M
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August2020

Volume 6

ED
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HECK

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Editorial
Calmly and Scientifically
New Products
Remdesivir (trade name: Veklury)
Favipiravir (trade name: Avigan Tablet)
CONTENTS （August , 2020, Vol. 6, No. 18）

Editorial
Calmly and Scientifically38

New Products
Remdesivir (trade name: Veklury)

39

Most likely ineffective for COVID-19

Favipiravir (trade name: Avigan Tablet)

46

Most probably no efficacy on COVID-19, and harmful

MED CHECK

August 2020/ Vol.6 No.18 ・ Page 37

M
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Editorial

HECK

Calmly and ScientificallyTranslated from the Editorial in Med Check(in Japanese) Jul 2020 ; 20 (90) ： 75

Do you know the book, “ The Sho ck

risk of bird flu, bringing him huge profits.

Doctrine” by Naomi Klein? This book,

Likewise, many stockholders, including

published in 2007, sells well again in thishim, will gain huge profits by the Japanesecorona-age. Shock doctrine can be defined

approval of remdesivir. However, as evident

as the execution of the disaster capitalism.

in the article of this volume, the quality ofWhen people are in a state of shock and

ACTT-1 trial, which underpins the approval oflose their composure due to disasters, cruelremdesivir, is questionable. In addition, manymarket fundamentalism, which does notof the ongoing clinical trials for favipiravir

work in ordinary times, passes through.

are largely observational studies with which

The reconstructions of New Orleans hit byefficacy cannot be determined.

Hurricane Katrina and Tohoku (north easternregion) in Japan hit by the Great East Japan

Earthquake would be typical examples.

In its editorial, BMJ (April 21, 2020)
warned that we should not waste time

At present, another shock doctrine isfor observational studies without control.

progressing here in Japan: remdesivir is

Nature (May 13, 2020) also said in its

approved in Japan for the first time in theeditorial "remdesivir provides an example

world and used clinically to treat COVID-19.

of the clinical chaos…..clinical trials must

Gilead Sciences, the manufacturer of thisbe as robustly designed as possible. Somechemical, will make huge profits. The

trials need to be small, initial explorations

name of this company is mentioned in theof potential treatments; but, after that,chapter 15 in “The Shock Doctrine”. Donald

researchers must think big." Even theRumsfeld, US Defense Secretary for theJapanese Medical Association’s Council ofBush Junior administration(2001-2006), wasExperts for COVID-19, which has made aonce the chairman of Gilead Sciences whichpoor evaluation of the ACTT-1 trial, said that

had the patent of Tamiflu. Since pandemic

it is essential to have a high-quality RCT and

is a national security issue, the conflictthe decision to disregard science is ultimatelyof interest occurs for Defense Secretary.

a disaster for the national health. A series

However, he never released his stocks of theof articles of Med Check and Med Check incompany during his tenure. Gilead’s share

English are effective measures against theprice increased nine-fold due to the outbreak

Shock Doctrine.

Page 38 ・ MED CHECK

August 2020/ Vol.6 No.18

New Products

Remdesivir (trade name: Veklury)
Most likely ineffective for COVID-19

Translated and revised from Med Check(in Japanese) Jul 2020 ; 20 (90):76-79
Med Check Editorial Team

Summary●Remdesivir (trade name: Veklury) is an antiviral agent that was initially developed for Ebola virus infection, but was
eventually proven ineffective. In Japan, it was officially approved for the treatment of COVID-19 for the first time in
the world as a “special case” in which the approval was granted within 3 days after application.
●Three placebo-controlled randomized controlled trials (RCTs) have been conducted to examine the efficacy andsafety of remdesivir on COVID-19. Of those, 2 were published as peer-reviewed papers for severe COVID-19.
● In the placebo controlled RCT conducted in China (Wuhan RCT), remdesivir did not reduce symptoms or death
compared to placebo.
● In the RCT (ACTT-1) led by the US National Institutes of Allergy and Infectious Diseases (NIAID), remdesivir did not
reduce severity of symptoms nor death in patients who had mild or moderate symptoms at the baseline. The same
was true in patients who had very severe symptoms, including those on ventilator. It was effective only in patientswith severe symptoms who required oxygen inhalation, but not ventilator. However, the symptom improvement andsurvival rate in these severe cases are unnaturally poor in the placebo group and unnaturally good in the remdesivirgroup. Therefore, it is highly likely that there was some bias in the study and the overall data is unreliable.
● In the SIMPLE trial comparing 5-day use and 10-day use, the number of cases that had recovered was significantly
higher in the 5-day use group than in the 10-day use group. When a treatment is effective, longer-term use
essentially yields better outcome. However, in this study, the opposite dose-response relationship was observed.
● In the special approval of remdesivir in Japan, the results of Wuhan RCT was excluded, and the opposite doseresponse relationship in the SIMPLE trial was ignored. It was based only on the results of ACTT-1, which is likely tohave bias in baseline characteristics.
Conclusion: The drug is most likely ineffective and should not be used.

