“Oft expectation fails, and most oft there where most it promises; and oft it hits where hope is coldest, and despair most fits.” William Shakespeare was not a virologist or an expert in clinical trials; he was, however, an astute observer of human nature. As SARS-CoV-2 traverses the world, we are desperate for something that can provide hope. Amidst a wide variety of potential therapeutic agents, one—remdesivir—has finally emerged with some positive findings.
Remdesivir is a nucleotide analogue that inhibits RNA polymerases. It has been shown to be active across several families of viruses, including coronaviruses, and interferes with SARS-CoV-2 in vitro. This antiviral has been used on a compassionate basis for severe COVID-19. In a cohort of 53 patients, with no control group, clinical improvement was noted in 68%.
A randomized, double blind, placebo-controlled trial (RCT) involving 237 patients with severe COVID-19 in Wuhan, China failed to demonstrate significant improvement with remdesivir as compared to placebo (hazard ratio = 1.23 [95% CI: 0.87-1.75]). There was a trend for a more rapid improvement for those initiating treatment within 10 days of symptom onset (hazard ratio = 1.52 [95% CI: 0.95-2.43]).
We have now received results from an interim analysis of a RCT conducted by the National Institute of Allergy and Infectious Diseases. This trial compared remdesivir (200 mg IV on day one, followed by 100 mg IV for the following 9 days) to placebo. Information on the eligibility criteria within the Adaptive COVID-19 Treatment Trial news release is a bit confusing. Better clarity is available through clinicialtrails.gov. Subjects were adults with laboratory-confirmed SAR-CoV-2 and admitted to the hospital with either pneumonia or reduced oxygenation (SpO2 ≤ 94% on room air, requiring supplemental oxygenation, or needing mechanical ventilation). The endpoints were a composite of outcomes demonstrating clinical improvement.
The results are encouraging. The median time to recovery was shortened from 15 days to 11 days (P<0.001) with a 31% reduction in the average time to recovery in those receiving remdesivir. Moreover, there was a non-significant trend for reduction in mortality (11.6% to 8.0%: P=0.059).
In an additional Phase III trial, the manufacturer compared a 10-day and 5-day course of remdesivir. There were no significant differences noted between the treatment times. In a post hoc analyses, however, there was an increase in the proportion (62% vs. 49%) of patients discharged from the hospital within 14 days, if treatment commenced within 10 days of symptom onset.
Some quick take home points for clinicians:
- Use of remdesivir appears to have significant clinical benefits for treatment of severe COVID-19
- This is an intravenous drug
- The adverse effect profile is reasonable
- As with many antivirals, clinical benefit is increased with early initiation
- The FDA approved an emergency use authorization (EUA) for remdesivir on May 1, 2020
- The EUA is for adults and children hospitalized with severe disease
- Severe disease is defined as patients with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator
Remdesivir is not a panacea. It does tell us that SARS-CoV-2 can be inhibited and provides a pathway for other agents. It is a step that provides a bit of hope.