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Commentary—Remdesivir: Research Update

Commentary
5/13/2020 Matthew E Levison, MD, Adjunct Professor of Medicine, Drexel University College of Medicine

COVID-19 Resources Home Page

Numerous antiviral agents continue to be investigated and developed as potential therapies for the SARS-CoV-2 virus [1,2]. Existing drugs, such as hydroxychloroquine, that purportedly have antiviral activity, are being used off-label, exposing patients to the drug’s well-known adverse effects without proof of efficacy. The only drug so far that has shown some evidence of clinical benefit in COVID-19 is remdesivir, which gained emergency use authorization (EUA) from the FDA for confirmed or suspected severe COVID-19 in hospitalized adults and children on May 1, 2020 [3].

Remdesivir is a broad-spectrum antiviral drug developed by the biopharmaceutical company Gilead Sciences. It is an adenosine nucleoside analogue that is given intravenously as a prodrug that rapidly enters target cells, where it is converted to an active nucleoside triphosphate metabolite that is incorporated into nascent viral RNA chains within the host cell. The drug results in premature termination of viral RNA synthesis by inhibiting RNA-dependent RNA polymerase. Once-daily dosing provides sustained intracellular levels of the active drug. The pharmacokinetics of remdesivir in severely ill patients, or in patients with renal or hepatic impairment, and any necessary dosage adjustment are not known.

Remdesivir was shown to exhibit antiviral activity against Ebolavirus and other filoviruses in host cell-based assays, and it suppressed Ebolavirus replication and protected against lethal disease 100% of rhesus monkeys experimentally infected with Ebolavirus[4]. These results prompted a randomized, controlled trial of remdesivir, comparing it to antibody-based therapeutics, in patients with Ebolavirus disease in the Democratic Republic of the Congo. However, the remdesivir intervention arm was terminated mid-study when remdesivir was found inferior to the comparators, with a higher mortality rate of 53.1% (93/175) [5].

Remdesivir has also been found to inhibit replication of human coronaviruses in human respiratory epithelial cell tissue culture, including the three new human coronaviruses that have emerged from zoonotic reservoirs in the past 20 years (SARS-CoV in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019), without inhibition of host RNA or DNA polymerases, and has been studied in macaque monkeys experimentally infected with these coronaviruses [6-8].

The therapeutic efficacy of remdesivir against SARS-CoV-2 was then studied in a small number of macaque monkeys after their inoculation with SARS-CoV-2 by a combination of intranasal, intratrachial, ocular, and oral routes. A mild, transient respiratory infection developed that lasted 9 to 17 days in control macaques. Remdesivir was started 12 hours after inoculation of SARS-CoV-2, at a time close to the peak of virus replication in the lungs, and administration continued once daily for 6 days. The remdesivir dosing scheme in the macaques was said to mimic remdesivir dosing in clinical studies with COVID-19 patients and to result in a similar systemic drug exposure. In this study, administering remdesivir 12 hours after infection reduced clinical symptoms, lung virus replication, and lung lesions. However, high viral RNA loads and infectious virus titers were not reduced in the nose, throat, and rectum in remdesivir-treated animals (sites from which SARS-CoV-2 is transmitted to others), which could possibly be due to inadequate tissue levels of the active drug metabolite at these sites [9,10]. The remdesivir metabolite was readily detectable in lung tissue of all remdesivir-treated animals, but tissue drug levels in upper respiratory tract were not determined. Known mutations in the RNA-dependent RNA polymerase that confer resistance to remdesivir in coronaviruses were not detected in any of the tested samples from remdesivir-treated animals.

However, this experimental animal model may not have mimicked COVID-19 in humans, who become sufficiently symptomatic to seek medical care only many days after SARS-CoV-2 infection has silently progressed;  the efficacy of an antiviral drug started with onset of symptoms may be significantly different than when that drug is given within 12 hours of infection. The effect of delayed therapy on the course of the disease was illustrated in a SARS-CoV (first outbreak) mouse model in which remdesivir was started only after virus replication and lung airway epithelial damage had peaked. In this model, despite reducing viral titers, remdesivir failed to reduce disease severity or increase survival, suggesting that antivirals must be given early, before lung damage has become significant [11].

