the presentation starts with a quick overview of COVID-19 followed by Remdesivir focused clinical trials assessment and evaluation for the treatment of Corona virus

1. Farah Al Souheil, pharmD, RPh
Lebanese International University, SOP

2. E V I D E N C E B A S E D A P P R O A C H
REMDESIVIR IN THE
MANAGEMENT OF COVID-19
Lebanese International University
School of Pharmacy
Advanced Pharmacy Practice Experience
Internal Medicine Rotation
June9,2020

3. OUTLINE
ReferencesAbbreviations
Remdesivir
Assessment
Treatment
• Treatment
approach
• Emerging
treatment
Quick
introduction
about COVID-
19
3

4. ABOUT COVID-19
Primary cases presented as
pneumonia of unknown etiology
Can infect the neurological,
respiratory, enteric, and hepatic
system
Can be isolated from birds &
mammals (camels, bats, mice,
dogs & cats
The virus is sensitive to
ultraviolet light and heat
Functionally inactivated with
ethanol (60%), ether (75%), and
chlorine-containing disinfectants
Lu R, Zhao X, Li J, et al.: Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet. 2020, 395:565-
574. 10.1016/S0140-6736(20)30251-8
4

5. FACTS & NUMBERS
Novel Coronavirus Pneumonia Emergency Response Epidemiology Team. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases
(COVID-19) in China [in Chinese]. Zhonghua Liu Xing Bing Xue Za Zhi. 2020 Feb 17;41(2):145-51
There are two
major types (or
strains) of the
virus (L and S)
The L type was
more prevalent
during the early
stages of the
outbreak (More
aggressive)
Detected in blood,
saliva, tears, and
conjunctival
secretions, and
feces
Transmission
occurs via aerosol
droplets, physical
or close contact,
nosocomial
transmission,
closed spaces
87% were
aged 30-79
1% were
aged ≤ 9
1% were
aged 10-19
3% were
aged ≥80
Reported cases’ age
in years
Globally,
7,200,742 cases
have been
reported as of 9
June, 2020
Spread from asymptomatic
contacts can occur
5

6. CLINICAL PRESENTATION
6
Most
common
Anorexia
Diarrhea, N/V
Abdominal pain
Sputum production
Conjunctival congestion
Sore throat, Rhinorrhea
Chest pain
Confusion, Headache
Fever (Children may
be afebrile)
Dry cough (59-82%)
Dyspnea ( 18-55%)
Myalgia (38-69%)
Fatigue (69.6%)
MostCommon
Patients with ARDS may
have tachycardia,
tachypnea, or cyanosis
with hypoxia
Pneumonia may be present
on chest imaging despite
having no Sx
Only 15% of patients
present with fever, cough,
and dyspnea
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD: Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing, Treasure Island, FL; 2020.

7. LAB WORKUP
ABG ( detect
hypercarbia
or acidosis)
CBC-D
Procalcitonin
CRP
Coagulation
screen
(D-dimer, PT)
Cardiac
enzymes
SCr
Serum LDH
Bilirubin
Amylase
AST and ALT
predict
clinical
deterioration
to ARDS
PaO2/FiO2
determines
ARDS
severity
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD: Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing, Treasure Island, FL; 2020
Leukopenia initially, thrombocytopenia, elevated CRP & liver enzymes
RT-PCR for SARS-CoV-2 in all patients with suspected infection
CXR: bilateral lung infiltrates, multiple GGOs, patchy shadowing
7
Expected:
Common to non-survivors Ferritin, Neutrophil , D-dimer, BUN & SCr

8. CLINICAL CLASSIFICATION
Mild
Cases
URTI
symptoms are
mild
Serious
symptoms (i.e.
dyspnea) are
absent
Pneumonia is
absent on
imaging
Moderate
Cases
Fever and
respiratory
tract
symptoms
(SOB &
tachypnea)
Pneumonia
present on
imaging
Severe
Cases
RR ≥ 30
breaths/min
Spo2 ≤ 93% at
rest
(PaO2)/(FiO2)
≤ 300 mmHg
> 50% lesions
progression within
24 to 48 hours in
lung imaging
Critical
Cases
Respiratory
failure requiring
mechanical
ventilation
Septic shock
Other organ
failure
8
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD: Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing, Treasure Island, FL; 2020.
Can quickly deteriorate into
severe/ critical cases
Even in severe
forms of the disease,
fever can be absent
or moderate

