sars-cov-2 and covid-19
TRANSCRIPT
SARS-CoV-2 and COVID-19
David H. Spach, MDProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington
Last Updated: November 2, 2020
Gretchen Snoeyenbos Newman, MDSenior FellowDivision of Infectious DiseasesUniversity of Washington
Treatment: Remdesivir (Veklury)
Sarah A. McGuffin, MDSenior FellowDivision of Infectious DiseasesUniversity of Washington
Remdesivir (Veklury)formerly GS-5734
Remdesivir
Chemical structure drawing by Kenton Unruh, Ph
Remdesivir
Remdesivir (Veklury)
Source: Tchesnokov EP, et al. Viruses 2019;11(4). pii: E326
• Adenosine nucleotide analogue prodrug• Broad-spectrum against several RNA viruses• Requires phosphorylation for activation triphosphate form• Competes for incorporation with adenosine triphosphate (ATP)• Does not act as classic chain terminator• Possible delayed chain termination (similar to entecavir)• Selectivity of ATP versus Remdesivir- Ebola RNA-dependent RNA polymerase ∼ 4:1- RSV RNA-dependent RNA polymerase ∼ 3:1- Human mitochondrial RNA polymerase ∼ 500:1
Remdesivir (Veklury)
• Class: Adenosine nucleotide analogue prodrug
• Approval Status: FDA approved for COVID-19 on October 22, 2020
• Mechanism: - Competes for incorporation with adenosine triphosphate (ATP)- Does not act as classic chain terminator- Possible delayed chain termination (similar to entecavir)
• Dose (Intravenous): Duration based on Disease Severity200 mg on day 1, followed by 100 mg daily for 5-10 days
• Adverse Events: - Elevated LFTs (typically 2-3x normal), unclear significance- GI symptoms (nausea, vomiting, gastroparesis, rectal bleeding)
Remdesivir (GS-5734) IC50 and MERS-CoV
Source: Sheahan TP, et al. Sci Transl Med. 2017;9(396). pii: eaal3653.
GS-5734 (µM)
% In
hibi
tion
120
0.0001
100
80
60
40
20
0
0.001 0.01 0.1 1 10 100
IC50=0.03 µM
Percent Inhibition of MERS-CoV in 2B4 Cells
Measuring Antiviral Efficacy
• EC50 – Effective Concentration- The concentration of an antiviral agent at which virus
replication is inhibited by 50% in a cell-based assay- Conceptually similar to the MIC (minimum inhibitory
concentration) for an antibacterial agent
• CC50 – Cytotoxic Concentration- Concentration of an antiviral agent required to kill 50% of cells
in uninfected culture
• SI – Selectivity Index- Ratio between the CC50 and EC50 (CC50/EC50)- A higher number signals a theoretically more safe and
effective drug
Antiviral Drugs Effective Concentration 50 (EC50)
Drug Concentration (semilog scale)
% R
espo
nse
100
0
50
0.1 1001.0 10
EC50
High Potency Medium Potency Low Potency
EC50 = The concentration of an antiviral agent at which virus replication is inhibited by 50% in a cell-based assay
Remdesivir EC50 and SARS-CoV-2
Source: Wang TP, et al. Cell Res. 2020;30:269-71.
Remdesivir [µM]
% I
nhib
ition
120
90
60
30
0
-30
0.1 1 10 100
EC50=0.77
Activity Against SARS-CoV-2 (2019-CoV): Vero E6 Cells)
Remdesivir EC50 and SARS-CoV-2
Source: Wang TP, et al. Cell Res. 2020;30:269-71.
Remdesivir [µM]
% I
nhib
itio
n
120
90
60
30
0
-30
0.1 1 10 100
EC50=0.77 120
90
60
30
0
-30
% Cytotoxicity
CC >100
Activity Against SARS-CoV-2 (2019-CoV): Vero E6 Cells)
Remdesivir for the Treatment of Covid-19ACTT-1—Final Report (Multinational)
Published Data — Randomized, Double-blind, Placebo-controlled Trial
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Remdesivir for the Treatment of Covid-19 (ACTT-1):
Study Design
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Study Design
• Background: A multicenter, double-blind, randomized, placebo-controlled trial of
intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower
respiratory tract involvement during February 21-April 19, 2020.
