Key words:
COVID-19, SARS-CoV-2, Remdesivir, Pharmaceutical perspective
Recently, the new type of “2019 Novel Coronavirus” (COVID-19) broke out in Wuhan, China, which rapidly became a pandemic threat to the whole world. The COVID-19 is caused by a previously unknown pathogen named severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2), which is the seventh newly discovered coronavirus strain[1]. According to the World Health Organization (WHO) statistics, COVID-19 has now taken over many countries around the world, which brings the number of infections worldwide to more than 3 million and the death toll to more than 260,000. COVID-19 had a devastating impact on all sectors of the world. More seriously, there is no specific drug to treat the disease because it’s a new virus. But there were similar outbreaks of coronavirus infection in 2003 and 2005 called SARS and MERS, respectively[2]. Both COVID-19 and SARS belong to the coronavirus family, and COVID-19 seems not to be very different from SARS regarding its clinical features, so the lessons we learned from the SARS are the best weapons to face this new global threat[3].
Prevention of COVID-19 transmission is accompanied by an aggressive global search for therapeutic drugs. Remdesivir (Gilead Sciences, Inc) is the first antiviral drug to make it to the public eye, which has become the magic bullet the public has been waiting for. So, the news about remdesivir is also all over the internet, and it is difficult to tell true or false. But where did this medicine come from?
As an adenosine nucleotide analogue pro-drug, remdesivir (GS-5734) shows broad-spectrum antiviral activity against many RNA viruses[4]. Remdesivir can inhibit the RNA virus through the targeting of the viral RNA dependent RNA polymerase (RdRp), and covalently incorporated into the primer strand at the first replicated base pair to terminate the chain elongation[5, 6]. Coronaviruses (CoVs) are single-stranded RNA viruses that infect most animal hosts and human, such as severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012[7]. Because of the unique CoV proofreading 3’-5’ exoribonuclease (ExoN), most nucleoside analogues have been incapable of inhibiting CoV replication except remdesivir[8]. Remdesivir’s use as a treatment for Ebola has made it an antiviral drug of global interest. In 2018, remdesivir was approved by the FDA to enter a phase 3 clinical trial to treat Ebola. However, in this clinical trial, remdesivir could reduce the death rate for Ebola patients to 50 percent, which were not as good as the other two antibody drugs[9]. So the clinical trial ended in failure and remdesivir faded from public view.
However, a recent outbreak of COVID-19 in Wuhan has put remdesivir on the altar, again. Firstly, on January 30, 2020, a case report entitled “First Case of 2019 Novel Coronavirus in the United States” published in N Engl J Med . The article reported the first case of “2019-nCoV” infection confirmed patient in the United States and described the identification, diagnosis, clinical course, and management of the case. After various treatments did not significantly improve the symptoms of the patient, clinicians pursued compassionate use of an investigational antiviral therapy “remdesivir”. So, treatment with intravenous remdesivir (a novel nucleotide analogue prod-rug in development) was initiated on the evening of day 7. Happily, on hospital day 8 (illness day 12), the patient’s clinical condition was improved[10]. Then on February 4, Wuhan Institute of Virology found remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87) effectively inhibited the recently emerged 2019-nCoV in vitro[11]. Besides, in recent years before the COVID-19 outbreak, there have been several studies reporting on remdesivir’s treatment on the coronavirus of SARS and MERS [12, 13]. Therefore, in view of that COVID-19 is coronaviruses and close to SARS, the remdesivir has become the hopes of all the world people to fight against the “2019-nCoV” infection. Meanwhile, the China Food and Drug Administration (CFDA) quickly approved Phase 3 clinical trials of the remdesivir through the green channel in Wuhan, China, which began on February 4 and expected to end on April 17.
However, could remdesivir be a magic bullet for the COVID-19 treatment? First let’s look at the pharmacodynamics relevant studies of remdesivir.
Actually, before approved into Phase 3 clinical trials in China, only the above two articles have suggested the therapeutic effect of remdesivir on the COVID-19. After careful reading, we found the curative effect about remdesivir was controversial in this case report. Firstly, in this case report [10], the low cycle threshold (Ct) values (18 to 20 in nasopharyngeal specimens and 21 to 22 in oropharyngeal specimens) on illness day 4 suggest the high levels of “2019-nCoV” virus in these specimens, which gradually reduced with the progress of the time. On illness day 11, the high Ct values (33 to 34 in nasopharyngeal specimens and 36 to 40 in oropharyngeal specimens) suggest the low levels of “2019-nCoV” virus in these specimens, which prompts before remdesivir treatment most of the “2019-nCoV” virus were eliminated by the immune system (As shown in Fig 1). This from another level indicates that the therapeutic effect of remdesivir on COVID-19 virus is questionable and need be discussed, which is easily ignored by people. Secondly, in the research by Wuhan Institute of Virology [11], remdesivir (EC50 = 0.77 μM; CC50 > 100 μM; SI > 129.87) could effectively inhibit the COVID-19 in vitro. This experiment only confirmed the remdesivir inhibition of COVID-19 short-term infection in vitro (2 hours), and no time-effect relationship of remdesivir inhibition was confirmed. Therefore, it is not sufficient to approve remdesivir for Phase 3 clinical trial based on these two studies.