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.