Remdesivir (trade name: Veklury)
Most likely ineffective for COVID-19
MedCheck Editorial team
July 17 2020

Animal experiment(1)：If enough remdesivir is administered before the onset of4) Warren TK et al. Nature 2016;531:381-5.
symptoms it reduced mortality. No test in which it wasadministered after the onset of symptoms was done. d3 after inoculation
d5 after inoculation
onset of symptom
RNA is appearedin plasmad3～10mg
d310mg,d4～3mg
d2～3mgd0 ：Ebola virus was inoculated i.m.

controld3 after inoculation
RNA is appearedin plasma

d0～3mgd210mg,d3～3mg

2

Animal experiment(2)：5) Lo MK et al. Sci Transl Med2019;11:eaau9242.

If remdesivir is administered one day after the inoculation and before the onsetof symptoms, it reduced mortality. However no animal test was done in whichremdesivir is administered after the onset of clinical symptoms.
Symptom onset in control group was d3
All died within 8 days
without remdesivir

Remdesivir
24 hr after
inoculation

3

Animal experiment(3)：6) de Wit E et al. Proc Natl Acad Sci 2020;117:6771-6.

inoculation

Prophylactic: remdesivir was started at one day before inoculation
Therapeutic: remdesivir was started at 12 hrs after inoculation

Remdesivir start
one day before and12 hrs after inoculation

D1: Symptom onset
Control one day before 12 hrs aftercontrol
Remdesivir start
12 hrs after inoculation
Remdesivir start one
day before inoculation
4

Animal experiment(4)：7) Sheahan TP et al. Transl Med. 2017:9(396):eaal3653.

Prophylactic: remdesivir was started at one day before inoculation
Therapeutic: remdesivir was started at one day after inoculation
No experiments was done in which remdesivir was commenced after onset of disease.
Symptom onset is at d2controlcontrol

WBP: whole-body plethysmography (pulmonary function test)

Mice were treated with 25mg/kg remdesivir b.i.d 50mg/kg/d⇒HED=4mg/kg/d (240mg/d for 60kg BW)
5

Animal experiment(5)：8) Williamson BN et al. bioRxiv 2020.04.15.043166. [Preprint.]

Therapeutic: This is rather prophylactic because administration started before onset of symptoms

Start 12hrs after
Symptom onset

Radiograph scores
ControlRemdesivir

These effects are not remarkable.
6Remdesivir is not a remedy for Ebola virus infection (1)9) Mulangu S et al. NEJM 2019: 381 (24): 2293-2303.

Remdesivir is the least effective among 4 agents including
3 monoclonal antibodies for reduction of mortality
Mortality ５０％

５３％

３５％

３４％

7

Remdesivir is not a remedy for Ebola virus infection (2)Less effective for reduction of mortality than any othermonoclonal antibodies (more than doubled mortality)
モノクローナル抗体１
Monoclonalantibody 1

33.5

モノクローナル抗体２
Monoclonalantibody 2

35.1

モノクローナル抗体３Monoclonal
antibody 349.7

Remdesivir
レムデシビル

53.1

Odds ratio of mortality: 2.25 (95%CI: 1.44, 3.51, p=0.0003) vs monoclonal antibody 12.10（95%CI: 1.37, 3.23, p=0.0007) vs monoclonal antibody 2010

20

30

40

5060

Mortality （％）

Compared with 2 kinds of monoclonal antibody, remdesivir increases
mortality by more than 2-fold from Ebola virus infection: This indicatesthat Remdesivir is not a remedy for Ebola virus infection.

8

Time course of special approval of Remdesivir
date

Source/facilities

contentsApril 23April 29

STAT(a news site in US)
Wuhan RCTApril 29

NIH (US） Press release

April 29

Gilead Sciences

Published screen shot of the summary of theLancet [10] disclosed by WHO.
Online publication at Lancet [10]:A placebo controlled RCT
Main results of ACTT [2] by National Institute ofAllergy and Infectious Diseases (NIAID) ：NCT04280705）
Press release of SIMPLE trial

May 1

FDA (US)EUA: Emergency Use Authorization

May 4

Gilead Sciences

Submitted approval application to MHLWMay 7

Held by web-conference

May 7Japanese Advisory Panelfor pharmaceuticals
Japanese MHLWMay 22

ACTT by NIAID

May 27SIMPLE trial

Online publication at NEJM [11]A placebo controlled RCT
Online publication at NEJM [12]Comparison of 5 day- and 10 day-treatment

Special approval of remdesivir first in the wold

9

WuhanRCT(1)10) Wang Y et al .Lancet.
2020: 395(10236):
1569-1578.