Keywords:
RCT, ACTT1, SIMPLE, dose-response relationship, baseline characteristics, bias

Introduction
On May 7, 2020, remdesivir (product name Veklury)

effective? How about its safety? Let us verify them in thisarticle.

was approved as a “special case” only 3 days after
the application was accepted [1]. This is because an

Remdesivir is a synthetic inhibitor of viral RNA

emergency use authorization (EUA) [2] was issued in

Remdesivir is metabolized in the human body to

the U.S. on May 2, and the Japanese Ministry of Health,a substance which acts as an analog of adenosine

Labor and Welfare interpreted that it had been alreadytriphosphate (ATP), which is the source of the genetic

approved abroad although EUA was not an official

information essential for viral and human cell replication

approval. On what basis the drug is claimed to bein the cells of the human body. Therefore, it is said that
MED CHECK

August 2020/ Vol.6 No.18 ・ Page 39

Figure 1: Remdesivir is not a remedy for Ebola virus infection

Compared with 2 kinds of monoclonal antibody, remdesivir increases mortality by double from Ebola virus infection: This indicates that
remdesivir is not a remedy for Ebola virus infection.

an incomplete viral RNA chain is formed and replication

Not an "Ebola remedy"

is stopped in the middle, which inhibits viral RNA

Remdesivir is often wrongly labeled as an "Ebola

synthesis. For details, please refer to the package insert

remedy," and even some infectious disease experts[3] and our article on favipiravir (trade name: Avigan).

describe it as such. However, as a result of a randomized
controlled trial [9] comparing remdesivir with 3 types

It works only if used before the onset of symptoms?

of monoclonal antibodies, which was conducted when

In an experiment on monkeys inoculated with lethal

the epidemic occurred in the Republic of Congo, theviruses such as Ebola virus [4] and Nipah virus [5],mortality rate in remdesivir group (53.1%) was higher

administration of a sufficient amount of remdesivir

than that in any types of monoclonal antibody (33.5%,

before symptom onset of the infectious disease reduced

35.1% and 49.7%). The odds ratio was more than 2-foldmortality (Supplementary slides 2 and 3).

higher (2.10 and 2.25) with remdesivir as compared with

In addition, in monkeys infected with infectious

2 of them (p<0.001) (Figure 1) (Supplementary slides 7,8).

diseases, such as MERS virus [6], SARS virus [7] or SARSCoV-2 [8], timely administration of a sufficient amountIt can be said that it is a substance that was developedof remdesivir before symptom onset reduced viral load

for the treatment of Ebola but has failed.

as well as symptoms. (No comparison was reported in
mortality. Supplementary slides 4-6).

Clinical studies of remdesivir for COVID-19

However, what is important in treating infectious

To date, 4 clinical studies of remdesivir on COVID-19

diseases in humans is whether or not a drug can be usedwere published as peer-reviewed papers [10-13]: twoto alleviate symptoms or reduce mortality after someplacebo-controlled randomized controlled trials (RCTs)

symptoms have appeared and the condition is expected[10,11], a case-series report of compassionate use [12]to deteriorate.

and the SIMPLE trial [13] which compares the use of

However, in the animal experiment of remdesivir, there

remdesivir for 5 days with 10-day use. The Japanese

is no report on an experiment in which the substancepackage insert [3] quoted one [11] of the 2 published

was administered after symptom onset. With such anplacebo-controlled RCTs, the case-series report [12] andexperiment, it is impossible to predict whether it will

the SIMPLE trial [13]. We do not discussed the case series

work for humans or not. Rather, we suspect that there

in this article as it does not offer any useful information

is no report because it does not work if it is used afteron the efficacy and safety of remdesivir. Let's take a look

symptom onset.

at the 3 RCTs [10,11,13].

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Results of RCT conducted in China (Wuhan RCT) [10]The most important endpoint according to our(Supplementary slides 10-17)

standard, "all-cause mortality (at day 28)" was 13.9%(1) No efficacy on symptom improvement and mortality

in the remdesivir group and 12.8% in the placebo

reduction in remdesivir group

group (Figure 2). As one of the baseline characteristics,

This RCT [10] is a placebo-controlled multicentre

the proportion of patients whose time from onset wastrial at 10 hospitals in Hubei (mainly Wuhan) , China

over 10 days was significantly higher in the remdesivir

independent of the manufacturer Gilead Sciencesgroup (54%) than in the placebo group (40%) (p=0.037).

(Gilead). Laboratory confirmed COVID-19 patients, who

Therefore, depending on whether time from onset was

had radiologically confirmed pneumonia with oxygen

10 days or less or over 10 days, various effect indicators

saturation 94% or less on room air or a ratio of arterial

were compared. Let's take a look at all-cause mortality byoxygen partial pressure to fractional inspired oxygen of

the time from onset to enrollment ( ≦ 10days or >10days) .

300 mmHg or less, were enrolled and were assigned in

All-cause mortality in the remdesivir vs. placebo groupa 2:1 ratio to intravenous remdesivir and intravenous

was 11% vs. 15% (p=0.56) in patients whose time fromplacebo infusion. The time from symptom onset toonset was 10 days or less. In patients whose time fromenrollment was 12 days or less. The study began on

onset was over 10 days, it was 14% vs 10% (P=0.51),

February 6, and patients who enrolled by March 12

and no significant difference was observed. (Figure 2)

were followed. The study ended on April 10. In this(Supplementary slides 12,13).

study, 158 patients and 78 patients were allocated to

The primary endpoints “ time to clinical improvement

remdesivir group and placebo group, respectively (One

(2 levels or more improvement or live discharge) withinpatient did not use any medication, and was excluded). The

28 days after randomisation”, was slightly shorter inprimary endpoint was time to clinical improvement up to

remdesivir group, but difference was not significant

day 28, defined as the time (in days) from randomisation(p=0.24). (Supplementary slides 14)

to the point of a decline of 2 levels on a 6-point ordinal(2) Respiratory failure and rate of viral elimination

scale of clinical status as follows:

contradict with tendency for symptom improvement
Remdesivir showed tendency to improve symptoms

