sars-cov-2 and covid-19

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


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


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


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


• 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


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


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


• 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)


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


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


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


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)


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


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)


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)





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


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





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)


Outcomes 10-day Remdesivir(n = 193)



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)





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)





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



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



0

20

40

60

80

100

5 7 11 14 28

Clin

ical

Impr

ovem

ent (

%)


10-Day Remdesivir

Effect of Remdesivir on Clinical Status in Patients With Moderate COVID-19: End Point Results


• 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


Adverse Events 10-day Remdesivir(n = 811)



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


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


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


Remdesivir for 5 or 10 Days in Patients with Severe Covid-19: Baseline Characteristics


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


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


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


• 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


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


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


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


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%)


Severe COVID-19: Baseline Characteristics


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.


Severe COVID-19: Results


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


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 (%

)


Remdesivir Placebo

Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results, Clinical Improvement Rates


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

(%)


Remdesivir Placebo

Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results, Mortality


6

10

15

5

9

13

0

5

10

15

20

Day 7 Day 14 Day 28

Deat

hs (%

)


Remdesivir Placebo

Remdesivir Randomized Controlled Trial in Adults with Severe COVID-19: Results


• 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


Severe COVID-19: Authors’ Conclusions


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


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


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


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.


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.


Compassionate Use of Remdesivir for Patients with Severe Covid-19: Safety


• 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


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


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


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


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


Lesion Score in Lung Tissue (each lung rated 0 to 4)

Favorable Lung Histology in Animals Receiving Remdesivir


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


• 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


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


Clinical Benefit of Remdesivir in Rhesus Macaques Infected with SARS-CoV-2: Study Design


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


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


• 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


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.”

sars-cov-2 and covid-19

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