10

Wuhan RCT(2): Main baseline characteristics

No difference

11

Wuhan RCT(3) Different baseline characteristics＜＞

P=0.037

Others are not different
12Wuhan RCT(4) Day 28 mortality by early or late commencement of remdesivir
Mortality at d28
d9, d10d11, d12

プラセボ
Placebo
Overall
レムデシビルRemdesivir
プラセボ
Placebo
Start at d9 or d10
レムデシビルRemdesivir
プラセボ
Placebo
Start at d11, or d12
レムデシビルRemdesivir
全体

13

P=0.8211日以後 10日以前に開始 に開始

14
15
11

P=0.56

10
140

510

Mortality at day 28 (%)

15

P=0.51
13

Wuhan RCT (5)：Kaplan-Meier curve of clinical improvement(ITT）
Figure 2: Time to clinical improvement in the intention-to-treat
Population: Adjusted hazard ratio for randomisation stratification
was 1・25 (95% CI: 0・88–1・78). *Including deaths before day 28
as right censored at day 28, the number of patients withoutclinical improvement was still included in the number at risk.

(A) Start early (at d9 or d10)
median days to clinical improvement
18 days vs 23 days
Hazard ratio: 1.52; 95%CI：0.95 - 2.43
(B) Start late (at d11 or d12)(B)
median days to clinical improvement
23 days vs 24 days
Hazard ratio: 1.07; 95% CI, 0.63 - 1.83

14

Wuhan RCT(6)：Adverse Events(AEs)

Most serious adverse events were not differentSerious
AdverseEvents15

Wuhan RCT(7)：Eventsleading todiscontinuation

SeriousAdverse
EventsRespiratory failure/ARDS: p=0.20

Non-significant increase of respiratory
failure/ARDS leading to discontinuation
was observed in Remdesivir group.
Respiratory failure and ARDS are main
symptoms of COVID-19.

What does this mean? 16

Wuhan RCT(8)：Accumulated rate of undetectable viral RNA in upper
respiratory tract specimen in viral positive population
Viral load
Upper respiratory tract

lower respiratory tract

Undetectable viral RNA in
Remdesivir group was nearly
10 % lower than control groupespecially in the survivours.
What does this mean?

17ACTT trial （1）11) Beigel JH et al. NEJM. 2020 May 22.

BACKGROUND: Although several therapeutic agents have been evaluated for the treatment ofcoronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.
METHODS: We conducted a double-blind, randomized, placebo-controlled trial of intravenous
remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement.
Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followedby 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was
the time to recovery, defined by either discharge from the hospital or hospitalization forinfectioncontrol purposes only.
RESULTS: A total of 1063 patients underwent randomization. The data and safety monitoring board
recommended early unblinding of the results on the basis of findings from an analysis that showed
shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538assigned to remdesivir and 521 to placebo) with data available after randomization indicated thatthose who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio forrecovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days
were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04).
Serious adverse events were reported for 114 of the 541 patients in the remdesivir group whounderwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent
randomization (27.0%).
CONCLUSIONS: Remdesivir was superior to placebo in shortening the time to recovery in adults
hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National
Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number,
18
NCT04280705.)
Adjusted HR for death= 0.74(95%CI： 0.50 to 1.10)

ACTT trial（2） Baseline characteristics

Level 7:
Receiving invasive
mechanical ventilationor ECMO

23% vs 28%
P=0.05919

ACTT trial（3） Fig. 2 Kaplan-Meier estimates of cumulative
recoveries by baseline severity.
Level ４．Not receiving oxygen
Overall
No difference

５．Receiving oxygen

Significant difference
only in this subgroup

６．High flow oxygen or
noninvasive ventilator

7．Invasive ventilator
or ECMONo difference

No difference

20

ACTT trial（4）4. No O2

5. O2

6.High O2

7．Invasive
MV/ECMO

2.9% vs 11%

21

ACTT trial（5） Kaplan-Meier Estimate of Survival by baseline

Overall

Level ４．Not receiving oxgen

It is very unnatural that there
are almost no difference ofmortality in placebo groups,
because the baseline severity
is greatly different.