1. Discharged or having discharge criteria

in both groups although the difference was not

2. Not requiring oxygen therapy

significant. However, it is not consistent with the rate of

3. Requiring oxygen therapy

discontinuation due to severe respiratory adverse events

4. Requiring high-flow oxygen or noninvasive ventilationand viral elimination.

5. Requring invasive mechanical ventilation or ECMO
(extracorporeal membrane oxygenation)
6. Death

Adverse events tended to occur more frequently inthe remdesivir group with 11.6% than in the placebogroup 5.1% in the placebo group (p=0.12). Especially, thenumber of patients who discontinued due to acute lung

Figure 2: All-cause mortality at day 28 by the time of commencement

MED CHECK

August 2020/ Vol.6 No.18 ・ Page 41

injury/acute respiratory distress syndrome (ARDS) was

outline of this study is summarized as follows [3,11].

higher in the remdesivir group (7 patients, 4.5%) than in(Supplementary slides 18)

the placebo group (1 patient, 1.3%) (p=0.20). Acute lung

In a double-blind, randomised, placebo-controlled trial

injury and ARDS are the most important conditions thatof in patients The primary was the time to recovery byindicate severe COVID-19. While symptoms, including

day 28 post randomization. A preliminary analysis ofrespiratory symptoms, improved, more severe respiratory

the primary was performed when 1,063 patients were

symptoms were observed as adverse events in theassigned to the remdesivir group (541) or the placebo

remdesivir group. We cannot explain such contradicting

group (522) at a ratio of 1:1 and 606 recovery cases

results. (Supplementary slides 15,16)

were obtained. Total 538 patients in the remdesivir

Moreover, since remdesivir is an antiviral agent, thegroup and 521 in the placebo group were analyzed. As

virus should be eliminated faster in remdesivir group,a result, the median time to recovery was 11 days in the

but the opposite tendency was observed (though not a

remedesivir group and 15 days in the placebo group (ratesignificant difference). In particular, the virus elimination

ratio: 1.32, 95% confidence interval: 1.12-1.55, p<0.001) .

rate in survivors was 80.4% in the remdesivir group,

The death rate was 8.0% in the remdesivir-treated groupand 89.1% in the placebo group (8.7% higher) (p=0.16).

and 11.6% in the placebo group (hazard ratio: 0.70,

This is another phenomenon which is difficult to explain.

95%CI:0.47-1.04, p=0.059).

(Supplementary slides 17)(2) Critical appraisal of the interim analysis of the ACTT-1
ACTT-1 study led by the National Institute of Allergy

study

and Infectious Diseases (Supplementary slides 18-24)

The percentages of severity Level 7 (cases with invasive(1)Information summarized in the package insert andventilator or ECMO) was 23% in the remdesivir group andabstract [11]28% in the placebo group before the start of the study

Results of the interim analysis of a placebo-controlled(p=0.059). The difference was nearly significant, but there

clinical trial (registration number: NCT04280705) led by

was no other major difference in background factors.

the National Institute of Allergy and Infectious Diseases(Supplementary slides 19)(NIAID) were published online in NEJM on [11]. The

Comparing the improvement of clinical symptoms andFigure 3: All-cause mortality at day 28 by the time of commencement

In all subgroups by baseline severity except level 5, mortality risk was not different between Remdesivir arm ■ and placebo group □ . Only inthe subgroup of level 5 (receiving O2) mortality was extremely different. But in the subgroup of level 5, mortality of placebo group is unnaturallyhigh (almost the same as those of the subgroups 6 or 7 with greater baseline severity) and mortality of remdesivir group is unnaturally low(almost the same as that of the subgroup 4). It is very hard to find appropriate reasons for that Remdesivir is effective only in the level 5.

Page 42 ・ MED CHECK

August 2020/ Vol.6 No.18

Figure 4: Main results of SIMPLE trial

MV: mechanical ventilation or ECMO, AEs: Adverse events, SAE: Serious AEs. OR:odds ratio, 95% CI: 95% confidence interval
Cardiorespiratory SAEs include acute respiratory failure, respiratory failure, septic shock and acute respiratory distress syndrome.

overall survival rate by severity at the start of the study,

Level 5 subgroup (222 patients in the remdesivir groupno difference was observed in the subgroup of severity

and 199 patients in the placebo group) are available

levels 4 (patients not receiving oxygen), 6 (receiving highand it is confirmed that there is no difference in theflow oxygen or non-invasive mechanical ventilation) and 7

baseline characteristics, the results of this study(receiving mechanical ventilation or ECMO). Only in levelremains unreliable. The baseline characteristics include

5 (receiving oxygen), there was a difference (Figure 3).

distribution of oxgen partial pressure or oxygen(Supplementary slides 20-23)

saturation, distribution of laboratory data related toseverity, such as creatinine level and severity score such

Mortality in Level 5 (2.4%) was almost similar to that

as APACHE II, MEDS, SAPS II or SOFA. (Supplementaryof Level 4 (1.5%) in the remdesivir group, while mortality

slides 24)

in Level 5 (10.9%) in the placebo group was similar to

APACHE II = Acute Physiology and Chronic Healththat of severer cases, Levels 6 (15.2%) and 7 (11.3%),

Evaluation II

and was extremely high (Figure 3). (Supplementary slides

MEDS = Mortality in Emergency Department Sepsis Score

21-23)SAPS II = New Simplified Acute Physiology Score

If remdesivir is effective in preventing aggravation

SOFA = Sequential Organ Failure Assessmentof COVID-19, why was there a difference only in themortality of Level 5 between the remdesivir group and