• Location: 73 sites in the United States, Europe, Asia, and Mexico
• Inclusion Criteria (n = 1062)- Age ≥18 years
- Hospitalized
- Lab confirmed SARS-CoV-2 (PCR or other public health assay) <72 hours of enrollment
- One or more of the following:
- Pulmonary infiltrates on chest imaging
- Rales or crackles on exam AND SpO2 ≤94% on room air
- Requiring mechanical ventilation or supplementary oxygen
• Exclusion Criteria- Pregnant or breastfeeding
- AST/ALT >5x ULN
- eGFR <30
Remdesivir for the Treatment of Covid-19 (ACTT-1):
Study Design
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Study Design• Primary Outcome: Time to recovery (discharge or no longer requiring supplemental O2)*
• Secondary outcomes:- Mortality at days 14 and 28
- Grade 3 or 4 adverse events, or severe adverse events
* This primary outcome was changed from an earlier primary outcome of recovery at day 15 as
evolving clinical information showed the prolonged course of COVID-19 disease. None of the
preliminary data was known at the time of this decision
Remdesivir for the Treatment of Covid-19 (ACTT-1): Study Design
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Remdesivir200 mg loading dose on day 1, then 100 mg maintenance dose daily on days 2-10
(n = 541)
PlaceboVolume equivalent loading and maintenance doses
(n = 521)
or
Arms and Interventions (1:1 randomization stratified by disease severity and site)
*If the hospital had a written policy or guideline, participants could receive other experimental or off-label treatments for COVID-19. Otherwise, other specific treatments were prohibited from study day 1 through day 29.
Remdesivir for the Treatment of Covid-19 (ACTT-1): Safety
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
• In the remdesivir arm, 98.2% received the drug as assigned- 36 patients discontinued due to an adverse event
• In the placebo arm, 99.2% completed infusions as assigned- 36 patients discontinued due to an adverse event
Remdesivir for the Treatment of Covid-19 (ACTT-1): Baseline Characteristics
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Baseline CharacteristicsRemdesivir
(n = 541)Placebo(n = 521)
Age, years (mean ± SD) 58.6 ± 14.6 59.2 ± 15.4
Male, n (%) 352 (65.1) 332 (63.7)
Coexisting conditions, n/total (%)
Hypertension 269/532 (50.6) 264/519 (50.9)
Obesity 242/531 (45.6) 234/518 (45.2)
Type 2 Diabetes 164/532 (30.8) 158/519 (30.4)
Duration of symptoms prior to randomization, days (median, IQR) 9 (6 - 12) 9 (7 - 13)
Remdesivir for the Treatment of Covid-19 (ACTT-1): Baseline Characteristics
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Baseline CharacteristicsRemdesivir
(n = 541)Placebo(n = 522)
Illness score on ordinal scale n (%)
4. Hospitalized, not receiving supplemental O2
75 (13.9) 63 (12.1)
5. Hospitalized, receiving supplemental O2
232 (42.9) 203 (39.0)
6. Hospitalized, non-invasive ventilation or high-flow O2 devices 95 (17.6) 98 (18.8)
7. Hospitalized, invasive mechanical ventilation, or ECMO 131 (24.2) 154 (29.6)
Baseline score missing 8 (1.5) 3 (0.6)
Remdesivir for the Treatment of Covid-19 (ACTT-1): Results
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
• Median time to recovery was significantly different: - Remdesivir 10 days (95% confidence interval [CI], 9 to 11)- Placebo 15 days (95% CI, 13 to 18) in those who received
placebo- Rate ratio for recovery, 1.29; 95% CI, 1.12 to 1.49; P<0.001)
Remdesivir for the Treatment of Covid-19 (ACTT-1): Results, Mortality by Days 15 and 29 (Kaplan-Meier Estimate)
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
6.7
1.6
7.7
11.9
2.9
13.0
0
5
10
15
20
Overall Mild-Moderate Severe
Mor
talit
y (K
apla
n-M
eier
Est
imat
e)
Baseline Disease Severity
Remdesivir Placebo
Remdesivir for the Treatment of Covid-19 (ACTT-1): Results, Days to Recovery
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
10
5
11
15
5
18
0
5
10
15
20
25
Overall Mild-Moderate Severe
Days
to R
ecov
ery
(Med
ian)
Baseline Disease Severity
Remdesivir Placebo
P<0.001
Remdesivir for the Treatment of Covid-19 (ACTT-1): Morality Results
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Outcome* *Hazard Ratio (95% CI)
Mortality (Overall) 0.73 (0.52 – 1.03)
Mortality, by ordinal score at baseline
4 0.82 (0.17 – 4.07)
5 0.30 (0.14 – 0.64)
6 1.02 (0.54 – 1.91)
7 1.13 (0.67 – 1.89)
*Hazard ratio based on comparison of remdesivir versus placebo
Remdesivir for the Treatment of Covid-19: Authors’ Conclusions
Source: Beigel JH, et al. N Engl J Med. October 8, 2020. [Online ahead of print]
Conclusions: “Our data show that remdesivir was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection.”
