Remdesivir: Does It Have a Place in the Treatment of COVID-19?

On May 1, 2020, the US Food and Drug Administration (FDA) issued an emergency use authorization for remdesivir in the treatment of coronavirus disease 2019 (COVID-19) infection in patients with ≤94% oxygen saturation (Sp0₂)on room air requiring supplemental oxygen, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).¹ This followed a press release issued 2 days earlier that announced positive preliminary results from a randomized controlled trial of remdesivir sponsored by the National Institutes of Health.² We are awaiting the complete data analysis from the total cohort of enrolled patients.

Groups from China identified remdesivir, among other drugs, to be very effective at blocking severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of cells in vitro,^3,4 targeting these existing drugs for study in COVID-19 infection. Remdesivir is an adenosine analogue that interferes with RNA replication by virus-derived RNA-dependent RNA polymerase.⁵ The drug had previously been shown to protect monkeys infected with MERS-CoV,⁶ Nipah virus,⁷ and Ebola virus.^8,9 However, in a human clinical trial to treat Ebola virus infection, remdesivir performed more poorly compared with 2 monoclonal antibodies.¹⁰

In a rhesus macaque monkey model, one group of 6 monkeys infected with SARS-CoV-2 was treated with remdesivir 12 hours after virus inoculation and then daily for 5 days, and another group of 6 infected monkeys served as controls.¹¹ The examinations, radiograph readings, and pathology assessments were made by investigators blinded to treatment.¹¹ All control animals showed tachypnea and dyspnea compared with only one of the treated animals, and chest radiographs done every other day showed more pulmonary infiltration in the control monkeys.¹¹ Lung tissue samples taken on day 7 post-inoculation showed significantly increased viral load and lung histology showed more severe interstitial pneumonia in control compared with remdesivir-treated animals.¹¹ Of note, there was no significant difference in viral load or infectious virus titer from nasal swabs or most throat swabs taken from remdesivir-treated animals vs controls throughout the study period.¹¹

Early in the COVID-19 pandemic, remdesivir was made available on a compassionate use basis for patients with a room air SpO₂ ≤94%; data were reported for 53 patients from 9 different countries who received at least one dose of the drug from late January to early March 2020.¹² The median age of the patients was 64, 75% were men, and on enrollment 30 were on mechanical ventilation and 4 were receiving extracorporeal membrane oxygenation.¹²  The median duration of symptoms before remdesivir was started was 12 days.¹² Forty patients completed the full 10-day course of remdesivir, with a 200-mg intravenous loading dose on day 1 and 100 mg/d thereafter.¹²  Improvement in oxygen support was defined as hospital discharge or a decrease of 2 categories as measured on an ordinal scale: 1- not hospitalized; 2- hospitalized, not requiring supplemental oxygen; 3- hospitalized, requiring supplemental oxygen; 4- hospitalized, requiring nasal high-flow oxygen, noninvasive mechanical ventilation, or both; 5- hospitalized, requiring invasive mechanical ventilation, ECMO, or both; 6- death.¹² The patients were followed for a median of 18 days after remdesivir was started, and 68% demonstrated improvement in oxygen support and 15% worsened; all of the patients (12 of 12) starting at category 2 or 3 on the scale improved, 5 of 7 starting at category 4 improved, and 19 of 34 patients starting at category 5 improved.¹² Of the 53 patients in the cohort, 7 died, 6 of whom started treatment at grade 5.¹²

The first peer-reviewed, published randomized, double-blind, placebo-controlled trial of remdesivir in patients with COVID-19 was done in China.¹³  Inclusion criteria included room air SpO₂ ≤94%, pneumonia on chest imaging, and enrollment within 12 days of the onset of COVID-19 symptoms; concomitant treatment with lopinavir-ritonavir, corticosteroids, and interferon alfa-2b was allowed.¹³ Patients were randomly assigned to remdesivir 200 mg intravenously on day 1 and 100 mg/d intravenously on days 2 through 10.¹³ Improvement was defined using the ordinal scale described above. A total of 158 patients received remdesivir and 78 received placebo, with 56% men and the median age 65 years. Comorbidities of hypertension, diabetes, and coronary artery disease were more common in the remdesivir group, respiratory rate >24/min was more common in the remdesivir group, more patients in the placebo group had ≤10 days of symptoms before study treatment, and only 1 patient started the study in category 5 on the ordinal scale.¹³ The study was underpowered to detect a decrease in time to improvement in the treatment group because it was terminated before the requisite number of patients were enrolled, and in fact the time to improvement was not significantly different between the remdesivir and placebo groups.¹³ There was also no difference between the 2 groups in nasopharyngeal/oropharyngeal viral load throughout the 28-day study.¹³

