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Pursuing Safe and Effective Anti-Viral Drugs for COVID-19

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Senior hospital patient on a ventilator
Stock photo/SoumenNath

Right now, the world is utterly focused on the coronavirus outbreak known as COVID-19. That’s certainly true for those of us at NIH. Though I am working from home to adhere rigorously to physical distancing, I can’t remember ever working harder, trying to do everything I can to assist in the development of safe and effective treatments and vaccines.

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.

References:

[1] Nucleoside analogues for the treatment of coronavirus infections. Pruijssers AJ, Denison MR. Curr Opin Virol. 2019 Apr;35:57-62.

[2] Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. Williamson B, Feldmann F, Schwarz B, Scott D, Munster V, de Wit E et. al. BioRxiv. Preprint posted 15 April 2020.

[3] Compassionate use of remdesivir for patients with severe Covid-19. Grein J, Ohmagari N, Shin D, Brainard DM, Childs R, Flanigan T. et. al. N Engl J Med. 2020 Apr 10. [Epub ahead of publication]

[4] Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Gao Y, Yan L, Liu F, Wang Q, Lou Z, Rao A, et al. Science. 10 April 2020. [Epub ahead of publication]

Links:

Coronavirus (COVID-19) (NIH)

Accelerating COVID-19 Therapeutic Interventions and Vaccines (NIH)

NIH Clinical Trial of Remdesivir to Treat COVID-19 Begins (National Institute of Allergy and Infectious Diseases/NIH)

Developing Therapeutics and Vaccines for Coronaviruses (NIAID)

COVID-19, MERS & SARS (NIAID)

NIH Support: National Institute of Allergy and Infectious Diseases

23 Comments

  • DR. SAUMYA PANDEY, PH.D. says:

    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:

    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 …

    • E. says:

      There’s a cure for the treatment. As soon as the outbreak of covid-19 in China began, I developed my own method of selecting substances, which works 100%, but due to bureaucratic obstacles can not offer people. To participate in grants and others you need to work in research centers, and I live in a small town and do Tibetan and Eastern medicine. The ones that are being offered for treatment now I have checked that no suitable virus bypasses chemicals – remedesevir only manages 10%. There is an inexpensive drug, but no one offers it, which completely kills the virus without side effects, those who used it got away with a slight cold, there was no pneumonia. I also made a face and hand tonic for the virus we use for a month no one got infected. The Chinese must have used it so they did it quickly.

      • Lily Gavronskaya says:

        Will be interested to learn more, and collaborate. There are “formal” and “informal” researchers everywhere, and we’re a community fighting for the same cause.

  • Mark Stidham says:

    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:

    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:

    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:

    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:

      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.

      • James says:

        Thanks for making commenting and having an opinion about the NIH possiblities. I must commend you guys effort in this time of Corona. please keep safe always

  • GerryL says:

    I do not understand patients with covid 19 pneumonia are forced to enroll in a phase 3 clinical trial in order to have a 50% chance of receiving the drug.
    Okay for patients with mild disease,who are expected to recover regardless, to be enrolled in such a trial but patients with life threatening pneumonia should be given the option of receiving the drug through some sort of open label trial.
    We have good scientific information supporting the use of the drug. The risk/reward ratio is favorable especially in patients who have severe disease.
    Also the drug may be more effective when given early. Maybe waiting for someone to be on a ventilator is too late.
    Regardless there is no logical reason why patients with covid 19 pneumonia should not somehow be given the option of receiving the drug. Perhaps given the present emergency Gilead can be persuaded to produce large quantities of the drug at a “reasonable “
    cost . The FDA bureaucracy should in this dire emergency allow Gilead to in these circumstances sell the drug. Or an open label trial if this is for some reason impossible.
    Heresy I realize to say such things. Bu as a patient previously involved in “clinical trials” for an extended period of time,
    and as a practicing MD for 40 years this is how I feel.

  • Kingsley Martin says:

    My understanding is that the virus disrupts the mechanism by which oxygen is stored and distributed around the body. The structure of myoglobin and haemoglobin are the keys, especially their sterospecificity. The heme groups are broken away from the Iron atoms, which are toxic to the human body when released. If the oxygen is not being taken up by the heme groups of infected people, what is the point of putting patients on ventilators? I am interested in the reports that Zinc has had some positive results. Would Zinc be able to substitute for the, at least, the Ferrous iron action in the heme? Just a thought for some young researcher, from an old Biochemist!