Clinical interest in remdesivir was rekindled in January 2020 by the rapid symptomatic improvement in the first patient with COVID-19 in the US, following compassionate use of remdesivir. The drug was started on the 7th hospital day (11th day of onset) soon after the patient became hypoxic and chest radiographs became abnormal [12]. The apparent success in one patient does not prove remdesivir is effective. Large clinical trials that compare remdesivir to placebos are required for this.

Due to the COVID-19 pandemic, the FDA designated remdesivir for “compassionate use” in March 2020, allowing patients with serious or life-threatening cases of the virus to have access to the drug. The first published report on a group of 53 patients who received remdesivir on compassionate use basis described clinical improvement in 36 patients (68%) with severe COVID19, including 17 of 30 patients (57%) receiving mechanical ventilation who were extubated. A total of 25 patients (47%) were discharged, and 7 patients (13%) died; mortality was 18% (6 of 34) among patients receiving invasive ventilation and 5% (1 of 19) among those not receiving invasive ventilation [13].

However, randomized, placebo-controlled trials (RCT) are the gold standard for determining drug efficacy. The first RCT in the US to evaluate the efficacy and safety of remdesivir for the treatment of COVID-19 began at the University of Nebraska Medical Center (UNMC) in Omaha in February 2020. The first trial participant was an American who was repatriated after being quarantined on the Diamond Princess cruise ship that docked in Yokohama, Japan and volunteered to participate in the study [14]. This study is ongoing.

Another ongoing multicenter RCT of remdesivir, coordinated by the National Institute of Health, released preliminary data showing a faster time to recovery of hospitalized patients with severe disease [15]. The analysis, which included 1,063 hospitalized patients with advanced COVID-19 and lung involvement, showed that patients who received remdesivir recovered 4 days faster than similar patients who received placebo (ie, 11 days vs 15 days). Results also suggested a survival benefit, with a mortality rate of 8% in the remdesivir group, compared with 11.6% in the placebo group, but this finding was not statistically significant (P = 0.059).

The results of this NIAID-coordinated study differed from a smaller (n = 237) multicenter RCT, conducted in Hubei, China, in hypoxic hospitalized adults (aged ≥18 years) with laboratory-confirmed SARS-CoV-2 infection and radiologically confirmed pneumonia [16]. Remdesivir (200 mg on day 1 followed by 100 mg daily) was started within 12 days of symptom onset in 158 patients and 79 patients received placebo; 1 patient withdrew. This study found remdesivir was not associated with statistically significant time to clinical improvement. However, one of the trial’s findings that patients with symptom duration of 10 days or less receiving remdesivir had a faster time to clinical improvement than those receiving placebo, although not statistically significant, suggests that remdesivir may have been started too late in the course of infection.

Gilead reported on preliminary results of study comparing a 5- vs 10-day remdesivir regimen [17]. The company expects to submit the full data to a peer-reviewed journal in near future. Patients in this study receiving a 10-day regimen had similar improvement in clinical status compared to patients on the 5-day course. More than half of patients in both treatment groups were discharged from the hospital by day 14 [17], and patients who received treatment earlier responded better [18]. The data suggest that by day 14, 62% of patients treated early were well enough to be discharged from the hospital compared to 49% of patients who were treated after the 10-day point [19]. The study demonstrates the potential for some patients to be treated with a 5-day regimen, which could significantly expand the number of patients who could be treated with the current supply of remdesivir [18].

In summary, studies in a non-human primate COVID-19 model have documented remdesivir can reduce viral replication in the lung and improve lung pathology, if given early enough in the course of the infection. This is a problem with COVID-19 in humans, when SARS-CoV-2 replication has already peaked before or at the onset of symptoms; if antiviral therapy is then not started until a week or more later when symptoms are maximal, the drug may not be able to prevent or limit damage to the lungs and other organs. A better option than remdesivir, which requires intravenous administration, may be an orally administered antiviral drug that could be given on an outpatient basis early in the course of the disease, before symptoms become severe enough to require hospitalization. RCTs that investigate the benefits of early antiviral treatments for mild infection, which could prevent serious complications, are needed, as are RCTs of remdesivir combined with immunomodulators. More data are needed to show that the remdesivir dosing used in the clinical trials is sufficient to rapidly clear the virus from various tissue foci. Perhaps, larger doses are required for this purpose and pharmacokinetic data are needed in patients with renal or hepatic failure. Also, emergence of remdesivir-resistant mutants needs to be monitored on an ongoing basis.

