Remdesivir, the First Experimental Medication to Treat 2019-novel Coronavirus (COVID-19) Infection

Update: Japan Approves Remdesivir For Use On Severe COVID-19 Patients

Japan approved the antiviral drug Remdesivir of the Gilead Sciences for the treatment of severe COVID-19 patients, making itself and the United States are the only two countries who have authorized use of remdesivir for the treatment of COVID-19.

The approval is under an exceptional approval pathway based on clinical data of phase III trial from the U.S. National Institute of Allergy and Infectious Diseases, referencing the United States’ Emergency Use Authorization of the drug to treat severe cases of COVID-19.

The infection of a novel coronavirus (2019-nCoV) found in Wuhan,  Hubei Province, a city of 11 million people in central China has been spreading rapidly, and the incidence rate is increasing worldwide. The COVID-19 virus can cause serious complications include pneumonia, severe acute respiratory syndrome, kidney failure, and even death in the most severe cases. As of February 17, 2020, there were 70532 confirmed cases in China, 8228 suspected cases, and 1767 deaths. There were confirmed cases reported in 34 provincial administrative regions in China; 25 foreign countries reported new coronavirus pneumonia cases, 691 confirmed cases, and 3 deaths. The reported number of infected patients far exceeding the total number of the 2003 SARS epidemic (37 countries, 8,098 cases and 774 deaths).

On February 11, 2020, the World Health Organization (WHO)  announced an official name COVID-19 for the disease that is causing the 2019 novel coronavirus outbreak in Wuhan, China. Since this outbreak first emerged, the US FDA and CDC are closely monitoring an outbreak of respiratory illness caused by  the COVID-19 pathogen emerged  in China and worldwide.

What is the 2019-novel coronavirus (COVID-19)?

There are hundreds of coronaviruses, some causing illness in people and others that circulate among animals including pigs, camels, civets, cats and bats. But occasionally a coronavirus mutates and can pass from animals to humans and then from human to human. However, three of the coronaviruses can have more serious outcomes in people, and those are severe Acute Respiratory Syndrome (SARS) which emerged in late 2002 and disappeared by 2004; Middle East Respiratory Syndrome (MERS), which emerged in 2012 and remains in circulation in camels; and the 2019 novel coronavirus, or known as COVID-19, which contains SARS-CoV and MERS-CoV, the genetic analyses suggest COVID-19 can cause severe respiratory illness in humans,  but, there is currently no effective treatment options or approved therapeutics are available for COVID-19. Therefore, there is much more to learn about the transmissibility, severity, and other features associated with COVID-19, a global effort and investigations are underway to contain its spread.

Clinical trial of Remdesivir in China

Remdesivir is the first experimental medication to treat 2019-novel coronavirus (COVID-19) infection, which is developed by Gilead Sciences, a US-based bio pharmaceutical company. The alternative names of the Remdesivir include Captisol-enabled Remdesivir; Captisol®-enabled GS 5734; GS-5734.

Although, Remdesivir is not yet licensed or approved anywhere globally. However,  Remdesivir showed promising preclinical results in vitro and in vivo activity in animal models against the viral pathogens SARS and MERS, which are coronaviruses and structurally similar to COVID-19.

Since this COVID-19 rapid spreading in China, there is no specific treatment against the new virus COVID-19 available. At the request of treating physicians, and with the support of local regulatory agencies, who have weighed the benefits and risks of the experimental drug Remdesivir, Gilead Sciences has provided Remdesivir for use in a small number of patients infected with COVID-19 for emergency treatment in the absence of any approved treatment options.

Based on available data in other coronaviruses, the company has supplied experimental antiviral Remdesivir and clinical trials have begun in Wuhan, Hubei province, China to test the drug’s safety and efficacy of the nucleotide analog. (A phase 3 randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of   Remdesivir  in hospitalized adult patients with severe COVID-19 (2019-nCoV) respiratory disease. Estimated enrollment: 452 participants. Experimental study for Remdesivir group:  200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days and Remdesivir placebo group: 200 mg loading dose on day 1 is given, followed by 100 mg iv once-daily maintenance doses for 9 days.  Estimated primary completion and study completion dates are April 3, 2020 and May 1, 2020, respectively).

Mechanism of antiviral drug Remdesivir

Remdesivir is a novel antiviral drug in the class of nucleotide analogs, and a prodrug of the related compound GS-441524, which originally were developed by Gilead Sciences as a treatment for Ebola virus disease and Marburg virus infections. (1)

Recently, Remdesivir has been recognized as a promising antiviral drug against a wide array of RNA viruses through the targeting of the viral RNA dependent RNA polymerase (RdRp). (2) Importantly, research data had indicated the prophylactic and therapeutic efficacy of Remdesivir in a mouse model of SARS/MERS-CoV infection and in vitro activity against multiple coronaviruses. (3)

It is important to note that infection with negative-sense RNA viruses is associated with a broad spectrum of human diseases. Remdesivir has been reported to cause premature termination of nascent RNA transcripts,  that acts early in infection and decreases RNA levels in a dose-dependent manner and parallels impairment of viral titer, which provided evidence to show that delayed chain termination could be a plausible mechanism of action of Remdesivir against COVID-19 infection.(4) Similar studies had confirmed that the antiviral mechanism for Remdesivir has been demonstrated to be through delayed chain termination of nascent viral RNA for Ebola virus, Nipah virus, and respiratory syncytial virus. (5)

Moreover, research findings revealed that Remdesivir in combination with another medication Chloroquine (a widely-used anti-malarial and autoimmune disease drug) are highly effective in the control of COVID-19 infection in vitro since these compounds have been used in human patients with a safety track record and shown to be effective against various ailments, therefore, it should be assessed in human patients suffering from the novel coronavirus disease. (6)

Together, the antiviral activities of Remdesivir and the parent nucleoside analog across multiple coronaviruses, providing evidence to support new indications for this compound against COVID-19 of significant public health concern. These results suggested that Remdesivir may improve disease outcomes in CoV-infected patients, and prove valuable in preventing future epidemics in the event of COVID-19 emergence in the future. (7)

To date (Feb. 16, 2020), no approved therapeutics are available against the new virus COVID-19 infection and no vaccine treatment is expected for at least 18 months according to WHO, therefore, developing effective antiviral agents like Remdesivir to combat the disease is urgently needed, which is also critical milestone reached in response to this outbreak. We are expecting that the new drug Remdesivir will be approved by the FDA after the clinical trials are completed in China and get to patients as soon as possible.

References:

1    Viruses. (2019) Apr 4;11(4)

2    Antiviral Research (September 2019) 169, 104541

3    Sci Transl Med. (2017) Jun 28;9(396)

4    Nature ( 2016) 531:381–385.

5    Sci Rep. (2018) Mar 5;8(1):3970

6    Cell Research (2020) 0:1–3

7    Nature Communications (December 2020) 11(1):222 

Author:  Lin Zhang

Date: Feb. 16, 2020

About the Author:

Lin Zhang, M.D., senior director of a health care industry company in the United States. With the experience in clinical medicine, biotechnology, health industry and other fields, he is responsible for the research and development of plant medicine, functional food and health products. He was a clinician and worked for the National Cancer Institute, FDA and the National Cancer Center of Japan for many years.

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