Reply to Yan and Muller, “Remdesivir for COVID-19: Why Not Dose Higher?”

Abstract

In their Letter to the Editor “Remdesivir for COVID-19: Why Not Dose Higher?” Yan and Muller assert that the clinical efficacy of remdesivir at its currently approved dose (200mg intravenously [i.v.] on day 1 followed by 100mg/day i.v. for up to 9 days) is questionable and advocate for higher dosing. However, the totality of the available data demonstrates that remdesivir, at its current dose, is a safe and efficacious treatment for patients hospitalized with coronavirus disease 2019 (COVID-19). In early 2020, Gilead and collaborators rapidly initiated multiple studies in parallel to address the urgent need for severe acute respiratory syndrome coronavirus 2 (SARSCoV-2) therapeutics. Selection of the RDV dosing regimen for the treatment of COVID19 was based on the pharmacokinetics (PK) bridge from animal data to human doses and efficacy using (i) the results of in vivo efficacy studies conducted in SARS-CoV-2and Middle East respiratory syndrome (MERS-CoV)-infected rhesus monkeys, (ii) available PK data in healthy rhesus monkeys, and (iii) PK and safety data from phase 1 singleand multiple-dose first-in-human studies (1–5). The dosing regimen selected (200mg i.v. loading dose, followed by 100mg/day i.v. maintenance dose for up to 10 days) proved to be safe and efficacious in three pivotal phase 3 studies, including ACTT-1, a randomized, double-blind, placebo-controlled study—the gold standard for evaluating the safety and effectiveness of investigational drugs. ACTT-1 evaluated the safety and efficacy of a 10-day remdesivir regimen compared with placebo in hospitalized adults with COVID-19 (n=1,062). Remdesivir was superior to placebo in shortening time to recovery (P , 0.001) and significantly improved odds of clinical improvement by day 15 compared with placebo (P , 0.001). The study also demonstrated safety, with a similar rate of adverse events in the remdesivir and placebo groups (6). Gilead-sponsored trials added to the evidence supporting remdesivir’s positive benefit-risk profile in hospitalized patients. SIMPLE-Severe, a phase 3 randomized, open-label, multicenter study in hospitalized patients with severe COVID-19, showed that a shorter 5-day course of remdesivir produced a similar outcome to the longer 10-day course (P = 0.1563) (7). SIMPLE-Moderate, a phase 3 randomized, openlabel, multicenter study, demonstrated that a 5-day remdesivir regimen produced greater odds of clinical improvement at day 11 compared with standard of care (P = 0.0174) (8). Both groups in SIMPLE-Moderate experienced similar rates of adverse events. Based on these data, the U.S. Food and Drug Administration issued an Emergency Use Authorization on 1 May 2020. Since then, remdesivir has received full or conditional approval in numerous countries, and .1 million patients have been treated with remdesivir at the current dose and duration. Collectively the data show that the approved dose of remdesivir achieves a favorable benefit-safety profile for patients. Virologic outcomes were not assessed in these studies in real time because of the need for rapid study execution and limited testing capacity during the early stages of the pandemic, but analyses from the ACTT-1 study are ongoing. A recent case report in an immunocompromised patient with prolonged SARS-CoV-2 shedding demonstrated Citation Juneja K, Humeniuk R, Porter D, Cao H, Feng J. 2021. Reply to Yan and Muller, “Remdesivir for COVID-19: why not dose higher?” Antimicrob Agents Chemother 65:e00085-21. https://doi.org/10.1128/AAC .00085-21. Copyright © 2021 American Society for Microbiology. All Rights Reserved. This is a response to a letter by Yan and Muller https://doi.org/10.1128/AAC.02713-20. Accepted manuscript posted online 18 March 2021 Published 18 March 2021