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19 (Multinational)
Published Data — Randomized open-label trial
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Design (1)
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Study Design• Background: Randomized, open-label trial of hospitalized patients with moderate COVID-
19 pneumonia between March 15, 2020 and May 20, 2020
• Location: 105 hospitals in the United States, Europe, and Asia
• Inclusion Criteria (n = 596 randomized; 584 began study):- SARS-CoV-2 infection confirmed by PCR ≤4 days before randomization- Admission to hospital for medical care for COVID-19- SpO2 >94% on room air at screening and radiographic evidence of pulmonary infiltrates- Age ≥18 years
• Exclusion Criteria:- Use of other agents with actual or possible antiviral activity against SARS-CoV- Creatinine clearance <50 mL/min, liver function tests >5x upper limit of normal- Pregnant or breastfeeding
• Primary Endpoint:- Clinical status on day 11 on a 7-point ordinal scale
• Exploratory endpoints:- Duration of hospitalization, duration of oxygen therapy, all-cause mortality- Follow-up through May 20, 2020
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Randomization
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Remdesivir 5-Day Course*: 200 mg IV on day 1, then 100 mg IV daily (n = 197 randomized; n =193 enrolled)
Remdesivir 10-Day Course*: 200 mg IV on day 1, then 100 mg IV daily(n = 199 randomized: n = 191 enrolled)
or
* Patients who had sufficiently improved could be discharged from the hospital before finishing their assigned course of treatment.
Standard Care(n = 200 randomized; n = 200 enrolled)
or
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Baseline Characteristics (1)
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Baseline Characteristics 10-day Remdesivir(n = 193)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Age, median (IQR), y 56 (45-66) 58 (48-66) 57 (45-66)
Male, n (%) 118 (61) 114 (60) 125 (63)
Race, No./total (%)
White 107/188 (57) 109/186 (59) 112/193 (58)
Black 37/188 (20) 35/186 (19) 27/193 (14)
Asian 31/188 (16) 34/186 (18) 37/193 (19)
Other 13/188 (7) 8/186 (4) 17/193 (9)
Hispanic or Latino ethnicity, No./total (%) 42/186 (23) 25/187 (13) 34/186 (18)
Body mass index, median (IQR) 28 (25-32)) 27 (24-30) 27 (24-31)
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Baseline Characteristics (2)
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Baseline Characteristics 10-day Remdesivir(n = 193)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Coexisting conditions, No. (%)
Cardiovascular Disease 111 (58) 111 (58) 107 (54) 107 (54)
Hypertension 85 (44) 82 (43) 81 (41)
Diabetes 85 (44) 71 (37) 76 (38)
Asthma 31 (16) 22 (12) 28 (14)
Concomitant medications, No. (%)
Steroids 29 (15) 33 (17) 38 (19)
Hydroxychloroquine/chloroquine 22 (11) 16 (8) 89 (45)
Lopinavir-ritonavir 11 (6) 10 (5) 43 (22)
Tocilizumab 1 (1) 1 (1) 10 (5)
Azithromycin 41 (21) 35 (18) 62 (31)
Effect of Remdesivir vs Standard Care on Clinical Status at 11 Days in Patients With Moderate COVID-19
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
7-Point Ordinal Scale
1: Death
2: Hospitalized, requiring invasive mechanical ventilation or extracorporealmembrane oxygenation
3: Hospitalized, requiring noninvasive ventilation or high-flow oxygen
4: Hospitalized, requiring low-flow supplemental oxygen
5: Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care
6: Hospitalized, not requiring supplemental oxygen or ongoing medical care
7: Not hospitalized
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Baseline Characteristics
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Baseline Characteristics 10-day Remdesivir(n = 193)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Day 1 clinical status on 7-point scale, No. (%)
3: Hospitalized, requiring noninvasive ventilation or high-flow oxygen 1 (1) 2 (1) 2 (1)
4: Hospitalized, requiring low-flow supplemental oxygen 23 (12) 29 (15) 36 (18)
5: Hospitalized, not requiring supplemental oxygen but requiring ongoing medical care
163 (84) 160 (84) 160 (80)
6: Hospitalized, not requiringsupplemental oxygen or ongoing medical care 6 (3) 0 2 (1)
Duration of hospitalization before first dose remdesivir, median (IQR), days
2 (1-3) 2 (1-3) 2 (1-3)
