Over the past several weeks, a mind-boggling array of possible therapies have been considered. None have yet been proven to be effective in rigorously controlled trials, but for one of them, it’s been a busy week. So let’s focus on an experimental anti-viral drug, called remdesivir, that was originally developed for the deadly Ebola virus. Though remdesivir failed to help people with Ebola virus disease, encouraging results from studies of coronavirus-infected animals have prompted the launch of human clinical trials to see if this drug might fight SARS-CoV-2, the novel coronavirus that causes COVID-19.
You may wonder how a drug could possibly work for Ebola and SARS-CoV-2, since they are very different viruses that produce dramatically different symptoms in humans. The commonality is that both viruses have genomes made of ribonucleic acid (RNA), which must be copied by an enzyme called RNA-dependent RNA polymerase for the virus to replicate.
Remdesivir has an affinity for attaching to this kind of polymerase because its structure is very similar to one of the RNA letters that make up the viral genome [1]. Due to this similarity, when an RNA virus attempts to replicate, its polymerase is tricked into incorporating remdesivir into its genome as a foreign nucleotide, or anomalous letter. That undecipherable, extra letter brings the replication process to a crashing halt—and, without the ability to replicate, viruses can’t infect human cells.
Would this work on a SARS-CoV-2 infection in a living organism? An important step was just posted as a preprint yesterday—a small study showed infusion of remdesivir was effective in limiting the severity of lung disease in rhesus macaques [2]. That’s encouraging news. But the only sure way to find out if remdesivir will actually help humans who are infected with SARS-CoV-2 is to conduct a randomized, controlled clinical trial.
In late February, NIH’s National Institute of Allergy and Infectious Diseases (NIAID) did just that, when it launched a randomized, controlled clinical trial to test remdesivir in people with COVID-19. The study, led by NIAID’s Division of Microbiology and Infectious Diseases, has already enrolled 805 patients at 67 testing sites. Most sites are in the United States, but there are also some in Singapore, Japan, South Korea, Mexico, Spain, the United Kingdom, Denmark, Greece, and Germany.
All trial participants must have laboratory-confirmed COVID-19 infections and evidence of lung involvement, such as abnormal chest X-rays, rattling sounds when breathing (rales) with a need for supplemental oxygen, or a need for mechanical ventilation. They are randomly assigned to receive either a round of treatment with remdesivir or a harmless placebo with no therapeutic effect. To avoid bias from creeping into patient care, the study is double-blind, meaning neither the medical staff nor the participants know who is receiving remdesivir.
There is also an early hint from another publication that remdesivir may benefit some people with COVID-19. Since the end of January 2020, Gilead Sciences, Foster City, CA, which makes remdesivir, has provided daily, intravenous infusions of the drug on a compassionate basis to more than 1,800 people hospitalized with advanced COVID-19 around the world. In a study of a subgroup of 53 compassionate-use patients with advanced complications of COVID-19, nearly two-thirds improved when given remdesivir for up to 10 days [3]. Most of the participants were men over age 60 with preexisting conditions that included hypertension, diabetes, high cholesterol, and asthma.
This may sound exciting, but these preliminary results, published in the New England Journal of Medicine, come with major caveats. There were no controls, participants were not randomized, and the study lacked other key features of the more rigorously designed NIH clinical trial. We can all look forward to the results from the NIH trial, which are are expected within a matter of weeks. Hopefully these will provide much-needed scientific evidence on remdesivir’s safety and efficacy in people with COVID-19.
In the meantime, basic researchers continue to learn more about remdesivir and its interaction with the novel coronavirus that causes COVID-19. In a recent study in the journal Science, a research team, led by Quan Wang, Shanghai Tech University, China, mapped the 3D atomic structure of the novel coronavirus’s polymerase while it was complexed with two other vital parts of the viral replication machinery [4]. This was accomplished using a high-resolution imaging approach called cryo-electron microscopy (cryo-EM), which involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera.
With these atomic structures in hand, the researchers then modeled exactly how remdesivir binds to the polymerase of the novel coronavirus. The model will help inform future efforts to tweak the structure of the drug and optimize its ability to disrupt viral replication. Such detailed biochemical information will be vital in the weeks ahead, especially if data generated by the NIH clinical trial indicate that remdesivir is a worthwhile lead to pursue in our ongoing search for anti-viral drugs to combat the global COVID-19 pandemic.