５．Receiving oxygen

６．High flow oxygen or
noninvasive ventilator

7．Invasive ventilator
or ECMO

22

Unnatural: mortality of placebo group is not different between subgroup 5 and more severe subgroup 6/7

ACTT trial （6） ：Comparison of day 14 mortality by baseline severity（Kaplan-Meier estimate ）
16

15.2

14.7 15.0

14.1

1412.7Mortality (%)

1211.3

10.9

108

6.7

64
20

1.5

2.5

2.0

2.4

4.Withoutflow
4. No O2 O2 5.Receiving
5 O2 O2 6.High6. High
O2 O2 7.Invasive
7. InvasiveMV/ECMO
MV/ECMO
Rmdesivir
Placebo
Total
Remdesivir

In all subgroups by baseline severity except level 5, mortality risk was not different between
Remdesivir arm■ and placebo group□. Only in the 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) andmortality of remdesivir group is unnaturally low (almost the same as that of the subgroup 4).
It is very hard to find appropriate reasons why Remdesivir was effective only in the level 5.
23

ACTT trial （7） Summary: Critical appraisal of preliminary report
1. There was no significant difference between remdesivir arm and placebo arm except one,
proportion of the level 7 of the baseline severity which was non-significantly different (p=0.059).
2. Comparing the improvement of clinical symptoms and the overall survival by baseline severity,
there was no difference between both groups in the sub groups of levels 4, 6 and 7. Difference
was only observed in the subgroup of level 5 (receiving oxygen).
3. At the level 5, all-cause mortality of the placebo group was unnaturally high, and there was no
significant difference from that at the levels 6 and 7.
4. On the other hand, all-cause mortality of the Remdesivir group in the level 5 was unnaturally
low, and there was almost no difference from that at the level 4.
5. If Remdesivir group and placebo group of the subgroup level 5 were combined, all-cause
mortality of the level 5 was at the mid point between levels 4 and 6 or 7 and this is very natural
biologically.
6. Taken together, it is doubtful whether 421 patients in the subgroup of level 5 wasappropriately allocated at randomization.
7. Unless details of baseline characteristics of the Level 5 subgroup (222 patients in theremdesivir group and 199 patients in the placebo group) are available and it is confirmed that
there is no difference in the baseline characteristics, the results of this study remains unreliable.
The baseline characteristics include distribution of oxygen partial pressure or oxygen saturation,
distribution of laboratory data related to severity, such as creatinine level and severity scoresuch as APACHE II, MEDS, SAPS II or SOFA.
APACHE II = Acute Physiology and Chronic Health Evaluation II, MEDS = Mortality in Emergency Department Sepsis Score,
SAPS II = New Simplified Acute Physiology Score, SOFA = Sequential Organ Failure Assessment.
24

SIMPLE trial （1）13)Goldman JD et al NEJM 2020 May 27

25

SIMPLE trial（2）26SIMPLE trial （3） Results
1.death + 2. invasive MV/ECMO
5-day vs 10-day
16.0％ vs 27.4％
OR=0.50 (95%CI：0.31-0.82)
p=0.006
10-day vs 5-day
OR= 1.98 (1.28, 3.23)
5-day group improved better
than 10-day group.
Moreover, 5 day group diedor become deteriorated
less than 10-day group.

P=0.021

According to theJapanese label
Better outcome
in 5-day group
27

SIMPLE trial （4） Results (2)： Main results
5-day group is significantly superior to 10-day group10-day vs 5-day

OR (95%CI), Pvalue
7.Discharge alive
O2
O2 O2+ 6.+6.No
Without

53.8
64.5
18.8
19.5

Others (3,4,5)0.64(0.43,0.96), p=0.030

0.95(0.58,1.57), p=0.8610-day

1.Death +2.Invasive MV

27.4

1.98(1.21,3.23), p=0.006

5-day

16.0
34.5

Any serious AEs

1.98 (1.27, 3.11), p=0.003

21.0

CardiorespiratorySAEs

19.3

2.42 (1.33, 4.40), p=0.003

9.00

10

20

30

40

50

Proportion (%)

60

70
28

SIMPLE trial (5)Adverse events(AEs) And
Serious AEs (SAEs)
Any SAEs double
10-day vs 5-day
OR=2.0 (1.3, 3.1),
p=0.003

Cardiorespiratory SAEs
10-day vs 5-day
OR=2.4 (1.3-4.4),
p=0.003

SAEs were 2-fold more reported in 10-day group than 5-day group.
Especially cardiorespiratory SAE （ARDS, (acute) respiratory failure,and septic shock) were 2.4-fold more frequently reported (p=0.003).
29