SIMPLE Study: Five-day use is better than 10-day use

placebo group? Why was the difference so marked only

(Supplementary slides 25-29)

in the Level 5 subgroup? It is difficult to explain thisThe SIMPLE trial [13,14] only compares the use ofphenomenon. However, as in cases of other severity

remdesivir for 5 days (5-day group: 200 patients) withlevels, even if remdesivir is ineffective, this is possible

10-day use (10-day group: 197 patients). The study does

when some kind of major bias is at work. The most likely

not include placebo or drug-free groups. In the peer-

bias we can think of is biased allocation of 421 Level 5

reviewed article [13], the authors reported “At baseline,

patients at the beginning within the Level 5 subgroup.

patients randomly assigned to the 10-day group had

Unless details of baseline characteristics of thesignificantly worse clinical status than those assigned
MED CHECK

August 2020/ Vol.6 No.18 ・ Page 43

to the 5-day group (P = 0.02) . By day 14, a clinicalWuhan RCT is not cited as a basis for approval

improvement of 2 points or more on the ordinal scale

Despite that the approval was treated as a special

occurred in 64% of patients in the 5-day group and incase, examination for approval requires evidence. The

54% in the 10-day group. After adjustment for baseline

approval was granted based on the 3 studies [11-13]

clinical status, patients in the 10-day group had acited in the above-mentioned package insert. The

distribution in clinical status at day 14 that was similar

Wuhan RCT [10] was not included as an evidence for theto that among patients in the 5-day group (P = 0.14). ".

examination.

However, the total ratio of "death + invasive ventilator/

I n t h i s r e g a r d , Yo s h i d a , a c h i e f o f t h e D r u g

ECMO" on day 14 was 16.0% vs. 27.4%, which is better

Administration Division, reportedly has commented asin the 5-day group (unadjusted odds ratio 0.50, 95%CI:

follows. "We are aware of the Lancet article [10], but

0.31-0.82, p=0.006) . The ratio of severely ill patientsthe planned number of cases was not included (as the(high flow oxygen/ventilator/ECMO) at baseline was higher

pandemic has ended) and the efficacy could not havein the 10-day group (26.5% vs. 35.0%, odds ratio 0.67,

been adequately assessed. It is also mentioned in the

p=0.066) . Even if this is taken into consideration, we

examination report (which is scheduled to be published)”suspect that the conditions of patients in the 10-day[14].

group deteriorated. (Supplementary slides 27,28)

The Wuhan RCT [10] is a placebo-controlled double-

In addition, the ratio of mildly ill patients who wereblind trial and is far more valuable than the other two

not on supplementary oxygen at the baseline wastrials [12, 13] cited in the package insert. Both Wuhan

17.0% vs. 10.7% (p=0.07), and not significant between

RCT and ACTT-1 [10,11] should be meta-analyzed, andthe 2 groups. However, the ratio of patients who had

based on the results of the analysis, the effectivenessrecovered (survived and discharged or hospitalized without

should be assessed. However, if one of them is excluded,

supplementary oxygen) was 70% vs. 58.9% (odds ratio

it is impossible to make fair assessment. We strongly

1.63, p=0.02), which was significantly lower in the 10-day

suspect that the reviewers had already decided togroup (Figure 4). (Supplementary slides 27,28)“approve” before assessment, and used only the results

It was reported in the NEJM that the adjusted risk ofthat would support their decision.

the median of time to recovery (probably hazard ratio) was
0.79 (95%CI: 0.61-1.01). P-value was not indicated, but
the upper limit of 95% CI was 1.01, very close to 1.0,
implying nearly significant difference.

Be careful of adverse reactions
As an adverse react ion, agg ravat ion of renal
dysfunction should be especially noted. It is stated in

Essentially, if a substance is effective, long-term use

the package insert [3] that "renal dysfunction may beshould yield better results than short-term use. However,aggravated by the accumulation of additives in thein the SIMPLE study, the opposite dose-response

renal tubules" and "non-clinical studies have shown that

relationship was confirmed.

remdesivir has an effect on the renal tubules".

Moreover, the number of serious adverse events in the

In addition to renal damage, liver damage, hypotension

10-day group was about 2 times higher than in the 5-day(lowered blood pressure) , nausea, vomiting, sweating,group (p=0.003). Especially, the total number of serious

tremor, various blood test values, blood chemistry test

adverse events related to respiratory failure (ARDS, acutevalues, etc. are also listed. However, these can be therespiratory failure, septic shock) was 2.4 times higher

symptoms of COVID-19, and it is difficult to distinguish(p=0.003). (Figure 4) (Supplementary slides 28,29)

whether they are caused by aggravation of the disease orThis result also contradicts with the results of theharm of remdesivir.

ACTT-1 study [11] and is consistent with the Wuhan
RCT [10], which showed tendency that acute respiratory

Conducting placebo-controlled trials would become

disorders occurred more frequently in the remdesivir

increasingly difficultgroup.