April 17, 2020 at 12:48 pm
A crisp snapshot with strong public health impact for innovative design of novel, patient-friendly ant-viral therapeutics and vaccines for diminishing the global Covid-19 pandemic.
Nucleos(t)ide-analogues and targeted drug-delivery with well-standardised anti-viral-biologics/bioassys/immunodiagnostic modalities with high sensitivity and specificty should be globally promoted for strategically and successfully addressing the Covid-19 infection and mortality trends, including reassessment of hospital case-records and state-based death-certificate-records post-Covid-19 fatalities for eventually developing a global disaster management Covid19-protocol in at-risk susceptible populations of varying genetic landscapes spanning United States of America to my homecountry India in Asia-Pacific region.
Overall, a thought-provoking article with broad-spectral clinical impact in he ever-expanding/evolving Covid-19 research field.
Rebecca Bernat says: April 17, 2020 at 2:45 pm
Agree – the most important thing to do is find medicines that work – blinded trials are essential, as well as a vaccine ASAP because as long as the virus is circulating, people will be risking their lives when returning to normal routines. There’s just no way around it. The virus is not magically going to go away. There are so few anti-viral drugs – most work on the replicative machinery such as this one, some block entry (Tamiflu), or target the viral proteases, a few immune effectors, I think that’s about it. Along with this pandemic giving a boost to anti-viral drug research, we need to understand the human component to this disease. Not as immediately essential as clinical trials and vaccines, but could be important for understanding who is more likely to get sick. Humans and infectious agents have evolved over the world together through history, and I expect that immune response genes are the most diverse genes that we humans possess as we are exposed to different vectors and viruses in different environments and must adapt quickly or die! As some people are suggesting that China is downplaying number of deaths, it could also be that their population genetically has a more favorable response to this virus …
Mark Stidham says: April 17, 2020 at 3:58 pm
Thank you for posting. It drives me crazy to see the desperate grasping to use what is available now without rationale. In addition to the nonsense around hydroxychloroquine, I’ve seen ivermectin mentioned. Your post helps communicate where and how the real answers will emerge.
Fernando Gregori says: April 17, 2020 at 4:29 pm
Dr Francis Collins, firstly I congratulate both your professional expertise and your willing to find an affordable and effective drug capable to fight the Sars Cov 2 replication. There is a delay about Remdesivir FDA approval that must be addressed urgently. What about the AR drugs that have been tested as well ? How do they act against the Covid19 disease?
Peter J. Wolczko says: April 17, 2020 at 5:25 pm
Great information. This is how the decisions must be made, using testing, data and analyzing the results. I always say a test is worth a thousand words. As a retired Sr. Quality Assurance Engineer, over my career, I have listened to people try to explain away defects without any data. Also have had people try to push so called corrective actions through that were nonsense, just to try and ship product for sales. If the corrective action is not 100%, no shipping. Safety first, then product. Please continue researching and testing and evaluating. You are doing the research in the most logical way. Thank you for all that you do.
Patricia C. says: April 17, 2020 at 6:28 pm
The program on the Genome was awesome and amazing. As a
participant in the original study, I was particularly interested in the
show. As a Cancer Patient, I have benefitted from many of the
protocols that have kept me alive through stage 4 MBC and will
eventually discover more ways to utilize Gene Transfer to eradicate
familial gene mutations like Lynch Syndrome and other inherited
mutations that are passed from generation to generation!
Dr. Collins and NIH are a blessing to this wonderful country!
We depend on NIH researchers to develop a protocol or cure
for Covid19.
May Dr. Collins and his staff stay safe during the Covid19 Crisis!
Mel says: April 18, 2020 at 9:20 am
Lest anyone jump for joy and take of their masks and go back to work and pretend all is normal again, we must not forget that in the largest group of fast-shuffle testing you reported it did not work on one-third of the people. Why not? If one-third of the patients die, this is not a success for them and their children. No one should be written off and ignored in an effort to conclude it is “under control”. It is not. Welcome news, yes. Beautiful news. But please encourage all the labs to continue to fight for the one -third who may not live another day if we quit now. If all of us can do something even if it is offering an untested notion or sewing cloth masks for our neighborhood, one more patient might live and we should present it. This is the time to ask what we can do for our country.
