What we know about this potential COVID-19 treatment drug - by Dr. Hasnain Hyder Karan

Current Developments:
As of May 15th, 2020, the total number of positive COVID-19 cases are at 4,534,673 globally, the United States with 1,442,924, Russia with 262,843, United Kingdom with 238,004, and Spain with 230,183 cases respectively.​4

International attention is eagerly fixated on the prospect of new COVID-19 treatments. One such potential treatment is ​remdesivir (RDV)​,an experimental drug created by Gilead Sciences which showed potential for broad antiviral activity as early as 2014.​14​Remdesivir (formerly GS-5734) gained recognition in the possible treatment of coronaviruses when it was found to inhibit severe acute respiratory syndrome coronavirus (SARS) and Middle East respiratory syndrome coronavirus (MERS-CoV) replication in human respiratory epithelial cells.​10​Both SARS and MERS-CoV belong to the same family of viruses as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) the virus responsible for coronavirus disease 2019 (COVID-19), spiking renewed interest in remdesivir.

In reference to preliminary results from the Adaptive COVID-19 Treatment Trial (ACTT), the Director of NIAID (National Institute of Allergy and Infectious Diseases) at the National Institutes of Health, Dr. Anthony S. Fauci had this to say: “The data shows that remdesivir has a clear cut, significant positive effect in diminishing the time to recovery”.​5,7​He further goes on to state that: “What is proven is that a drug can block this virus”.​5,7

In response, the U.S. Food and Drug Administration (FDA) on May 1st, 2020 issued emergency use authorization (EUA) for remdesivir in the treatment of adults and children with suspected or confirmed COVID-19 whose symptoms are severe.​3As remdesivir has gained EUA by the FDA, it is important to clarify how remdesivir works within our cells, what data has been compiled to prove or disprove its efficacy, the latest on the Adaptive COVID-19 Treatment Trial (ACTT), and the reaction of governments around the world to the preliminary results of ACTT.

Remdesivir, how does it work?
Ribonucleic acids (RNA)
​are macromolecules essential for the expression of genetic data in humans, viruses, and bacteria. RNA’s are composed of ​nucleotides​,which are in turn composed of a sugar (ribose or deoxyribose), a nitrogenous base (adenine, guanine, cytosine, uracil (RNA), thymine (DNA)) and either one to three phosphate molecules. Multiple nucleotide polymers attached to one another by phosphodiester bonds, form either ribonucleic acids (RNA) or deoxyribonucleic acids (DNA). Remdesivir is a prodrug of a ​nucleotide analogue​,a molecule which contains a comparable nitrogenous base, ribose sugar, and a phosphate molecule, essentially mimicking an organic nucleotide. This prodrug after activation in the body by certain enzymes (esterases/kinases) interacts with ​RNA polymerases​,enzymes ​which in viruses replicate viral RNA in human cells. Viruses such as SARS-CoV-2 use ​RNA dependent RNA polymerases (RdRp)​, this means they use an RNA template to create more RNA, rather than using a DNA template for RNA creation which occurs normally. ​Remdesivir hampers the replication process of SARS-CoV-2 by mimicking a nucleotide (adenosine based), and inhibiting the ability of RNA dependent RNA polymerases to further elongate the viral RNA chain delaying RNA chain completion.

Selected data regarding Remdesivir:
In an article by the New England Journal of Medicine, remdesivir was provided to 61 patients with confirmed COVID-19 and subsequent data was collected on follow up.8​ This report is based on data from an expanded access delivery of RDV. Expanded access or compassionate use basis is a​ potential pathway for a patient with a serious disease ​to gain access to an investigational medical product ​(drug, biologic, or medical device) for treatment outside of clinical trials when no other viable alternative therapy options are available.​15​​Patients in this cohort received remdesivir over a period of 10 days, from January 25th - March 7th 2020.​8

Of the 53 patients whose data was analyzed and clinical status documented, 36 had signs of clinical improvement, a nearly 68% increase from baseline on follow up.​8​19 out of 34 patients with baseline status of invasive ventilation had a decreased need for oxygen support.​85 out of 7 patients with baseline status of noninvasive ventilation had a decreased need for oxygen support.​8100% of patients in the low flow and ambient air cohorts had improvements in their clinical conditions.​8The report was not without drawbacks, it outlined that 60% of patients in the cohort experienced adverse effects such as: “increased liver enzyme levels, diarrhea, rash, kidney impairment and hypotension”.​8In addition, 23% of patients in the cohort also experienced severe adverse reactions​8, calling into question the safety aspect of the medication. Furthermore ​improvement based on decreasing viral load levels (amount of viral particles present in the bloodstream) is another potential area of improvement. Without evidence of decreased viral load in tandem with decreased oxygen requirements in patients it may suggest improvement based on the diseases natural progression rather than as a result of remdesivir​.​8

Although this expanded access review provided insight into RDV as a treatment, it unfortunately is not a ​randomized controlled trial​.A randomized controlled trial (RCT), is a clinical trial involving two arms: a treatment arm which receives the new medication and a control arm which receives a placebo medication (harmless pill with no benefit). The advantage of a RCT over the compassionate use basis report is the ability to detect differences in the efficacy of a new drug (remdesivir) as compared to a placebo or the current treatment regimen.