On April 29, 2020, Gilead Sciences, Inc. announced in a press release early results from SIMPLE (Study to Evaluate the Safety and Antiviral Activity of Remdesivir [GS-5734™] in Participants With Severe Coronavirus Disease [COVID-19]; ClinicalTrials.gov Identifier: NCT4292899), a randomized, open-label, multicenter, phase 3 trial of remdesivir for 5 days vs 10 days in patients with COVID-19.¹⁴ In this trial 397 patients with pneumonia on chest imaging and SpO₂ ≤94% but not on mechanical ventilation were enrolled to receive remdesivir 200 mg intravenously on day 1 followed by 100 mg/d until day 5 or day 10. No significant difference was seen at day 14 between the two groups in ≥2-point improvement on a 7-point ordinal scale, in percentage discharged from the hospital, nor in mortality.¹⁴ Gilead is continuing to enroll participants in the study and is including patients on mechanical ventilation in the expansion phase.¹⁴ Additionally, a second SIMPLE trial (Study to Evaluate the Safety and Antiviral Activity of Remdesivir [GS-5734™] in Participants With Moderate Coronavirus Disease [COVID-19] Compared to Standard of Care Treatment; ClinicalTrials.gov Identifier: NCT04292730) has enrolled patients with COVID-19 with SpO₂ >94% and is comparing 5 days remdesivir vs 10 days remdesivir vs standard care.

ACTT (Adaptive COVID-19 Treatment Trial; ClinicalTrials.gov Identifier:  NCT04280705) is another randomized, double-blind, placebo-controlled trial of remdesivir in the treatment of patients with COVID-19 that has recently been conducted at 68 sites, mostly in the United States but also in Europe and Asia.² The trial enrolled 1063 patients, and preliminary data from an interim analysis of a subset of these patients were released on April 29, 2020.² Inclusion criteria included confirmed SARS-CoV-2 infection and radiographic evidence of pulmonary infiltrates, or with room air Sp0₂ ≤94%, or requiring supplemental oxygen, or requiring mechanical ventilation. Patients receiving remdesivir improved in a significantly shorter time from initiation of study treatment — a median of 11 days for patients receiving remdesivir compared with 15 days for patients receiving placebo.² The trend toward survival benefit with remdesivir was not statistically significant for the subset of patients reported.² These results led to the remdesivir emergency use authorization issued by the FDA.¹ Results from an analysis of the full data set are expected soon.

Up to now, remdesivir has been a promising antiviral drug in search of a human disease. Although it is not the cure for COVID-19 that we hope for, findings from ACTT suggest that it may speed clinical recovery and those from SIMPLE suggest that 5 days of treatment is as effective as 10 days. The study from China did not show a clinical benefit of remdesivir, but the study was limited by underpowering and by the fact that the remdesivir group may have been sicker at baseline; both or either of these limitations could have affected the study such that any potential remdesivir benefit would not have been revealed. We await the complete data set from ACTT and publication of the results from SIMPLE to better understand the potential role of remdesivir in the treatment of COVID-19.

References

1. US Food and Drug Administration. Emergency Use Authorization for Emergency Use of Remdesivir. US Food and Drug Administration; May 1, 2020.
2. NIH clinical trial shows remdesivir accelerates recovery from advanced COVID-19. Press release. NIH National Institute of Allergy and Infectious Diseases; April 29, 2020.
3. Wang M, Cao R, Zhang L, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Letter. Cell Res. 2020;30:269-271.
4. Choy K-T, Wong AY-L, Kaewpreedee P, et al. Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res. 2020;178:104786.
5. Agostini ML, Andres EL, Sims AC, et al. Coronavirus susceptibility to the antiviral remdesivir (GS-5734) is mediated by the viral polymerase and the proofreading exoribonuclease. mBio. 2018;9(2): e00221-18.
6. de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc Natl Acad Sci. 2020;117(12):6771-6776.
7. Lo MK, Feldmann F, Gary JM, et al. Remdesivir (GS-5734) protects African green monkeys from Nipah virus challenge. Sci Transl Med. 2019;11(495):eaau9242.
8. Warren T, Jordan R, Lo M, et al. Nucleotide prodrug GS-5734 is a broad-spectrum filovirus inhibitor that provides complete therapeutic protection against the development of Ebola virus disease (EVD) in infected non-human primates. Open Forum Infect Dis. 2015;2(suppl 1):LB-2.
9. Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531:381-385.
10. Mulangu S, Dodd LE, Davey RT, et al. A randomized, controlled trial of Ebola virus disease therapeutics. New Engl J Med. 2019;381:2293-2303.
11. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. bioRxiv. 2020.04.15.043166.
12. Grein J, Ohmagari N, Shin D, et al. Compassionate use of remdesivir for patients with severe Covid-19 [published online April 10, 2020]. New Engl J Med. doi:10.1056/NEJMoa2007016
13. Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet. 2020;395(10236):1569-1578.
14. Gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe COVID 19. Press release. Business Wire. https://www.businesswire.com/news/home/20200429005424/en/. April 29, 2002. Accessed May 15, 2020.

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