In the first published placebo-controlled trial of remdesivir for treating severe COVID-19, Yeming Wang and colleagues were unable to attain their primary endpoint of time to clinical improvement. Although admittedly underpowered due to early trial termination, remdesivir did not appear to affect rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral RNA load decline and mortality when compared with placebo. Given these disappointing findings, we are left to wonder if a lack of clinically significant outcomes in placebo-controlled trials could have been predicted. By inhibiting early coronavirus life cycle in vitro and in animal models, remdesivir might require initiation before the peak viral replication, which is not feasible in the clinical human presentation of COVID-19.
In cell cultures exposed to murine coronavirus, early remdesivir initiation substantially decreased viral titres compared with control. However, this treatment effect was completely lost when initiation occurred just 8 h after infection. In another study, mice administered early remdesivir relative to inoculation with SARS-CoV had substantially reduced lung damage compared with untreated cohorts, an effect that was lost when initiation was delayed by 2 days after inoculation. The need for early treatment has been identified in additional animal models, as Wang and colleagues confirm, with remdesivir initiation following peak viral replication being unable to affect disease severity or mortality.
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I do hope that's true.
