Monday 4 May 2020
Remdesivir: Empty hype or genuine hope?
Asanka Wijetunga BSc (Adv). MD Student
Many drugs have been touted as ‘cures’ for the COVID-19 pandemic, including the anti-malarial chloroquine, the anti-influenza Favipiravir, and the anti-Ebola Remdesivir. With the media and world leaders boldly weighing in on their effectiveness, often with little regard for clinical findings, it can be hard to distinguish the fact from the fancy. Following the recent release of data from a 1000-strong double-arm clinical trial of Remdesivir, I will briefly explore what the science says about its effectiveness in treating COVID-19.
For coronaviruses to replicate within a host cell, they must first produce many copies of their own RNA genetic code, a task performed by viral RNA polymerase. This enzyme works by binding to a strand of viral RNA and producing a complementary transcript using available nucleotides. Remdesivir belongs to a drug class known as “nucleoside analogues”: it looks like a normal RNA nucleotide and is therefore incorporated by RNA polymerase into the transcript (Figure 1). However, once Remdesivir is incorporated, it prevents more nucleotides from being added, thus terminating transcription.
Remdesivir was initially synthesised during the West African Ebola epidemic of 2015, and was found to be effective in animal models and early clinical trials1. It showed promise in treating MERS, another deadly coronavirus, in vitro and in a prophylactic setting, where it significantly reduced viral load, clinical signs and radiological findings in rhesus monkeys.2
The first double-blind placebo-controlled trial of Remdesivir in 158 patients in China showed patients who were treated early with 10 days of Remdesivir (<10 days after symptom onset) improved more quickly than placebo controls (18 vs 23 days). However, this result was non-significant, and there was even no numerical difference if Remdesivir was delayed for >10 days. Promisingly, no deaths in this study were linked to the therapy, and less serious adverse events were noted in the Remdesivir than in the placebo group (18% vs 26%)3.
An independent US Government NIH “ACTT” trial of 10 days of Remdesivir showed that patients treated with the drug have a significantly faster recovery (11 days vs 15 days, p<0.001), and a numerically reduced mortality rate (8.0% vs 11.6%, p=0.059)4. Mortality rates amongst those hospitalised with severe COVID-19 have been documented to be as high as 14.3%5.
On the same day as the above Chinese study, Remdesivir’s manufacturer Gilead released preliminary results of the SIMPLE trial: a phase 3 trial of Remdesivir in patients hospitalised with severe COVID-19. A 5 and 10-day regimen of the drug have proven to be statistically similar at suppressing the virus, with a mortality rate of 7%6. All trials used the same dosing regimen (200mg initially, followed by 100mg daily for the remainder of the study).
Despite the somewhat underwhelming findings, experts are not too concerned – no severe adverse events have been consistently identified, and the drug does appear to work in many patients. An arsenal of drugs with variegated mechanisms of action will be required to fight the virus due to the inevitable development of resistance and mutations. In fact, the drug has been given emergency US FDA approval for use in critically ill COVID-19 patients. Remdesivir, though not the miracle drug we hoped for, is certainly a promising stepping-stone towards bringing COVID-19 to its knees.
- Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531:381-5.
- 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. Proceedings of the National Academy of Sciences of the United States of America 2020;117:6771-6.
- Wang Y ZD, Du G, Du, R, Zhao, J, Jin, Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. The Lancet 2020;In Press
- (NIH) NIoH. NIH clinical trial shows Remdesivir accelerates recovery from advanced COVID-19. In: (NIH) NIoH, ed. Bethesda, MD 2020.
- Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England) 2020;395:497-506.
- Maffei D CS. Gilead’s Investigational Antiviral Remdesivir Receives U.S. Food and Drug Administration Emergency Use Authorization for the Treatment of COVID-19. In: Inc GS, ed. Gilead Sciences Inc 2020.
- Gordon CJ, Tchesnokov EP, Feng JY, Porter DP, Gotte M. The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus. The Journal of biological chemistry 2020;295:4773-9.