An editorial of the British Medical Journal [15] states"A drug with potential—don’t waste time on uncontrolled
observations". Another British journal, the Nature [16]Page 44 ・ MED CHECK

August 2020/ Vol.6 No.18

also calls for "clinical trials must be as robustly designed

References

as possible.... move quickly to larger, collaborative

1) Notes on the use of Remdesivir, Director of Drug Evaluation and Management

trials.." They both emphasize the importance of placebocontrolled large-scale trials.
However, as explained at the beginning of this article,
there is no animal experiment that showed reductionof mortality or symptom improvement if it were usedby imitating the human clinical use: antivirals arecommenced after the symptoms appeared. We suspectthat appropriate animal studies have not been publishedbecause an experiment which had imitated humanuse may have shown the substance was ineffective.
Moreover, in a large-scale trial which involved 6000
patients and was funded by the manufacturer (Gilead),there was no placebo group, or even a remdesivir-freecontrol group. It is suspected that the manufacturer wasafraid that if an appropriate trial was conducted, thesubstance would be proven ineffective.

Division, Pharmaceutical and Life Health Bureau, Ministry of Health, Labor andWelfare (in Japanese)
https://www.mhlw.go.jp/content/000628073.pdf
2) NIH Clinical Trial Shows Remdesivir Accelerates Recovery fromAdvanced
COVID-19 https://www.niaid.nih.gov/news-events/nih-clinical-trial-showsremdesivir-accelerates-recovery-advanced-covid-19 (April 29, 2020)
3) Package insert of Remdesivir (Veklury for injection 100mg) (in Japanese) May
2020
4) Warren TK, Jordan R, Lo MK, et al. Therapeutic efficacy of the small molecule
GS-5734 against Ebola virus in rhesus monkeys. Nature 2016;531:381-5. PMID:
269342205) Lo MK, Feldmann F, Gary JM, et al. Remdesivir (GS-5734) protects African
green monkeys from Nipah virus challenge. Sci Transl Med2019;11:eaau9242.
PMID:31142680
6) de Wit E, Feldmann F, Cronin J, et al. Prophylactic and therapeutic remdesivir(GS-5734) treatment in the rhesus macaque model of MERS-CoV infection. Proc
Natl Acad Sci USA2020;117:6771-6. PMID:32054787
7) Sheahan TP, Sims AC, Graham RL. Et al. Broad-spectrum antiviral GS-5734 inhibits
both epidemic and zoonotic 4 coronaviruses. Sci Transl Med. 2017 Jun 28; 9(396):
eaal3653. PMID: 28659436
8) Williamson BN, Feldmann F, Schwarz B, et al. Clinical benefit of remdesivir inrhesus macaques infected with SARS-CoV-2. bioRxiv 2020.04.15.043166.
[Preprint.] doi:10.1101/2020.04.15.043166
9) Mulangu S et al. A Randomized, Controlled Trial of Ebola Virus Disease
Therapeutics 2019: 381 (24): 2293-2303. PMID:31774950
10) Wang Y, Zhang D, Du G, et al. Remdesivir in adults with severe COVID-19:
a randomised, double-blind, placebo-controlled, multicentre trial. .Lancet.

Conclusion
Neither animal experiments with remdesivir-infectedanimals nor the clinical trials by the manufacturer were
properly designed to prove efficacy and safety. Therefore,
the possibility of demonstrating the efficacy and safetyof the drug against COVID-19 seems extremely slim in
the future.
Firstly, in an experiment with COVID-19 infectedanimals, in which remdesivir is administered after
symptom onset, remdesivir must be proven to reduce
death. Then, a placebo-controlled trial of appropriate
scale should be conducted in humans under strict
management to prove efficacy and safety. Unless2020 May 16;395(10236): 1569-1578. Epub 2020 Apr 29.PMID: 32423584
SupplementaryAppendix:
11) Beigel JH, Tomashek KM, Dodd LE et al. (ACTT-1 Study Group Members)
Remdesivir for the Treatment of Covid-19 - Preliminary Report..N Engl J Med.
2020 May 22. Online ahead of print. PMID: 32445440 https://www.nejm.org/doi/
pdf/10.1056/NEJMoa2007764?articleTools=true
12) Grein J, Ohmagari N, Shin D et. al. Compassionate use of Remdesivir for patientswith severe Covid-19. N Engl J Med, April 10 (online), 2020．PMID: 32275812
https://www.nejm.org/doi/pdf/10.1056/NEJMoa2007016?articleTools=true
13) Goldman JD, Lye DCB, Hui DS et al (GS-US-540-5773 Investigators) Remdesivirfor 5 or 10 Days in Patients with Severe Covid-19. N Engl J Med. 2020 May 27..
Online ahead of print. PMID: 32459919
14) Gilead Announces Results From Phase 3 Trial of Investigational Antiviral
Remdesivir in Patients With Severe COVID-19 https://www.gilead.com/news-andpress/press-room/press-releases/2020/4/gilead-announces-results-from-phase-3trial -of-investigational-antiviral-remdesivir-in-patients-with-severe-covid-19
15) Ferner RE. Adrug with potential—don’t waste time on uncontrolled observations
BMJ 2020; 369 doi: https://doi.org/10.1136/bmj.m1610 (Published 22 April
2020)16) Nature Editorial. Coronavirus drugs trials need scale and collaboration. Nature
2020: 581: 14 May: 120. https://www.nature.com/articles/d41586-020-01391-9

these are realized, we should consider that remdesivir
is ineffective, and thus it should not be used for thetreatment of COVID-19.