Duration of symptoms before first dose remdesivir, median (IQR), days
8 (5-11) 8 (5-11) 9 (6-11)
Effect of Remdesivir on Clinical Status in Patients With
Moderate COVID-19: Results (1)
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Outcomes 10-day Remdesivir(n = 193)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Day 11 clinical status, No. (%)
1: Death 2 (1) 0 4 (2)
2: Hospitalized, requiring invasive mechanical
ventilation or extracorporeal
membrane oxygenation
1 (1) 0 4 (2)
3: Hospitalized, requiring noninvasive
ventilation or high-flow oxygen0 5 (3) 7 (4)
4: Hospitalized, requiring low-flow
supplemental oxygen12 (6) 7 (4) 11 (6)
5: Hospitalized, not requiring supplemental
oxygen but requiring ongoing medical care44 (23) 38 (20) 46 (23)
6: Hospitalized, not requiring supplemental
oxygen or ongoing medical care9 (5) 7 (4) 8 (4)
7: Not hospitalized 125 (65) 134 (70) 120 (60)
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Results (2)
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Outcomes 10-day Remdesivir(n = 193)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Primary end point: difference in clinical status vs standard care, odds ratio (95% CI)*
1.65 (1.09-2.48) [Reference]
P value 0.18 0.02
Clinical Improvement, No. (%) ‡
Day 5 72 (37) 61 (32) 66 (33)
Day 7 92 (48) 106 (56) 94 (47)
Day 11 126 (65) 134 (70) 121 (61)
Difference in percentage vs standard care at day 11 (95% CI)
4.8 (−5.0 to 14.4) 9.7 (0.1-19.1)
Day 14 148 (77) 146 (76) 135 (68)
Day 28 174 (90) 171 (90) 166 (83)
* The proportional odds assumption was not met for the 10-day remdesivir group comparison‡ An improvement of at least 2 points from baseline on 7-point ordinal scale.
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Results (3)
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Outcomes 10-day Remdesivir(n = 193)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Recovery, No. (%) *
Day 5 74 (38) 67 (35) 71 (36)
Day 7 94 (49) 114 (60) 101 (51)
Day 11 132 (68) 141 (74) 128 (64)
Difference in percentage vs standard care at day 11 (95% CI)
4.4 (−5.0 to 13.8) 9.8 (0.3-19.0)
Day 14 153 (79) 153 (80) 145 (73)
Day 28 178 (92) 175 (92) 170 (85)
* An improvement from a baseline score of 2 to 5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7.
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Clinical Improvement
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
* An improvement from a baseline score of 2 to 5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7.
37
48
65
77
90
32
56
7076
90
33
47
6168
83
0
20
40
60
80
100
5 7 11 14 28
Clin
ical
Impr
ovem
ent (
%)
Days after Study Inclusion
10-Day Remdesivir 5-day Remdesivir Placebo
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Clinical Improvement
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
* An improvement from a baseline score of 2 to 5 to a score of 6 or 7 or from a baseline score of 6 to a score of 7.
0
20
40
60
80
100
5 7 11 14 28
Clin
ical
Impr
ovem
ent (
%)
Days after Study Inclusion
10-Day Remdesivir
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: End Point Results
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
• Primary End Point: Clinical Status at day 11- Patients randomized to the 5-day remdesivir group had significantly
higher odds of a better clinical status on the 7-point ordinal scale compared with those randomized to standard care (odds ratio, 1.65; 95%CI, 1.09-2.48)
- The difference in clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not statistically significant (P = .18 P = .02)
• Exploratory End Points- No significant differences between the remdesivir groups and
standard care for any of the exploratory end points (duration of oxygen therapy or hospitalization, mortality)
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Adverse Events
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Adverse Events 10-day Remdesivir(n = 811)
5-day Remdesivir(n = 191)
Standard Care(n = 200)
Any adverse event 56 (45-66) 58 (48-66) 57 (45-66)
Any grade ≥ 3 adverse event 118 (61) 114 (60) 125 (63)
Any serious adverse event 10 (5) 9 (5) 18 (9)
Discontinuation of treatment because of adverse event
8 (4) 4 (2) NA
Death* 3 (2) 2 (1) 4 (2)
Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: Authors’ Conclusions
Source: Spinner CD, et al. JAMA. 2020;324:1048-57.
