Student Contributor: Kushal Das
Introduction
The world is racing towards development of a novel vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for causing COVID-19. However, development of a vaccine and its eventual availability might take several years and even under extraordinary circumstances of current pandemic, it might still take about 12-18 months for a potential vaccine to be available. The ongoing pandemic necessitates immediate treatment against SARS-CoV-2 which is why several potential antiviral drugs against SARS-CoV-2 are currently being investigated and or undergoing clinical trials worldwide. A typical antiviral agent against a pathogen would also go through various phases of clinical trials and approvals from regulatory agencies might take several years to bring a drug into the market. In order to provide urgent treatment for COVID-19 patients, several preexisting drugs with known safety profile in animals and humans are tested first. As these drugs have a known human safety profile, it would take less time to receive approvals from regulatory agencies to develop a potential drug for COVID-19 patients. One such previously used antiviral drug, Remdesivir has shown promising results in controlled trials in US, Europe and Asia. Multiple randomized clinical trials of Remdesivir are being conducted to determine the safety and effectiveness.
Rational for use of Remdesivir
Remdesivir (GS-5734) is an investigational nucleotide analog that has a broad-spectrum antiviral drug against RNA viruses such as filoviruses, paramyxoviruses, pneumoviruses and coronaviruses including SARS-CoV and MERS-CoV. Studies have demonstrated that it effectively inhibits human and zoonotic coronavirus in cell culture, mouse and in non-human primate model of infection. The drug was first used by Gilead Science Inc. (USA) to treat Ebola virus disease and Marburg virus infections. Even though drug has not been that effective against Ebola, it was found to be safe in clinical trials. Importantly, Remdesivir showed antiviral activity against many betacoronaviruses including SARS-CoV and MERS-CoV better than Ebola for which it was developed initially. Since SARS-CoV-2 has 80% sequence similarity with SARS-COV and MERS-CoV, particularly in the RNA dependent RNA polymerase, a drug that targets RNA dependent polymerase of SARS-COV would be potentially effective against SARS-CoV-2 as well. The drug was allowed to enter into clinical trials for treatment against SARS-CoV-2 based on the availability of human-safety profile of the drug and also approved for emergency use in COVID-19 patients in the US.
Mechanism of action of Remdesivir
Remdesivir inhibits RNA dependent RNA polymerase and impedes viral replication. Remdesivir is a broad-spectrum antiviral prodrug that resembles RNA base, adenosine. During viral replication, Remdesivir can be incorporated in a nascent RNA chain instead of adenine, causing premature chain termination and abrupt stoppage of viral replication. The drug is more effective in the initial phases of infection during which the drug targets viral replication in the upper respiratory tracts of the human body. The drug is thought to evade proof reading by viral exoribonuclease as it does not cause immediate chain termination. This is in sharp contrast to nucleotide analogs that have been shown to be less efficacious against coronaviruses due to the proof-reading ability of virus exonuclease.
Efficacy and ongoing trials of Remdesivir
Compassionate use of drugs refers to the use of a new unapproved drug for treatment in patients in absence of any available treatment on a case by case basis. Remdesivir has been approved only for compassionate use in severe COVID-19 patients by U.S. Food and Drug Administration (FDA). The first compassionate use of Remdesivir in a US patient after hospitalization exhibited a significant increase in oxygen saturation and decrease in fever and other symptoms of COVID-19 without any observable adverse effect. In a relatively larger study of compassionate use of Remdesivir on COVID-19 patients, 68 % of patients have increased oxygen saturation and were extubated from mechanical ventilation. Mortality rate in these patients was 13% which was well below to that of World Health Organizations reports of 50% in severe COVID-19 patients. Administration of the drug in US, UK and Japan also resulted in acceptable recovery rate in severe COVID-19 patients. Remdesivir has shown superior therapeutic efficacy relative to Lopinavir and Ritonavir against MERS-CoV both in terms of reducing viral load and pathology in a mouse transgenic model. Other studies indicated that Remdesivir is effective both as prophylactic and therapeutic treatments against SARS-CoV-2. The patients are also less likely to develop resistance to this drug. Gilead Sciences is currently testing safety and efficacy of Remdesivir in two phase III clinical trials with a dosing regimen for 5 and 10 days respectively for treatment of patients with severely and moderate symptoms of COVID-19. Initial data from Gilead Sciences released on April 29, 2020 suggested that a 10-day treatment exhibited similar improvement relative to a five-day treatment. It remains to be seen that in how the drug performs in other randomized clinical trials conducted by National Institute of Allergy and Infectious Diseases (NIAID), World Health Organization (WHO) and Inserm in France.
Precautions
The drug is most potent when given early during acute infection and would not be an ideal choice for patients with mild infections. Besides the drug has to administered intravenously and is expensive. The drug is also contraindicated in patients with known hypersensitivity to any ingredient of Remdesivir.
Conclusions
Overall, Remdesivir has shown promise in the treatment of moderate to severe COVID-19 patients. The ongoing randomized clinical trials will provide more insight on its safety and efficacy and eventual approval of Remdesivir. Remdesivir could be a potential first treatment for the COVID-19 patients.
References
Huang, J., Song, W., Huang, H., and Sun, Q. (2020). Pharmacological Therapeutics Targeting RNA-Dependent RNA Polymerase, Proteinase and Spike Protein: From Mechanistic Studies to Clinical Trials for COVID-19. J Clin Med 9 DOI: 10.3390/jcm9041131.
Jean, S.S., Lee, P.I., and Hsueh, P.R. (2020). Treatment options for COVID-19: The reality and challenges. J Microbiol Immunol Infect DOI: 10.1016/j.jmii.2020.03.034.
Ko, W.C., Rolain, J.M., Lee, N.Y., Chen, P.L., Huang, C.T., Lee, P.I., and Hsueh, P.R. (2020). Arguments in favour of remdesivir for treating SARS-CoV-2 infections. Int J Antimicrob Agents 55, 105933 DOI: 10.1016/j.ijantimicag.2020.105933.
Kupferschmidt, K., and Cohen, J. (2020). Race to find COVID-19 treatments accelerates. Science 367, 1412-1413 DOI: 10.1126/science.367.6485.1412.
Martinez, M.A. (2020). Compounds with Therapeutic Potential against Novel Respiratory 2019 Coronavirus. Antimicrob Agents Chemother 64 DOI: 10.1128/AAC.00399-20.
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