  • Sergio Mora Mercado says:

    As a medical science researcher I suggest:
    • When a patient already has the Covid 19 virus then he is developing immunity
    • The advance of body deterioration is inevitable in each case
    • So it is important in addition to the development of vaccines
    • Conducting clinical trials of antiviral treatment known as acyclovir would be interesting, especially for chronic patients.
    • Herpes simplex virus is a cousin of Covid 19, something can be positive when treating chronic patients to know if this drug works in the evolution of the disease,
    • It is my suggestion according to what I have studied as a researcher in medical sciences
    • Always somewhat witty, but imagining possible responses, is acceptable in clinical trials.

  • Donna Holmes Parks says:

    Thank you for your postings, Dr. Collins. I am relieved to see that NIH is taking the lead in coordinating COVID-19 treatment research. I have a great of faith in you, and respect for your integrity.
    Don’t forget to play your guitar.

  • Josephine Safar says:

    I think this will be the lesson that all the world they need to learn because when the Sars happen they had 16 years tell today to find medicine and vaccines but no they set and forgot about they should know that in the future will be another virus coming we need to be prepared if in 2003 they started making vaccines and medicine now they didn’t need to worry people was immune to this respiratory virus . Government is their responsibility to look after public health they can’t just set and forget about not getting prepared for surprise virus came to all I hope this will be a lesson all country they learn so they could do vaccines and medicine because even if this covid-19 go away will be another virus again in the future so please do something now so we will be prepared next time o don’t know what is wrong with government they don’t use their brain is like us public we tell them how to do their job that is a shame

  • Bridget says:

    Medicines roots were in nature, lest we not forget that. Is there research being done on iv vitamin c., zinc, vitamin d and their role to boost oxygenation in the blood and or boost the immune system overall to help fight the virus? Also what about essential oils? There is evidence of steam distillation from 1000s of years ago of oils, and some research already in their role to potentially help fight viruses. These methods are available now, have minimal side effects, are affordable, and fast to get. These viruses are likely to continue to mutate thus a vaccine will not be the answer as it can not keep up. This should also be a wake up call for people to help suppet their immune system via nutrition- you are what you eat! Will NIH be reminding people of that as well I hope?!

  • Jane says:

    I am a nurse and have a BSc in Life Science. My thoughts for consideration please:

    I believe there is a glutamine residue on the spike protein of Covid 19 as in SARS-CoV-2? If so would a glutamine metabolism inhibitor work as a treatment in theory? I cannot find any trials underway when I search Covid 19 and glutamine. See as an example:

    Choi YK, Park KG. Targeting Glutamine Metabolism for Cancer Treatment. Biomol Ther (Seoul). 2018;26(1):19–28. doi:10.4062/biomolther.2017.178.

    In a land where anything is possible an aerosol delivery via nebuliser please!

  • Donald R VanDeripe says:

    Sevoflurane posteatment prevents oxidative and inflammatory injury in ventilator-induced injury [PloS One 2018: 13(2):e0192896]. Is Sevoflurane being used in patients who go on ventilators? If not, why not! The 7 flourine atoms per molecule of Sevofluorane may confer a lipid affinity which could attack the protective lipid bilayer of the Covid-19 virus. Add one drop of sevoflurane to a petri dish (or other container) with Covid-19 virus; incubate at body temperature for ~6 hours- examine under microscope—- Does the sevoflurane destroy the integrity of protective bilayer???

  • Tibor Wittmann says:

    On the basis of study carried out by Gilead in 1800 patients – the study (double blinded) containing placebo arm (serious cases are also involved) – remdesivir may be ethically accepted (approved)?

    • Tibor Wittmann says:

      Correction of my reply above:- placebo arm may be ethical ? The Gilead study earlier demonstrated the beneficial effect of remdesivir.

  • Wittmann Tibor says:

    More preciously: the study- containing remdesivir and placebo arms ,launched by NIH in late February in patients , many of them with serious complication of COVID-19 infection – may be ethical? While the erlier study carried in 1800 patients by Gilead demostrated beneficial effect of remdesivir. During the study and in case of visible superiority of the remdesivir arm how was the treatment of patients receiving placebo continued? When progression of the disease was detected in the placebo receiving patients, they treatment necessite conversion on remdesivir treatment( arm). It was done?

  • Kevin D says:

    They already have a potent anitviral for covid, And they have known since 2005!!! Why haven’t they promoted this cheap effective solution???FROM THE “We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection”[Moderator’s note: of primate cells studied in a laboratory dish.]

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232869/

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