Remdesivir as Treatment for COVID-19

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.

Rhesus monkeys with Remdesivir survived from Ebola virus
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.

Molecular profile of remdesivir.
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.

Lung tissue restored to normal after treatment with remdesivir in mice with SARS coronavirus.
Source: Sheahan et al. Science Translational Medicine 2017.
Therapeutic and prophylactic treatment with remdesivir improved pulmonary function in mice with SARS coronavirus.
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/

Remdesivir significantly inhibits virus replication if given pre and post infection.
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.

Source: https://www.medrxiv.org/content/10.1101/2020.03.09.20032896v1.full.pdf
Black dot: PCR Positive; White dot: PCR Negatve; Gray dot: PCR inconclusive
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:

Source: Twitter

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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