This leads us to a randomized placebo controlled double blind trial conducted in China whose data was published on April 29th, 2020 by the Lancet.​11​The study analyzed 236 patients from ten hospitals in Wuhan, Hubei Province, China enrolled between February 6th - March 12, 2020.​11​Of the 236 patients, 158 patients were assigned to the RDV wing, and 78 to the placebo wing.​11​The study defined clinical improvement as “a 2 point reduction in patients admission status on a six point ordinal scale or live discharge from the hospital whichever came first”.​11

The six point ordinal scale, is a guideline to understand baseline patient status improvement. The WHO ordinal scale​12​for clinical improvement is provided adjacently as an example. If the patient's baseline for example is ventilation + additional organ support, a score of 7, clinical improvement by this studies criteria would be an improvement to non-invasive ventilation or high flow oxygen, a score of 5.

The study results indicated that “the time to clinical improvement in the remdesivir group was not significantly different to that of the control group”​11​and furthermore the “28 day mortality was similar between both the remdesivir and control groups”.​11​While not covered in the expanded access report mentioned earlier, this trial specified that “viral load decreased similarly between both groups and that the remdesivir group showed no significant difference at day 5 from placebo but had a ​slightly more rapid decline in viral load​.”​11​The study concluded that “​intravenous remdesivir was adequately tolerated but did not provide significant clinical or antiviral effects in patients seriously ill with COVID-19.​”​11

Latest on the Adaptive COVID-19 Treatment Trial:
The ​Adaptive COVID-19 Treatment Trial (ACTT)​is a robust adaptive, randomized, double-blind, placebo-controlled trial, with enrollment of 800-1000 subjects, and conducted in up to 39 sites.​1The trial closed enrollment on April 20th, 2020, with the study currently in phase 3 and expected to be completed by April 1st, 2023.​1,2 ​On April 29th, 2020 in a NIAID press release, preliminary data from ACTT concluded that hospitalized patients with advanced COVID-19 lung involvement who received remdesivir recovered faster than similar patients who received placebo.​9

“Preliminary results indicate that patients who received remdesivir had a 31% faster time to recovery than those who received placebo (p<0.001). Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group (p=0.059)​”.​9

The medication remdesivir therefore showed accelerated time to recovery, and resulted in a decreased mortality rate compared to placebo in patients with COVID-19. The specifics of the results from the ACTT trial will be released for review in peer reviewed medical journals in the coming weeks.​9​Most current RDV clinical trials are in phase 3, with safety and dosing parameters elucidated. Medications are required to successfully clear 4 clinical trial phases before they are approved by the FDA for sale in the United States.

Government regulatory reaction to ACTT results:

As of May 7th, 2020 in a Gilead Inc. press release, the Japanese Ministry of Health, Labour and Welfare (MHLW) has granted regulatory approval of Veklury​®​​(remdesivir) as a treatment for COVID-19.6​In addition Gilead has been working towards the distribution of remdesivir through manufacturing partners in Europe, and South Asia.​17​Global access to the drug is considered a priority with Gilead in talks with the United Nations Children’s Fund as being a potential partner for distribution in developing countries.​17 While emergency use and regulatory access has been granted by the United States and Japanese governments respectively, the World Health Organization (WHO) cautions against medical associations recommending and administering unproven treatments to patients with COVID-19 which presumably includes remdesivir.​13 The WHO recently launched its own clinical trial comparing 4 treatment options which includes:

1. Remdesivir
2. Ritonavir/Lopinavir
3. Interferon beta-1a
4. Chloroquine/Hydroxychloroquine

The clinical trial, also known as “Solidarity”, aims to discover whether any of the agents listed above slow disease progression or increase survival.​13​As of April 21st, 2020 over 100 countries are participating via the trial.​13

The contrasting findings of the expanded access report, and randomized clinical control trials add to the dubious nature of whether remdesivir is even a treatment yet. What we do know is that remdesivir exerts some modest positive effect over no treatment at all for COVID-19 patients via the ACTT results. Until the results of the ACTT/Solidarity trials are available in peer reviewed medical journals and multiple other trials conducted to confirm their veracity, we will just have to take the NIAID and Gilead’s preliminary results at face value, remdesivir is proving to be a medication worth employing.