Conclusions: “Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a
statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients
randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard
care, but the difference was of uncertain clinical importance. ”
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19 (Multinational)
Published Data — Randomized, Open-Label Trial
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Study Design
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Study Design
• Background: Randomized, open-label, phase 3 trial – ongoing at time of publication
• Location: 55 sites in US, Italy, Spain, Germany, Hong Kong, Singapore, South Korea, Taiwan during March 6 to March 22, 2020
• Inclusion Criteria (n = 397)- Age ≥12 years- SARS-CoV-2 infection confirmed by PCR within 4 days prior to randomization- Radiographic evidence of pulmonary infiltrates- SpO2 ≤94% on room air OR receiving supplemental O2
• Exclusion Criteria- Mechanical ventilation or ECMO- Multiorgan failure- AST/ALT >5x the upper limit of normal- Creatinine clearance <50 mL/min- Concurrent treatment with other agents directed at COVID-19
• Primary outcome- Clinical improvement by 2 points on a 7-point ordinal scale on day 14
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Study Design
Remdesivir 5 days200 mg IV on day 1 followed by 100 mg IV for 4 days
(n = 200)
Remdesivir 10 days200 mg IV on day 1 followed by 100 mg IV for 9 days
(n = 197)
or
Arms and Interventions (1:1 randomization*)
*Patients were not stratified by disease severity
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Baseline Characteristics
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Baseline Characteristics*5-Day Group
(n = 200)
10-Day Group
(n = 197)
Age, years – median (IQR) 61 (50 – 69) 62 (50 – 71)
Male, n (%) 120 (60) 133 (68)
Coexisting conditions
Hypertension, n (%) 100 (50) 98 (50)
Diabetes, n (%) 47 (24) 43 (22)
BMI, median (IQR) 29 (25 – 34) 29 (25 – 33)
Duration of symptoms prior to remdesivir, days – median (IQR) 8 (5 – 11) 9 (6 – 12)
* There were no significant differences between groups
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Baseline Characteristics
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Baseline Clinical Status*5-Day Group
(n = 200)
10-Day Group
(n = 197)
Score on ordinal scale†2. Invasive mechanical ventilation or ECMO‡
4 (2) 9 (5)
3. Non-invasive ventilation or high-flow O2
49 (24) 60 (30)
4. Low-flow supplemental O2 113 (56) 107 (54)
5. Hospitalized, not requiring supplemental O2
34 (17) 21 (11)
*Ordinal scale also included: 1. Death, 6. Hospitalized, not requiring ongoing medical care other than remdesiviradministration, and 7. Not hospitalized†Patients in the 10-day group had significantly worse clinical status (P = 0.02)‡Requirement for invasive mechanical ventilation or ECMO developed between screening and randomization
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Results
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Outcome 5-day group(n = 200)
10-Day Group(n = 197)
Clinical Improvement, n (%)*
Day 5 33 (16) 29 (15
Day 7 71 (36) 54 (27)
Day 11 116 (58) 97 (49)
Day 14† 129 (64) 107 (54)
*Defined as increase of at least 2 points from baseline on ordinal scale. No statistically significant differences between groups were observed.†Primary outcome of the study
Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Results
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
• Similar duration of hospitalization between the groups• Discharge rates by duration of symptoms was different- 62% for fewer than 10 days of symptoms - 49% for 10 or more days of symptoms
• Serious adverse events differed between the two groups after adjusting for baseline clinical status- 21% in the 5-day group- 35% in the 10-day group
Remdesivir for 5 or 10 Days in Patients with Severe Covid-
19: Authors’ Conclusions
Source: Goldman JD, et al. N Engl J Med. 2020 May 27. [Epub ahead of print]
Conclusions: “In patients with severe Covid-19 not requiring
mechanical ventilation, our trial did not show a significant
difference between a 5-day course and a 10-day course of
remdesivir.”
Remdesivir in Adults with Severe COVID-19: A
Randomized, Double-blind Trial (China)
Published Data — Randomized, double-blind, placebo-controlled trial
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Design
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Study Design
• Background: A randomized, double-blind, placebo-controlled, multicenter trial of remdesivir in adults with severe COVID-19 conducted between February 6, 2020 and March 12, 2020
• Location: 10 hospitals in Hubei, China
• Inclusion Criteria (intended n = 453; actual n = 237)
- Age ≥18 years- PCR positive test for SARS-CoV-2 infection- Pneumonia on chest imaging- SpO2 ≤94% on room air or PaO2:FiO2 <300mmHg- Symptom onset ≤12 days prior to enrollment