9. CRITICAL CASES CLASSIFICATION
No organ failure
other than the lungs
Great chance of
recovery by:
Early stage
May be
complicated by
other mild or
moderate
dysfunction of
other organs
Middle stage
Diffuse
consolidation
of both lungs
(ECMO)
Failure of other
vital organs
High mortality
risk
Late stage
Stage Oxygenation Index
(mmHg)
Compliance of Respiratory
System (mL/cmH2O)
Early 100-150 ≥30
Middle 60-100 15-30
Late ≤60 ≤15
Anti-viral
Anti-cytokine
Supportive care
9
Handbook of COVID-19 Preventionand Treatment：Part two diagnosis and treatment. (2020, March 30). Retrieved from https://events.mybiogate.com/covid-19/handbook-of-
covid-19-preventionand-treatment%EF%BC%9Apart-two-diagnosis-and-treatment/
Case fatality
rate for critical
patients is
49%

10. STAGING
10
Siddiqu HK, Mehra MR. COVID-19 Illness in Native and Immunosuppressed States: A ClinicalTherapeutic Staging Proposal. Journal of Heart and Lung
Transplantation. doi: 10.1016/j.healun.2020.03.012

11. Oxygen
• Target SpO₂
≥90%
• Rate of 5
L/min
• Patients with
severe
ARDS,
hypoxemia,
or shock
Fluids
• Aggressive
fluid
resuscitation
may worsen
oxygenation
Symptom
relief
• Antipyretic/
analgesic
• For the relief of
fever and pain
• Systemic
corticosteroids
is not
recommended
to treat ARDS
Antiviral
Treatment
• Shock
• Respiratory
failure
• Other organ
failure that
requires
monitoring in
the ICU
Empirical
Antimicrobials
• Antibiotics for
secondary
bacterial
infection
• Neuraminidase
inhibitor until
influenza is
R/O
• Given within 1
hour if sepsis is
suspected
• De-escalate
empirical
therapy based
on test results
SUPPORTIVE CARE
11
Coronavirus disease 2019 (COVID-19). (2020, April 3). Retrieved from https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html

12. Promising
Novel
Agents
12

13. INVESTIGATIONAL TREATMENT OPTIONS
13

14. DATABASE SEARCH
• Over 500 clinical trials have been
registered
• RCTs have investigated the efficacy of:
KT, LD, JP, GH, JF & EM. A real-time dashboard of clinical trials for COVID-19. Open AccessPublished:April 24, 2020DOI:https://doi.org/10.1016/S2589-
7500(20)30086-8. PlumX Metrics
14
Lopinavir–ritonavir compared with standard of care
Favipiravir compared with arbidol
Lopinavir–ritonavir compared with arbidol
Remdesivir
Hydroxychloroquine monotherapy or in combination with azithromycin
IL-6 inhibitors (tocilizumab and sarilumab)
Convalescent plasma therapy
Stem-cell transfusion
Database
PubMed
Medline
EMBASE
Cochrane
Librar
MedRxiv
Clinical
trial
registries

15. DATABASE SEARCH
• Remdesivir compared to:
15
Hydroxychloroquine Lopinavir/ritonavir
Standard of care
according to local
COVID-19 treatment
guidelines
Direct acting
antivirals
KT, LD, JP, GH, JF & EM. A real-time dashboard of clinical trials for COVID-19. Open AccessPublished:April 24, 2020DOI:https://doi.org/10.1016/S2589-
7500(20)30086-8. PlumX Metrics

16. REMDISIVIR (RDV)
Broad-spectrum
antiviral activity
against RNA viruses
Developed in response
to the Ebola outbreak
MOA: termination of
RNA synthesis by
incorporating its active
triphosphate form into
RNA
Highly specific for
viral polymerases
High genetic hurdle to
resistance in
coronaviruses
Extended intracellular
half-life (>35 hours)
Dose: 200 mg (IV) on
day 1 followed by 100
mg IV daily for up to
10 days, infused over
30–60 minutes
Mohamed A. Hendaus (2020): Remdesivir in the treatment of Coronavirus Disease 2019 (COVID-19): A simplified summary, Journal of Biomolecular Structure and Dynamics, DOI:
10.1080/07391102.2020.1767691 / (Agostini et al., 2018; Brown et al., 2019; Mulangu et al., 2019)
16