 

References

 

  1. Bergman SJ, Cennimo DJ, Miller MM, et al: Treatment of coronavirus disease 2019 (COVID-19): Investigational drugs and other therapies. Medscape May 11, 2020.  https://emedicine.medscape.com/article/2500116-overview#a5
  2. The Centre for Evidence-Based Medicine: COVID-19 registered trials and analysis. https://www.cebm.net/covid-19/registered-trials-and-analysis/
  3. FDA. Fact sheet for health care providers emergency use authorization (EUA) of remdesivir (GS-5734). May 1, 2020. Available at https://www.fda.gov/media/137566/download
  4. Warren, T., Jordan, R., Lo, M. et al: Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys. Nature 531: 381–385, 2016. doi: https://doi.org/10.1038/nature17180
  5. Mulangu S, Dodd LE, Davey RT, et al: A randomized, controlled trial of Ebola virus disease therapeutics. N Engl J Med 381(24):2293-2303, 2019.
  6. Sheahan TP, Sims AC, Graham RL, et al: Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 9(396): pii: eaal3653. doi: 10.1126/scitranslmed.aal3653, 2017  
  7. Choy KT, Yin-Lam Wong A, Kaewpreedee P, et al: Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro. Antiviral Res 178:104786, 2020.
  8. Wang M, Cao R, Zhang L, et al: Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Res 30:269-271, 2020. doi: 10.1038/s41422-020-0282-0. Epub 2020 Feb 4 
  9. Munster V, Feldmann F, Williamson B, et al: Respiratory disease and virus shedding in rhesus macaques inoculated with SARS-CoV-2. bioRxiv 10.1101/2020.03.21.001628. Available at: https://www.biorxiv.org/content/10.1101/2020.03.21.001628v1.full.pdf.
  10. Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir in rhesus macaques infected with SARS-CoV-2. bioRxiv PREPRINT doi: https://doi.org/10.1101/2020.04.15.043166. Available at: https://www.biorxiv.org/content/10.1101/2020.04.15.043166v1.full.pdf.
  11. Sheahan TP, Sims AC, Baric RS: Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med 9(396): eaal3653, 2017. 
  12. Holshue ML, DeBolt C, Lindquist S, et al: First case of 2019 novel coronavirus in the United States. N Engl J Med 382:929-936, 2020. doi: 10.1056/NEJMoa2001191 
  13. Grein J, Ohmagari N, Shin D, et al: Compassionate use of remdesivir for patients with severe Covid-19. New Eng J Med April 10, 2020 DOI: 10.1056/NEJMoa2007016. 
  14. National Institutes of Health: NIH clinical trial of remdesivir to treat covid-19 begins. https://www.nih.gov/news-events/news-releases/nih-clinical-trial-remdesivir-treat-covid-19-begins. February 25, 2020. Accessed May 13, 2020.
  15. National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID): NIH clinical trial Shows remdesivir accelerates recovery from advanced COVID-19.Apr 29. 2020. Available at https://www.niaid.nih.gov/news-events/nih-clinical-trial-shows-remdesivir-accelerates-recovery-advanced-covid-19. Accessed May 13, 2020
  16. Wang Y, Zhang D, Du G, et al: Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial. Lancet Published online April 29, 2020    https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(20)31022-9.pdf.
  17. Coppock K: Remdesivir demonstrates positive results in phase 3 trial for COVID-19. Pharmacy Times April 29, 2020. https://www.pharmacytimes.com/news/remdesivir-demonstrates-positive-results-in-phase-3-trial-for-covid-19
  18. Gilead Science: Gilead announces results from phase 3 trial of investigational antiviral remdesivir in patients with severe COVID-19. April 29, 2020 [press release]. Available at https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19
  19. Terry M: Gilead reports positive results from two trials of remdesivir for COVID-19. BioSpace April 29, 2020. Available at https://www.biospace.com/article/gilead-s-remdesivir-appears-helpful-in-treating-covid-19/

COVID-19 Resources Home Page

Matthew Levison, MD

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Obsessive-Compulsive Disorder (OCD) and Related Disorders in Children and Adolescents
Adolescent patients who have obsessive-compulsive disorder (OCD) are most likely to also have which of the following