• Exclusion Criteria
- Pregnant or breastfeeding- Cirrhosis or AST/ALT > 5x upper limit of normal- GFR <30mL/min per 1.73 m² or renal replacement therapy- Treatment with another investigational drug in the 30 days before screening
• Duration of follow up
- 28 days or until discharge
Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Study Design
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Remdesivir*200 mg IV on day 1, followed by 100 mg IV on days 2–10 as single daily infusion
(n = 158)
Placebo*Equivalent volume given on day 1 and on days 2–10 as single daily infusions
(n = 78)
or
Arms and Interventions (2:1 randomization)
* Patients in both groups were allowed to receive concomitant lopinavir-ritonavir, interferons, and/or corticosteroids as part of standard care
2x
1x
Remdesivir Randomized Controlled Trial in Adults with
Severe COVID-19: Baseline Characteristics
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Baseline Characteristics* Remdesivir(n = 158)
Placebo(n = 78)
Age, years, median (IQR) 66.0 (57.0–73.0) 64.0 (53.0–70.0)
Male, n (%) 89 (56%) 51 (65%)
Comorbidities, n (%) 112 (71%) 55 (71%)
Hypertension 72 (46%) 30 (38%)
Diabetes 40 (25%) 16 (21%)
Coronary Heart Disease 15 (9%) 2 (3%)
Adjunctive Therapies
Receiving interferon alfa-2b 29 (18%) 15 (19%)
Receiving lopinavir–ritonavir 27 (17%) 15 (19%)
Antibiotic treatment 121 (77%) 63 (81%)
Corticosteroids therapy 60 (38%) 31 (40%)
Remdesivir Randomized Controlled Trial in Adults with
Severe COVID-19: Baseline Characteristics
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Six-Category Scale on Day 1*Remdesivir
(n = 158)Placebo(n = 78)
2—hospital admission, not requiring supplemental oxygen
0 3 (4%)
3—hospital admission, requiring supplemental oxygen
129 (82%) 65 (83%)
4—hospital admission, requiring high-flow nasal cannula or non-invasive mechanical ventilation
28 (18%) 9 (12%)
5—hospital admission, requiring extracorporeal membrane oxygenation or invasive mechanical
ventilation
0 1 (1%)
6—death 1 (1%) 0
* Scale used to define clinical status: 1 = discharged or having reached discharge criteria (defined as clinical
recovery [e.g. normalization of pyrexia, respiratory rate, O2 saturation >94% on room air, and relief of cough], all
maintained for at least 72 hours). Note clinical status 1 (discharged) not applicable for this baseline table.
Remdesivir Randomized Controlled Trial in Adults with
Severe COVID-19: Results
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Outcome Remdesivir(n = 158)
Placebo(n = 78)
Difference (95% CI)
Time to clinical
improvement, days
21.0 (13.0 to 28.0) 23.0 (15.0 to 28.0) 1.23 (0.87 to 1.75)
Day 28 mortality 22 (14%) 10 (13%) 1.1% (–8.1 to 10.3)
Duration of invasive
mechanical ventilation, days
7.0 (4.0 to 16.0) 15.5 (6.0 to 21.0) –4.0 (–14.0 to 2.0)
Duration of oxygen support,
days
19.0 (11.0 to 30.0) 21.0 (14.0 to 30.5) –2.0 (–6.0 to 1.0)
Duration of hospital stay,
days
25.0 (16.0 to 38.0) 24.0 (18.0 to 36.0) 0.0 (–4.0 to 4.0)
Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results, Undetectable Viral RNA
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
18.3
28.2
40.5
50.4 62.671.0
74.8 75.6
20.0
29.238.5
49.2
69.275.4
81.5 83.1
0
20
40
60
80
100
0 3 5 7 10 14 21 28
Accu
mul
ated
Rat
e of
Un
dete
ctab
le V
iral R
NA (%
)
Days after Study Inclusion
Remdesivir Placebo
Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results, Clinical Improvement Rates
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
3
27
65
3
23
58
0
20
40
60
80
Day 7 Day 14 Day 28
Clin
ical I
mpr
ovem
ent R
ates
(%)
Days after Study Inclusion
Remdesivir Placebo
Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results, Mortality
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
6
10
15
5
9
13
0
5
10
15
20
Day 7 Day 14 Day 28
Deat
hs (%
)
Days after Study Inclusion
Remdesivir Placebo
Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
• Authors were unable to enroll nearly half the planned number of participants due to resolution of the COVID-19 outbreak in Hubei, China
• There were no differences in the rates of:- Time to clearance of virus- Clinical benefits- Mortality
Remdesivir Randomized Controlled Trial in Adults with
Severe COVID-19: Authors’ Conclusions
Source: Wang Y, et al. Lancet. 2020;395:1569-78.
Interpretation: “In this study of adult patients admitted to
hospital for severe COVID-19, remdesivir was not associated with
statistically significant clinical benefits. However, the numerical
reduction in time to clinical improvement in those treated earlier
requires confirmation in larger studies.”
Compassionate Use of Remdesivir for Patients with Severe COVID-19 (International)
Published Data — Compassionate Use, Case Series
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Design
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.