Citations:

  1. “Adaptive COVID-19 Treatment Trial (ACTT) - Full Text View.” ​Full Text View - ClinicalTrials.gov​,National Institute of Allergy and Infectious Disease, 21 Feb. 2020, clinicaltrials.gov/ct2/show/NCT04280705?term=Remdesivir&draw=2&rank=9.
  2. “Adaptive COVID-19 Treatment Trial (ACTT).” ​National Institute of Allergy and Infectious Diseases​,U.S. Department of Health and Human Services, 1 Apr. 2020, www.niaid.nih.gov/clinical-trials/adaptive-covid-19-treatment-trial-actt.
  3. Commissioner, Office of the. “Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment.” ​U.S. Food and Drug Administration​,FDA, 1 May 2020, www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization -potential-covid-19-treatment.
  4. “COVID-19 Map.” ​Johns Hopkins Coronavirus Resource Center​,Jan. 2020, coronavirus.jhu.edu/map.html.
  5. Fox, Maggie, et al. “FDA Will Reportedly Authorize Use of Remdesivir for Covid-19 after Trial Shows 'Positive Effect' on Recovery Time.” ​CNN​,Cable News Network, 30 Apr. 2020, www.cnn.com/2020/04/29/health/gilead-sciences-remdesivir-covid-19-treatment/index.html.
  6. “Gilead Announces Approval of Veklury® (Remdesivir) in Japan for Patients With Severe COVID-19.” ​Gilead Creating Possible: Press Releases​,Gilead Sciences Inc., 7 May 2020, www.gilead.com/news-and-press/press-room/press-releases/2020/5/gilead-announces-approval-of-veklury-remdesivir-i n-japan-for-patients-with-severe-covid19.
  7. Gittelson, Ben. “Trump, Fauci Tout 'Good News' from Remdesivir Drug Trial in Treating COVID-19.” ​ABC News​, ABC News Network, 29 Apr. 2020, abcnews.go.com/Politics/trump-fauci-tout-good-news-remdesivir-drug-trial/story?id=70407208.
  8. Grein, Jonathan, et al. “Compassionate Use of Remdesivir for Patients with Severe Covid-19.” ​New England Journal of Medicine​,2020, doi:10.1056/nejmoa2007016.
  9. “NIH Clinical Trial Shows Remdesivir Accelerates Recovery from Advanced COVID-19.” ​National Institute of Allergy and Infectious Diseases​,U.S. Department of Health and Human Services, 29 Apr. 2020, www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19.
  10. Sheahan, Timothy P., et al. “Broad-Spectrum Antiviral GS-5734 Inhibits Both Epidemic and Zoonotic Coronaviruses.” Science Translational Medicine​,vol. 9, no. 396, 2017, doi:10.1126/scitranslmed.aal3653.
  11. Wang, Yeming, et al. “Remdesivir in Adults with Severe COVID-19: a Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial.” ​The Lancet​,29 Apr. 2020, doi:10.1016/s0140-6736(20)31022-9.
  12. “WHO R&D Blueprint Novel Coronavirus COVID-19 Therapeutic Trial Synopsis.” ​World Health Organization Coronavirus R+D Blueprint​,18 Feb. 2020, www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_synopsis_ Final_18022020.pdf.
  13. “‘Solidarity’ Clinical Trial for COVID-19 Treatments.” ​World Health Organization​,World Health Organization, 2020, www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov/solidarit y-clinical-trial-for-covid-19-treatments​.
  14. “Development of Remdesivir.” ​Gilead Creating Possible: RDV Development Factsheet ,Gilead Inc., 2020, www.gilead.com/-/media/gilead-corporate/files/pdfs/covid-19/gilead_rdv-development-fact-sheet-2020.pdf.
  15. Commissioner, Office of the. “Expanded Access.” ​U.S. Food and Drug Administration​,FDA, 27 Apr. 2020, www.fda.gov/news-events/public-health-focus/expanded-access​.
  16. “NIH Clinical Trial Testing Antiviral Remdesivir Plus Anti-Inflammatory Drug Baricitinib for COVID-19 Begins.” National Institute of Allergy and Infectious Diseases​,U.S. Department of Health and Human Services, 8 May 2020, www.niaid.nih.gov/news-events/nih-clinical-trial-testing-antiviral-remdesivir-plus-anti-inflammatory-drug-baricitinib​.
  17. Miessler, James. “Gilead Works to Expand International Access to Remdesivir.” ​FDAnews RSS​,WIRB-Copernicus Group, 7 May 2020, www.fdanews.com/articles/197009-gilead-works-to-expand-international-access-to-remdesivir.

Image citations:

  1. “3.3 The Nucleus and DNA Replication - Anatomy and Physiology.” ​OpenStax​,Rice University , 2020, openstax.org/books/anatomy-and-physiology/pages/3-3-the-nucleus-and-dna-replication. License: https://creativecommons.org/licenses/by/4.0/
  2. “Microbiology.” ​Lumen Microbiology​, OpenStax Microbiology, courses.lumenlearning.com/microbiology/chapter/rna-transcription/. License: https://creativecommons.org/licenses/by/4.0/
  3. “Remdesivir: How It Attacks a Virus @AFP Pic.twitter.com/OIwEAJu46g.” ​AFP Graphics​,AFP Graphics, 1 May 2020, twitter.com/afpgraphics/status/1256105637685145610.
  4. “WHO R&D Blueprint Novel Coronavirus COVID-19 Therapeutic Trial Synopsis.” ​World Health Organization Coronavirus R+D Blueprint​,18 Feb. 2020, www.who.int/blueprint/priority-diseases/key-action/COVID-19_Treatment_Trial_Design_Master_Protocol_s ynopsis_Final_18022020.pdf.