Gilead’s drug Remdesivir has attracted a lot of attention for its potential therapeutic benefit in combatting COVID-19. In this post, I’ll summarize what we currently know about this drug (as of March 18, 2020).
Background
Remdesivir first hit the news during the Ebola epidemic from 2013-2016. At that time, the United States Army Medical Research Institute of Infectious Diseases showed promising evidence that it blocked the Ebola virus in Rhesus monkeys.
That research is more fully described here: https://www.nature.com/articles/nature17180. Once daily dosing of this drug for 12 days suppressed the Ebola virus, improved clinical disease and pathophysiological markers, and led to 100% survival of monkeys.
Source: Warren et al. Nature 2016
In light of these findings, remdesivir was fast tracked through clinical trials, where its safety profile was established, and even used in one human patient with Ebola. Because of its mechanism against RNA viruses, clinicians and researchers supported research for this drug against other infectious diseases.
Mechanism of Action
Remdesivir is a type of nucleotide analog, which contain a sugar molecule, three phosphate groups, and a dummy nucleic acid analog. The basic idea is that during viral replication, a virus needs nucleotides to make viral RNA or DNA and thus more virus. However, if the virus incorporates this dummy nucleotide analog, it cannot form a complete viral genome, so the virus eventually becomes defective and dies.
Below is the molecular profile of remdesivir. This drug mimics an alanine metabolite, and once it gets incorporated into a nucleotide triphosphate, it interferes with RNA-dependent RNA-polymerases leading to premature termination and thus decreases virus RNA production.
Source: Warren et al. 2016.
Source: https://www.nature.com/articles/nature17180
Application for Coronaviruses
Back in 2017, scientists were thinking about using remdesivir for human and zoonotic coronaviruses. At that time, scientists were trying to develop therapies against the endemic MERS-CoV virus which was prominent from 2013-2016, but they astutely noted that this therapy is most important for pandemic coronaviruses that may emerge in the future (Sheahan et al. Science Translational Medicine 2017). Source: https://stm.sciencemag.org/content/9/396/eaal3653
In their studies, Sheahan et al. showed that remdesivir successfully inhibited the MERS and SARS coronaviruses at safe doses, was effective in suppressing various animal coronaviruses (bat, pig, camel), and improved pulmonary function in mice infected with SARS virus. Notable figures from their study are below.
Source: Sheahan et al. Science Translational Medicine 2017.
Source: Sheahan et al. Science Translational Medicine 2017.
Application for COVID-19
The big question on everyone’s mind is whether this new drug can be used to combat the COVID-19 pandemic. Wang et al. evaluated the efficacy of this drug in vitro with cells affected with COVID. They remarked that this drug blocked virus infection at low micromolar concentrations and showed high selectivity. My understanding of these experiments is that remdesivir is effective in decreasing viral loads, but may be even more effective if given before the virus is administered in the first place. Source: https://www.nature.com/articles/s41422-020-0282-0/
Source: Wang et al. Nature 2020.
Clinical Experience with Remdesivir
Given these past studies, there have been many clinical arguments favoring the use of remdesivir for COVID-19. In fact, the first case of COVID-19 in the USA was treated with remdesivir for compassionate use after day 7 of pneumonia. This patient’s condition improved the following day without any significant adverse effects. Gilead is now involved with several clinical trials to examine the efficacy of this drug to fight our current pandemic.
A preprint of the first 12 patients with COVID-19 in the USA is now online. https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf
Three of these patients received remdesivir shown below (patients 6, 8, 9 with the purple shading). My interpretation of this data is that all of these patients benefited from this drug, with increasing oxygen saturation/decreasing oxygen requirement, decreasing fever, and decreasing viral loads.
Patients had transient gastrointestinal symptoms including nausea, vomiting, gastroparesis, or rectal bleeding following administration of remdesivir. 2/3 patients had a significant increase in their liver function enzymes.
Red square: Virus isolation succesful; Gray square: virus isolation not successful
Source: https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf
Obtaining Remdesivir in the United States
Here are the steps it takes to get remdesivir for compassionate use from Gilead:
Gilead is now transitioning from compassionate use requests to expanded access programs for this medication as of March 22.
Conclusions
In summary, there are a lot of reasons to be optimistic about remdesivir. I am quite hopeful that these clinical trials will show good results to suppress COVID-19. I do wonder however about antiviral resistance, safety profile, and access to the millions of people across the world who may need this drug.
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