Study Design
• Background: Case series of 61 patients diagnosed with severe COVID-19 infection who received remdesivir through compassionate use from January 25, 2020 to March 7, 2020 in multiple international sites
• Evaluation: Incidence of key clinical endpoints (multiple)
• Inclusion Criteria (enrolled, n = 61; final analysis, n =53)- PCR positive for SARS-CoV-2 in nasopharyngeal sample- SpO2 ≤94% on room air, or need for oxygen support- Creatinine clearance >30 mL per minute- AST and ALT <5x the upper limit of normal
• Exclusion Criteria- Use of other investigational agent for COVID-19
• Planned Treatment- Remdesivir: 200 mg IV loading dose on day 1, then 100 mg IV daily x 9 days (total 10 days)- Standard supportive care
• Duration of follow up- 28 days
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Baseline Characteristics
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.
Baseline Characteristics* Invasive Ventilation(n = 34)
Non-Invasive O2 Support(n = 19)
Age (median, IQR, years) 67 (56 - 72) 53 (41-68)
Male, n (%) 27 (79) 13 (68)
Coexisting conditions, n (%) 25 (74) 11 (58)
Hypertension 9 (26) 4 (21)
Diabetes 8 (24) 1 (5)
Hyperlipidemia 6 (18) 0 (0)
Asthma 5 (15) 1 (5)
Duration of symptoms prior to remdesivir (median, IQR, days) 11 (8 – 15) 13 (10 – 14)
*Of the 61 patients approved for compassionate use remdesivir, 7 were excluded from analysis due to lack of baseline information and 1 was excluded due to an error in remdesivir dosing
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Baseline Oxygen Support
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.
Baseline Characteristics* Invasive Ventilation(n = 34)
Non-invasive O2 Support(n = 19)
Oxygen Support Category, n (%)
Invasive mechanical ventilation 30 (88) NA
Extracorporeal membrane oxygenation (ECMO) 4 (12) NA
Noninvasive positive-pressure ventilation NA 2 (11)
High-flow oxygen NA 5 (26)
Low-flow oxygen NA 10 (53)
Ambient air NA 2 (11)
*Of the 61 patients approved for compassionate use remdesivir, 7 were excluded from analysis due to lack of baseline information and 1 was excluded due to an error in remdesivir dosing
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Results (Overall)
Source: Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.Reproduced with permission Massachusetts Medical Society. © 2020 Massachusetts Medical Society.
Clinical improvement defined as decrease of ≥2 points on 6-point ordinal scale or live discharge
Note: in this analysis shown below, death was not considered a treatment failure and the cumulative incidence of clinical improvement was 84% when. When death considered failure, the cumulative incidence of clinical improvement was 74%
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Results (Baseline O2 Support)
Source: Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.Reproduced with permission Massachusetts Medical Society. © 2020 Massachusetts Medical Society.
Clinical improvement defined as decrease of ≥2 points on 6-point ordinal scale or live discharge
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Results (Baseline O2 Support)
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.Reproduced with permission Massachusetts Medical Society. © 2020 Massachusetts Medical Society.
Clinical improvement defined as decrease of ≥2 points on 6-point ordinal scale or live discharge
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Safety
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.
• 32 patients (60%) reported adverse events most commonly:- Increased hepatic enzymes- Diarrhea- Rash- Renal impairment- Hypotension
• 4 patients (8%) discontinued remdesivir:- 1 due to worsened renal failure- 1 due to multiorgan failure- 2 due to elevated aminotransferase levels
Compassionate Use of Remdesivir for Patients with Severe Covid-19: Authors’ Conclusions
Source: Grein J, et al. N Engl J Med. 2020:382:2327-36.
Conclusions: “In this cohort of patients hospitalized for severe Covid-19 who were treated with compassionate-use remdesivir, clinical improvement was observed in 36 of 53 patients (68%). Measurement of efficacy will require ongoing randomized, placebo- controlled trials of remdesivir therapy.”
