-2. 7 , 8 Here, we investigated the efficacy of remdesivir treatment in arhesus macaque model of SARS-CoV-2 infection 9 . In contrast to vehicle-treated animals, animals treated with remdesivir did not show signs of respiratory disease and had reduced pulmonary infiltrates on radiographs and reduced virus titers in bronchoalveolar lavages 12hrs after the first treatment administration. Virus shedding from the upper respiratory tract was not reduced by remdesivir treatment. At necropsy, lung viral loads of remdesivir-treated animals were lower and there was a reduction in damage to the lungs. Thus, therapeutic remdesivir treatment initiated early during infection had a clinical benefit in SARS-CoV-2-infected rhesus macaques. Although the rhesus macaque model does not represent the severe disease observed in a proportion of COVID-19 patients, our data support early remdesivir treatment initiation in COVID-19 patients to prevent progression to pneumonia.

Protocol for the DisCoVeRy trial: multicentre, adaptive, randomised trial of the safety and efficacy of treatments for COVID-19 in hospitalised adults

“… 10 Remdesivir has shown an in vitro activity on SARS-CoV-2 11 and a clinical benefit in rhesus macaques infected with SARS-CoV-2. 12 A large RCT has shown that remdesivir shortened the time to recovery in adults hospitalised with COVID-19 as compared with placebo but the results were not significant for mortality. 13…”

Coronavirus biology and replication: implications for SARS-CoV-2

“…The current model suggests steric hindrance as a likely reason for termination, disturbing the positioning of the RNA and thus hampering the translocation to the next position 86 , 88 . RDV was shown to reduce virus replication of SARS-CoV-2 in vitro 90 and was demonstrated to restrict clinical symptoms of SARS-CoV-2 in rhesus macaques upon early pre-symptomatic treatment 91 . However, a recent randomized, double-blind, placebo-controlled clinical trial in humans with severe COVID-19 showed limited clinical efficacy of RDV treatment 92 and further studies will be necessary.…”

Experimental Models for the Study of Central Nervous System Infection by SARS-CoV-2

“…Bao et al ( 111 ) and Chandrashekar et al ( 112 ) intratracheally and intranasally inoculated rhesus monkeys with the SARS-CoV-2 virus to study the possibility of reinfection. Williamson et al ( 113 ) used rhesus monkeys that had previously been inoculated through the intranasal, oral, ocular, and intratracheal routes for pharmacological research. These animals have also been used for the development of vaccines ( 106 , 107 , 114 , 115 ).…”