Remdesivir: the new wonder drug for COVID-19?

Many patients who die after infection with COVID-19 develop respiratory complications including severe pneumonia and respiratory failure.

Treatment options are currently limited, although recently dexamethasone has been shown to reduce deaths by a third of hospitalised patients with severe respiratory complications.1 While the search for a vaccine continues, several anti-viral treatments have been explored. COVID-19 is an RNA virus and requires a protease enzyme, chymotrypsin-like protease (3CLpro) for replication and since lopinavir and ritonavir are protease inhibitors, it was thought that these agents could represent an effective treatment for the virus.

Sadly, an early Chinese trial used the combination of lopinavir and ritonavir in hospitalised patients with COVID-19 showed no benefit from the addition of the two anti-viral agents compared to standard care.2 However, studies in mice demonstrated that another anti-viral, remdesivir, had greater activity than either lopinavir and ritonavir against Middle East respiratory syndrome (MERS), another coronavirus3 and might therefore represent a more promising treatment for those with COVID-19.

Remdesivir was developed by Gilead Sciences after the company embarked on a programme to identify treatments for RNA-based viruses such as Ebola and other coronaviruses.4 In their search for an effective agent, one candidate that emerged from early testing was named GS-5734 (remdesivir) and was shown to have anti-viral activity against Ebola virus in rhesus monkeys.5

In addition, the drug also had in vitro activity against many different viruses including other coronaviruses such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS).6 However, when the in vivo effectiveness of remdesivir was tested in a clinical trial against Ebola virus, use of the drug was terminated early due to a lack of efficacy compared to other agents.7

Remdesivir is a pro-drug that requires activation within a cell where it is converted within cells to remdesivir triphosphate, a structural analogue of adenosine, one of the nucleotides that is incorporated by the viral RNA polymerase enzyme into newly formed RNA. Because the drug is an analogue rather than an actual nucleoside, further replication of the virus is halted.8

Clinical studies

Remdesivir currently has no licensed indications but in May 2020, the MHRA issued a scientific opinion under the early access to medicines scheme, to allow the drug to be used as a treatment for COVID-19.9 Despite the lack of a licence, the drug is now indicated for the treatment of people aged 12 years and over, weighing at least 40kg and hospitalised with either suspected or confirmed SAR-CoV-2 infection and severe disease.

The suggested dose for patients requiring invasive ventilation is 200mg on day 1 followed by a daily maintenance dose of 100 mg for 9 days. In contrast, for patients not requiring ventilation, the same dosage is recommended but for 5 rather than 10 days.

To date, two randomised trials and one observational study exploring the efficacy of remdesivir have been published.10-12 These results have been summarised in a Cochrane review,13 which clearly show that compared to placebo, the 14 to 28-day all-cause mortality is not significantly different to placebo (relative risk (RR) = 0.74, 95% confidence interval (95% CI) 0.40–1.37).

However, remdesivir was significantly better than placebo at reducing the need for supportive measures, for example, non-invasive ventilation or mechanical ventilation in patients with a WHO progression score (which measures disease severity, ranging from 1 = not hospitalised to 8 = death) level 6/7 or above between days 14 to 28 (RR = 0.76, 95% CL, 0.62 – 0.93).

NICE has produced a review of the current available evidence and concluded that there is “some benefit with remdesivir compared with placebo for reducing supportive measures” but that “no statistically significant differences were found for mortality and serious adverse events”.14

The NICE review did not include one recent open label study which randomised 397 patients, not requiring mechanical ventilation, to remdesivir for either 5 or 10 days with a median duration of treatment of 5 days. By day 14, 64% of patients given remdesivir for 5 days vs 54% for 10 days, had a clinical improvement of 2 or more points, on a scale ranging from 1 (death) to 7 (not hospitalised).15 However, the study did not include a control group and so the magnitude of the observed benefit could not be determined.

On 25 June 2020, the European Medicines Agency (EMA) recommended granting a conditional marketing authorisation for remdesivir (brand name Veklury) for the treatment of adults and adolescents 12 years and over with pneumonia who require supplemental oxygen.16 This decision was based on the results of the National Institute of Allergy and Infectious Diseases (NIAID) trial, which evaluated the effectiveness of a 10-day course of the drug in over 1,000 hospitalised patients compared to placebo.

According to a press release from the EMA, the NIAID study found that patients treated with remdesivir recovered after about 11 days compared with 15 days for those taking placebo. For patients with mild to moderate disease there was no difference compared to placebo but an effect was seen in those with severe COVID-19, where time to recovery was 12 days versus 18 days.

However, there were no differences for patients who started remdesivir when they were already in receipt of mechanical ventilation or extracorporeal membrane oxygenation. The difference in 28-day mortality is currently not available. The EMA has recommended a treatment regimen of 200mg on day one, followed by 100mg daily for at least 4 days.

In summary, and to date, there is some limited evidence to indicate that remdesivir reduces the time to recovery in patients with severe disease which has prompted the EMA to approve the use of the drug. Nevertheless, the available data has yet to reveal improvements in 28-day mortality. In a rapidly changing world, the results of further comparative and on-going trials will hopefully add more concrete evidence on whether remdesivir is a valuable addition to the currently available treatments for patients with COVID-19.

References

1. RECOVERY Collaborative Group. Effect of dexamethasone in hospitalised patients with COVID-19 – Preliminary report. medRxiv preprint doi: https://doi.org/10.1101/2020.06.22.20137273.
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11. Wang Y et al. Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2020;Apr 29: doi.org/10.1016/ S0140-6736(20)31022-9
12. Grein J et al. Compassionate use of remdesivir for patients with severe Covid-19. N Engl J Med 2020;Jun 11: DOI: 10.1056/NEJMoa2007016.
13. Pharmacologic treatments for COVID-19 patients. https://covid-nma.com/living_data/index.php.
14. NICE Evidence review. Remdesivir for treating hospitalised patients with suspected or confirmed COVID-19. www.nice.org.uk/advice/es27/evidence/evidence-review-pdf-8771329261.
15. Goldman JD et al. Remdesivir for 5 or 10 days in patients with severe Covid-19. N Engl J Med 2020; May 27: doi: 10.1056/NEJMoa2015301
16. European Medicines Agency. First COVID-19 treatment recommended for EU authorisation. www.ema.europa.eu/en/news/first-covid-19-treatment-recommended-eu-authorisation.