Remdesivir Prophylaxis and Therapy in Rhesus Macaque Model of MERS-CoV Infection
Published Data — Animal Model
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
Remdesivir Therapy and Prophylaxis of
in Animal Model of MERS-CoV Infection
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
TreatmentRemdesivir 5 mg/kg IV 12hrs after
inoculation and 1x/day until day 6
(n = 6)
Vehicle ControlPlacebo IV given 12 hrs after or 24 hrs
prior to inoculation
(n = 6)
Study Design
• Background: Three-arm study testing efficacy
of remdesivir prophylaxis and treatment of
MERS-CoV in rhesus macaque model
• Primary Endpoints:- Clinical status
- Virologic clearance
- Chest radiograph data
- Lung histopathology
• Study Design:- Three arms (treatment, prophylaxis, control)
- Animals monitored clinically and with CXR
- All animals sacrificed on day 6
- All animals necropsied
ProphylaxisRemdesivir 5 mg/kg IV 24 hrs prior to
inoculation and 1x/day until day 6
(n = 6)
Remdesivir Therapy and Prophylaxis of in Animal Model of MERS-CoV Infection
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
Inoculation
Days after Inoculation1 2 3 4 5 6-1 0
Prophylactic Remdesivir
Therapeutic Remdesivir
MERS-CoV
Clinical Exam
Reduction of Lung Tissue MERS-CoV Load in Remdesivir-Treated Macaques
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
Viral Loads in Respiratory Tracts of Necropsy Samples in Six Lung Lobes
Favorable Lung Histology Scores in Animals Receiving Prophylactic Remdesivir for MERS-CoV Infection
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
Lesion Score in Lung Tissue (each lung rated 0 to 4)
Favorable Lung Histology in Animals Receiving Remdesivir
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
Vehicle control Prophylactic remdesivir Therapeutic remdesivir
Representative H&E Image of Lung Tissue, magnification 100x
Staining of lung sample with polyclonal α-MERS-CoV antibody, magnification 200x
Remedesivir Therapy and Prophylaxis of MERS-CoV in Animal Model: Conclusions
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
• Monkeys given remdesivir either prophylactically or as treatment had better clinical scores and fewer infiltrates on chest radiographs than controls
• There was lower viral load of MERS-CoV in respiratory tract of monkeys given prophylactic remdesivir
• Lung examination revealed gross (visible) lesions covering less of the lung in animals treated with remdesivir and no gross lung lesions in those given prophylactic remdesivir
• Histologic evaluation showed normal tissue in animals treated prophylactically and less severe pneumonia in those given treatment dosing
Remedesivir Therapy and Prophylaxis of MERS-CoV in Animal Model: Authors’ Conclusions
Source: de Wit E, et al. Proc Natl Acad Sci U S A. 2020;117:6771-6.
Conclusions: “The data presented here support testing of the efficacy of remdesivir treatment in the context of a MERS clinical trial. It may also be considered for a wider range of coronaviruses, including the currently emerging novel coronavirus 2019-nCoV.”
Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2
Published Data — Animal Model
Source: Williamson BN, et al. Nature. 2020;585:273-6.
Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2: Study Design
Vehicle Solution (Control Group)Vehicle solution IV 12 hours after inoculation and then daily through day 6(n = 6)
Remdesivir Group10 mg/kg IV 12 hours after inoculation, then 5 mg/kg daily through day 6(n = 6)
Study Design
• Background: Blinded, placebo-controlled study to evaluate the effect of remdesivir on SARS-CoV-2 infection using a rhesus macaque model
• Primary Endpoints:- Clinical status- Viral load and infectious virus measure- Chest radiograph data- Lung histopathology
• Study Design:- Two arms: (1) treatment, (2) control- Animals monitored clinically and with CXR- All animals sacrificed on day 7- All animals necropsied
Source: Williamson BN, et al. Nature. 2020;585:273-6.
Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2: Study Design
Source: Williamson BN, et al. Nature. 2020;585:273-6.
InoculationDays after Inoculation
1 2 3 4 5 6-1 0
SARS-CoV-2
Clinical Exam
RemdesivirVehicle Solution
7
Loading dose
Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2: Results, Clinical Benefit
Source: Williamson BN, et al. Nature. 2020;585:273-6.
1.0 1.5 1.0 0.8 0.5 0.52.0
8.0
12.010.5
12.3
8.3 7.7
8.7
0
5
10
15
20
0 1 2 3 4 5 6 7
Aver
age
Daily
Clin
ical S
core
Days Post Inoculation
Remdesivir (n = 6) Vehicle Solution (n = 6)
P<0.001 on days 1, 6, 7P<0.0001 on days 2, 3, 4, 5
Clinical scores: based on weight, temperature, pulse oximetry, blood pressure, respiration rate, and chest radiographs
Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2: Results
Source: Williamson BN, et al. Nature. 2020;585:273-6.
• Remdesivir metabolite was detected throughout the lungs
• Clinical, radiologic, and pathologic disease scores were lower in remdesivir treated animals than in controls
• Viral load and infectious virus in the nose, throat, and rectum were not different between remdesivir and control groups through the duration of the study
Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2: Authors’ Conclusions
Source: Williamson BN, et al. Nature. 2020;585:273-6.
Conclusions: “Thus, treatment with remdesivir initiated early during infection had a clinical benefit in rhesus macaques infected with SARS-CoV-2. Although the rhesus macaque model does not represent the severe disease observed in some patients with COVID-19, our data support the early initiation of remdesivirtreatment in patients with COVID-19 to prevent progression to pneumonia.”