treatment for COVID-19

The discovery that the antiviral drug remdesivir prevented MERS-CoV disease in monkeys supports the clinical trial testing of remdesivir as a treatment for COVID-19.

Three different coronavirus outbreaks (SARS, MERS, COVID-19) have emerged from animal reservoirs in the past two decades that have caused severe disease and concerns over global spread.

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) first appeared in 2012, eight years after the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) first emerged from China in late 2002/2003.  Although no cases of SARS-CoV have been detected since 2004, MERS-CoV continues to circulate with 2,499 reported cases and 861 deaths as of December 2019. The case fatality rate of MERS-CoV is 35% as compared to SARS-CoV which was around 10%.

Since the emergence of MERS-CoV, scientists have focused on developing animal models in which to test new treatments. Currently, there are no FDA-approved antivirals or vaccines for the treatment and prevention of MERS-CoV.

However, a new report from NIH’s National Institute of Allergy and Infectious Diseases (NIAID), published in the Proceedings of the National Academy of Sciences describes a step forward for remdesivir in the approval process for coronavirus treatment.

Remdesivir is an experimental antiviral drug with broad activity

Remdesivir (GS-5734) developed in 2014 by the biotechnology company Gilead in Foster City, California was initially developed to fight infectious viral diseases such as Ebola.  As a nucleotide analogue prodrug, it is not active outside the cell. Studies indicate that in the cell, it is metabolized into more active metabolites that inhibit coronavirus replication through interference with viral enzymes (RNA polymerases) that are necessary for replication. Host RNA or DNA polymerases are not affected.

Studies have demonstrated that MERS-CoV enters cells with the help of an S protein or spike to help attach to host cells. The virus then hijacks or delays the normal immune system response as the infection steadily progresses.

Already, remdesivir has proven effective in treating monkeys infected with Ebola and Nipah viruses and human clinical trials are currently underway. Thus far, studies suggest that two other drugs are more effective than remdesivir in treating Ebola.

Multiple in vitro (test tube) studies have demonstrated that remdesivir has broad antiviral activity against viruses from different families (including filo-, pneumo-, and paramyxoviruses) without any noted adverse toxic effects.  For example, replication of a wide range of coronaviruses including SARS-CoV and MERS-CoV was inhibited in human airway (lung) epithelial cells.

In vivo studies with mice also demonstrated that remdesivir was effective against SARS-CoV.

Remdesivir prevented MERS-CoV in monkeys when administered before infection and improved disease symptoms when administered after the animals were infected.

Researchers randomly assigned 18 male rhesus macaques to three groups of six at NIAID’s Rocky Mountain Laboratories in Hamilton, Montana.

One group of monkeys was treated prophylactically (24 h before MERS-CoV infection) with 5 mg/kg remdesivir. Another group was similarly given 5 mg/kg remdesivir but therapeutically (12 h after MERS-CoV infection which is close to the peak time for MERS-CoV replication).  A control group did not receive any remdesivir. The treatment was continued once daily for six days. On the sixth day, researchers assessed viral RNA levels and lesions (damage) present in lung tissues.

The researchers observed signs of respiratory disease in the control group, which included increased respiration rates and lung lesions that consisted of minimal to marked interstitial pneumonia.

Animals treated prophylactically exhibited normal lung tissue with significantly lower levels of MERS-CoV replication compared to the control group. No lesions were present in the lung tissues.

Since one-third of MERS-CoV cases are acquired in the hospital (through nosocomial transmission), prophylactic remdesivir treatment could prevent disease in healthcare personnel or individuals who are in close contact with already diagnosed MERS-CoV patients.

For patients already diagnosed with MERS-CoV, remdesivir may reduce virus replication and decrease the severity of lung lesions.

Five out of six animals treated with remdesivir after infection had increased respiration rates that were still significantly lower than the control group at days three and six. This group also demonstrated lower levels of MERS-CoV replication in the lungs than the control group but levels were higher than the prophylactically treated group.

Moreover, the total area of lungs affected by lesions was significantly smaller than the control group and the lung damage was less severe.

Researchers observed various levels of pneumonia severity when treated therapeutically. Two out of six animals did not show any evidence of pneumonia.

Clinical trials of remdesivir for COVID-19 are currently underway and needed for MERS-CoV

Now that remdesivir has demonstrated in vitro and in vivo activity in animal models against SARS-CoV and MERS-CoV, which are coronaviruses that are structurally similar to COVID-19, there is potential for it to be also effective as a treatment for COVID-19.

The drug is being advanced into human clinical trials for COVID-19 treatment in China, given the current necessity for treatment.  Results from these studies are expected to be available this spring.

Even though remdesivir is not yet licensed or approved by any drug regulators globally and there is no data available on its effectiveness as a treatment for COVID-19, it has been administered for emergency treatment in a small number of patients in the absence of other approved treatment options. No adverse effects have been seen in these cases.

Written by Maria-Elena Bernal

References:

  • Wit, E. de, Feldmann, F., Cronin, J., Jordan, R., Okumura, A., Thomas, T., … Feldmann, H. (2020, February 13). Prophylactic and therapeutic remdesivir (GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Retrieved from https://www.pnas.org/content/early/2020/02/12/1922083117#F3
  • (n.d.). Remdesivir prevents MERS coronavirus disease in monkeys. Retrieved from https://www.eurekalert.org/pub_releases/2020-02/nioa-rpm021320.php
  • Characterizing MERS-CoV Disease. (n.d.). Retrieved from https://www.niaid.nih.gov/diseases-conditions/characterizing-mers-cov-disease
  • (n.d.). Retrieved from https://www.gilead.com/science-and-medicine/pipeline
  • Severe 2019-nCoV Remdesivir RCT – Tabular View. (n.d.). Retrieved from https://clinicaltrials.gov/ct2/show/record/NCT04257656
  • Company Statements. (n.d.). Retrieved from https://www.gilead.com/news-and-press/company-statements/gilead-sciences-statement-on-the-company-ongoing-response-to-the-2019-new-coronavirus
  • Gilead Assesses Ebola Drug as Possible Coronavirus Treatment (1). (n.d.). Retrieved from https://news.bloomberglaw.com/pharma-and-life-sciences/gilead-assesses-ebola-drug-as-possible-coronavirus-treatment
  • https://www.who.int/ebola/drc-2018/summaries-of-evidence-experimental-therapeutics.pdf?ua=1
  • https://www.nature.com/articles/srep43395

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