MED CHECK

August 2020/ Vol.6 No.18 ・ Page 45

New Products

Favipiravir (trade name: Avigan Tablet)

Most probably no efficacy on COVID-19, and harmful
Translated and revised from Med Check(in Japanese) Jul 2020 ; 20 (90):80-82
Med Check Editorial Team

Summary● Favipiravir (trade name: Avigan) was proven ineffective for treatment of seasonal influenza, but has been approved
and stockpiled in Japan for almost unlikely novel influenza.
● Placebo-controlled trials of appropriate scale against novel coronavirus infection (COVID-19) have not been
published in any country so far. In Japan, only an observational study has been conducted, with which efficacy
cannot be evaluated. According to the very recent press release, no statistically significant improvement wasobserved in a Japanese small open trial comparing a favipiravir group with a standard care group for 6 days.
● In a Chinese open study which mainly involved non-severe cases and compared favipiravir with other drugs, thedrug did not reduce the primary endpoint, “recovery at Day 7” nor mortality.
● The structure and action of favipiravir is very similar to those of an anticancer drug, 5-fluorouracil. In observational
studies, the dose used in treating COVID-19 was 2 to 5 times higher than the no-observed-adverse-effect level(NOAEL) in animals, which is approximately half the toxic dose in mice or rats, or approximately the same dose indogs when converted into blood exposure (Area under the curve). Moreover, for some people, it was estimated thatblood level will reach lethal level in rats or dogs. Hence it is very dangerous.
● No experiments have been conducted on animals infected with SARS-CoV-2.
Conclusion: Most likely ineffective and harmful. Should not be used.

Keywords:
RCT, open label trial, lethal dose, toxic dose, NOAELIntroduction

Avigan is an anticancer drug analog

As of July 14, the Japanese government has not given

The structure of Avigan is very similar to an anti-

approval for the use of favipiravir (trade name Avigan)cancer drug, 5-fluorouracil (5-FU) (Figure) , and its

in COVID-19, as the efficacy and safety have not been

pharmacological action and toxicity are also similar. 5-FU

confirmed.

is an analog of substances (uracil, adenine etc: generally

Avigan was developed for influenza, but was confirmed

termed as nucleobases) needed for the replication of RNA

to be ineffective against seasonal influenza. However, itessential for protein synthesis and cell division, and is

was approved only because it has a different mechanism

classified as an “antimetabolite”.

of action from other anti-influenza virus agents [1]. Here

Avigan and remdesivir (page 39) are called "RNA-we describe our analysis based on the data which we

dependent RNA polymerase inhibitors". They are also

have as of now.

antimetabolites because they are analog of uracil,
guanine (favipiravir) or adenine (remdesivir), which are
the sources of RNA, and interfere with RNA synthesis

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August 2020/ Vol.6 No.18

Figure : Similarity of favipiravir and anti-cancer agent 5-FU

(metabolism) just like 5-FU.

decrease in hematopoietic ability, and the exposure

Influenza virus and coronavirus are viruses that have

(AUC0-t) for Avigan at this dose was 1490 μg・h/mL (average

only RNA in their genes. Avigan and remdesivir interfereof both sexes). When administered twice a day, AUC0-t iswith the replication of viral RNA. Just like 5-FU inhibitsroughly equivalent to AUC0-12 (half-day exposure). At thenot only RNA synthesis in cancer cells but also RNA

average dose in the observational study (3600 mg on thereplication in normal human cells, Avigan damages

first day, 800 mg twice a day after the second day, used fornormal cells as well.

10.4 days in total) [3], the half-day exposure at Day 6 is

In addition, as these antiviral agents stop normal RNA

estimated to be 739, almost half of the toxic exposure in

replication in the middle, they could prevent viral load

rats. Decreased hematopoiesis is toxicity unique to anti-

increase temporarily. However, it has no efficacy tocancer drugs, and myelosuppression reduces the number

eliminate the virus from infected cells. Therefore, it canof white blood cells, making infections more likely. The

be easily inferred that they have only limited therapeutic

lethal exposure of 200 mg/kg in rats (male 3430 μg・h/

effect, such as that they are not effective at small dose.

mL) is only 5 times higher than the clinical exposure.

In general, the blood concentration of a drug varies
Clinical dose is a toxic dose, which is lethal in somegreatly from person to person, and it can be 5 to 10

peopletimes higher than the mean concentration in some

We examined the Summary Basis of Approval (SBA) of

people. This means that in some people, the clinicalAvigan for the approval as an anti-influenza virus agent

dose might reach the lethal dose of animals. In fact, in a[2].

patient with slow metabolism of Avigan, and extremely

In a 1-month study in rats, 1 out of 15 males

high blood concentration, after administration of 1600

died at 200 mg/kg due to decreased bone marrow

mg on the first day and 400 mg twice a day after thehematopoiesis and circulatory disorders such as,

second day, AUC 0-12 reached 1743 μg・h/mL. If thispulmonary edema (congestion and edema of the lung) .

patient uses the dose for COVID-19, the AUC would

Moreover, 80 mg/kg is the toxic dose that causes

reach 3486 μg・h/mL and be estimated to exceed the
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August 2020/ Vol.6 No.18 ・ Page 47

Table 1：Estimation of half-day human exposure (AUC0-12) of unchanged Avigan when it is used for COVID-19
at day 6 when the level may be steady state.

*a: from the package insert of Avigan for influenza.
*b: Interim report of observational study of favipiravir for COVID-19
http://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_favip_0526.pdf*c: 738.64=553.98 × 1600/1200,*d: 739 ≒ 738.64(*c)*e: Note：τ = dosing interval . AUC τ ≒ AUC0-12 as Avigan was given twice a day in animal toxicity tests.
*f: 1743 μg・h/mL is the measured data of a person among 6 healthy males in JP111 trial inSBA*g: 3486=1743 × 800/400. If combined with the data of 8 healthy persons, these data show that one in 14 person
reached extremely high concentration equivalent to the lethal dose for rats as shown in the Table 2.

Table 2：Prediction of toxicity risk in humans from the toxicokinetic data of favipiravir*a：HED: Human Equivalent dose. To convert animal dose (mg/kg) to HED for a person weighing 60 kg, divide the animal dose (mg/kg) by the conversion
factors for mouse, rat and dog (12.3, 6.2 and1.8) respectively.
*b*c: Rtio of the human half-day exposure (estimated value = 739*b, 3486*c) to the animal half-day exposure for NOAEL, toxic dose, and lethal dose of eachanimal. For example, ratio of exposure of extreme person was 1.0 times. It was calculated by 3486 (extreme person's AUC)/3430 (AUC of rats' lethal dose).

lethal AUC of the male rats (3430 μg・h/mL) (Table 1, 2).

bacterial infection are observed. The lethal dose in dogs

In a 1-month dog study, some dogs in the 300 mg/

is almost the same as the AUC of some patients who tend

kg group were moribund in one week, and the doseto have extremely high blood concentration (AUC: 3486

was reduced to 100 mg/kg, but later 2 out of 5 died

μg・h/mL). At 30 mg/kg (AUC=659 μg・h/mL), which is(average 150 mg/kg, AUC = 3836 μg・h/mL). Pathologically,

below the clinical dose, signs of decreased hematopoiesis

hemorrhagic necrosis of the lungs, inflammation, and(reticulocyte count) was already observed.

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August 2020/ Vol.6 No.18

In an experiment with juvenile dogs (8 weeks old,which was then given to 35 patients (after group) .

equivalent to 2-11 years old in humans), 9 out of 12 dogs

The improvement rate at Day 14 showed remarkabledied after administration of favipiravir at 60 mg/kg fordifference: 62% in the Kaletra group and 91% in theone month. AUC was 1285 μg·h/mL, which was 60% of

Avigan group. However, the patients in the Avigan groupthe average exposure in humans and much lower than

was younger (43 years old vs. 49 years old) , had lessthat of people with extremely high blood contraction.

fever (63% vs. 82%, p=0.11) and had more lymphocyte

The causes of death are pneumonia, thrombosis in the

counts (1.5 vs. 1.2 × 109/L, p=0.06), suggesting favorable

lungs and liver, pulmonary infarction, and degeneration/

background in the Avigan group. Therefore, it may be

necrosis of the cardiac papillary muscles.

hard to conclude that the improvement observed was theIt has been reported that COVID-19 causes not only

effect of Avigan.

pneumonia but also thrombosis in various parts of the
body. If pneumonia and/or thrombosis occur while using(2) Comparison with other antiviral agents [5]:Avigan, it would be impossible to distinguish whether

The second report is a published un-reviewed paper inthey are caused by the virus or are adverse reactions to

medRxive. It is a randomised controlled trial using anti-

the drug.

influenza virus drug (umifenovir: brand name Arbidol) as a

In addition, 30 mg/kg is considered to be a non-toxic

control.

level in 8-week-old dogs, but when the dose is doubled to

The primary endpoint, "improvement at Day 7" was60 mg/kg, most of the dogs died. This suggests that the

61% in the Avigan group compared with 52% in the

drug is a dangerous substance with a very narrow safetycontrol group, which was not a significant difference

margin. (See Table 2 for details).

(p=0.14). This study reported that since the number ofTeratogenic effect of Avigan is well known and is, of

severely ill patients was higher in the Avigan group, if

course, a serious harm. However, as mentioned above

they are excluded and only moderately ill patients were

the fact that the toxic and lethal doses are used incompared, significantly higher rate of improvement

treating COVID-19 in humans is more important point

was observed in the Avigan group. In addition, relief ofin considering whether it is appropriate to use the drug

fever and cough, which were secondary endpoints, werein humans. It should also be noted that no experimentsignificantly faster in the Avigan group (both p<0.0001).

has confirmed that Avigan improves the symptoms in

There was no death in either group. The proportion ofanimals infected with SARS-CoV-2.

patients with elevated uric acid level was significantly
higher in the Avigan group (14% vs. 2.5%, p=0.001).

No evidence of efficacy against COVID-19

If the above two trials were meta-analyzed, ignoring

Currently, 3 comparative trials of Avigan for COVID-19

the background, there was no significant difference inhave been published [4-6]. Two of them are non-blinded,

the effect (p=0.17). Moreover, there were more young

and the remaining one is the only placebo-controlled

patients in the Avigan group, and the difference wasblind trial, but is a small-scale trial with less than 10

nearly significant (p=0.065).

patients in each group. Therefore, it is impossible toassess the efficacy and safety of Avigan with these 3(3) Placebo-controlled small-scale study [6]:trials. On July 10 2020, researchers of a small open

The third is an open label trial without peer-review

label trial on asymptomatic or mildly ill patients within which Avigan (9 patients) was compared with an anti-

COVID-19 [7] issued a press release on their results

influenza virus agent baloxavir (Xofluza:10 patients)

which did not show any significant efficacy [8].

and placebo (10 patients). The percentages of patients
who turned viral negative after 14-day treatment were

(1) Report on comparison with an anti-HIV agent:

77%, 70%, and 100% in the favipiravir, baloxavir, andThis is an open-label, nonrandomised, before-after

control group respectively. The effect on improving

controlled study comparing an anti-HIV agent (lopinavir/

symptoms was not observed: the medians of time fromritonavir, trade name Kaletra) which was given to 45

randomization to clinical improvement was 14, 14 andpatients at first (before group) and favipiravir (Avigan)

15 days, respectively.

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August 2020/ Vol.6 No.18 ・ Page 49

(4) An open label comparative trial done in Japan [7]:This is a multicenter, open-label, randomized trial ofthen, it should be considered that Avigan is "ineffective"
and should not be used.

favipiravir in asymptomatic and minimally symptomaticpatients infected with SARS-CoV-2 to evaluate viral load
reduction. They compared immediate favipiravir arm

Referenceswith delayed arm. Favipiravir was commenced on day 1

1) Avigan: Examination Report by PMDA

for immediate arm (n=36) and on day 6 for delayed arm2) Summary of application dosier for "Avigan" (pharmacology, toxicity, kinetics,(n=33) [7]. According to the press release [8], the primary

3) Fujita Medical University. Interim Report of Favipiravir observational study.

clinical overview)

outcome, the percentages of patients who turned viral

http://www.kansensho.or.jp/uploads/files/topics/2019ncov/covid19_favip_0526.

negative after 6 days (before the start of delayed arm) were

4) Cai Q, Yang M, Liu D et al Experimental Treatment with Favipiravir for COVID-19:

66.7% in immediate arm and 56.1 % in the delayed arm:
adjusted odds ratio was 1.42 (95% CI:0.76-2.26, p=0.269).

Even if efficacy of viral reduction in asymptomatic andpdf
An Open-LabelControl Study：Engineering Available online 18 March 2020
https://www.sciencedirect.com/science/article/pii/S2095809920300631?via% 3D
ihub5) ChenC, Zhang Y, Huang J et al.：Favipiravir versus Arbidol for COVID-19: A
Randomized Clinical Trial

minimally symptomatic patients infected with SARS-

https://www.medrxiv.org/content/10.1101/2020.03.17.20037432v4 https://

CoV-2 were proved, it cannot be said that favipiravir is

6) Lou Y, Liu L, Qiu Y：Clinical Outcomes and Plasma Concentrations of Baloxavir

useful for the treatment of COVID-19, because of the
toxicity of favipiravir described in this article.

www.medrxiv.org/content/10.1101/2020.03.17.20037432v4.full.pdf
Marboxil and Favipiravir in COVID-19 Patients: an Exploratory Randomized,
Controlled Trial：2020.04.29.
https://www.medrxiv.org/content/10.1101/2020.04.29.20085761v1 https://www.medrxiv.org/content/10.1101/2020.04.29.20085761v1.full.p7) Protocol of Favipiravir for SARS-CoV-infected patients

No placebo-controlled trials designed for COVID-19
In Japan, there is no plan to conduct a placebocontrolled trial aiming at full-scale approval as of July
2020. Only 2 observational studies in which Avigan
is used for all patients and 2 trials with un-blindedtreatment group as a control are designed wereregistered. One is a trial funded by a manufacturer(Fujifilm Toyama Chemical) (96 cases), and the other is theone described above.
Globally, there are 2 placebo-controlled Phase III trials(256 cases and 100 cases each) and 2 placebo-controlled

Phase II trials are planned, but enrolment has not been
carried out yet according to the Clinical trial.gov.
Conclusion
The clinical dose of Avigan is the dose at which
toxicity, including death for some people, was observedin animals, and the toxic symptoms are similar to those of
COVID-19. It is extremely difficult to distinguish whether
they are symptoms of the disease or toxic signs of the
drug. There is no experiment using Avigan on SARSCoV-2 infected animals. In Japan, even the manufacturer
has no plan to conduct a placebo-controlled trial.
It should be confirmed in an animal study thatthe drug reduces mortality in infected animals after
symptom onset. Then, a placebo-controlled study of an
appropriate scale should be conducted in humans understrict management to prove safety and efficacy. Until

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August 2020/ Vol.6 No.18

https://rctportal.niph.go.jp/en/detail?trial_id=jRCTs041190120
8) Press release: About the final report of favipiravir (Avigan) specific clinical study (inJapanese). https://www.fujita-hu.ac.jp/news/j93sdv0000006eya.html

M
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HECK

2020

Vol.6

No.18

Editor-in-Chief: HAMA, Rokuro (MD)
Deputy Editor: KIMOTO, Yasusuke (MD)Managing Editor: SAKAGUCHI, Keiko
Editorial Staff: NAKANISHI,Takeaki(Pharmacist); TAKANO, Yoshihiko(MD[pediatrician]/Pharmacist) ; YANAGI, Motokazu (MD); YASUDA, Yoshinobu(Pharmacist)
Translators: NAKAMURA, Akari ; TAKAMACHI, Koji

Advisors:HONZAWA,Tatsuo (MD[GP]); KIM,Mieko(Pharmacist);
MUKAI, Junji (Pharmacist); SEGAWA,Yusuke; SUMIDA, Sachie(MD[Dermatologist]); TERAOKA, Akio (Pharmacist) ; TOI, Chihiro(Pharmacist); UMEDA, Tadahito (MD[psychiatrist])
Editorial Officers: SAKAGUCHI, Keiko
Production Team: UMEKI, Yukiko; SAKAGUCHI, Keiko; MATSUMOTO, Koji
Information Technology (IT): KURODA, Akira (Systems Engineer)
Copyright NPOJIP
www.npojip.org
Registered address:#602, Katsuyama 2-14-8, Tennouji-ku,
Osaka JAPAN 543-0043
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August 2020/ Vol.6 No.18 ・ Page 51