17. TIMELINE
May 7, 2020 Approval of Remdesivir in Japan for Patients With Severe COVID-19
May 1, 2020 FDA Emergency Use Authorization for the Treatment of COVID-19
Apr 29, 2020 Results of Phase 3 Trial of Remdesivir in Patients With Severe COVID-19
Apr 29, 2020 Positive Data Emerging From NIAID’s Study of Remdesivir for COVID-
19
Apr 10, 2020 Data on 53 Patients Treated With Remdesivir Through the Compassionate
Use Program Published in NEJM
Mar 25, 2020 Request to Rescind Remdesivir Orphan Drug Designation
Feb 26, 2020 Initiation of Two Phase 3 Studies of Remdesivir for the Treatment of
COVID-19
17

18. EARLY CONFLICTING DATA
ST, SA, GR et al. 28 June 2017, posting date. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med doi:10.1126/scitranslmed.aal3653/ (Sheahan
18
Nucleotide analogues have
low efficacy against
coronaviruses due to the
presence of the virus
exonuclease proofreading
enzyme
Remdesivir was found to be
effective against SARS-CoV,
MERS-CoV
Remdesivir was
administered to the first
US case of COVID-19
on a compassionate use
basis

19. EARLY CONFLICTING DATA
Disappointing results emerged from
the first gold-standard clinical trial
for Remdesivir
• No benefit in patients in China
with severe COVID-19
• The Lancet medical journal
No apparent benefit of using IV
remdesivir over the placebo in
decreasing the time to clinical
improvement, mortality, or time to
clearance of virus
• Conducted in China-Japan
Friendship Hospital and Capital
Medical University in China
• Only enrolled half the sample size
needed due to decline in COVID-
19 cases
Positive early findings from a U.S.-
designed clinical trial
• Conducted at 180 sites around the
world
19
ST, SA, GR et al. 28 June 2017, posting date. Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses. Sci Transl Med doi:10.1126/scitranslmed.aal3653/ (Sheahan

20. EARLY EXPERIENCE WITH REMDESIVIR IN SARS-COV-2
PNEUMONIA
Four critically ill
COVID-19 patients
• Previously treated
with other
antivirals
Intervention:
• IV RVD 200 mg
LD followed by
100 mg daily IV
for up to 10 days
• IV Tocilizumab
800 mg STAT
before RVD
Results:
• 3 patients showed
signs of liver
injury
• Lymphocyte
count increased
• Nasal swab
became negative
in 3/4 of patients
on day 3
• PCR reverted to
positive after
RDV
discontinuation
in 1 patient due
to a shorter
course of
therapy
Conclusion:
• Although limited
by the low
number of
subjects studied,
may serve as a
pilot study
Durante-Mangoni, E., Andini, R., Bertolino, L., Mele, F., Florio, L. L., Murino, P., … Zampino, R. (2020). Early experience with remdesivir in SARS-CoV-2 pneumonia.
Infection. doi:10.1007/s15010-020-01448-x
20
Case Series
Dropouts:
One patient experienced
TDP requiring CPR
One died due to multiple
organ failure

21. COMPASSIONATE USE OF REMDESIVIR FOR
PATIENTS WITH SEVERE COVID-19
Patients with severe complications due tp COVID-19 who had SpO2≤ 94% in room air
• 64% of the patients were on mechanical ventilation at baseline
10-day course of IV RDV 200 mg on day 1 followed by 100 mg daily for the remaining 9 days
Follow-up
• On follow-up (median =18 days)
• 68% had an amelioration in oxygen-support
• 57% were extubated
• 47% were discharged
• After 28 days of follow-up
• Cumulative incidence of clinical improvement was 84% according to Kaplan-Meier analysis
Mortality rate was 13%
• Higher in the subgroup of patients on invasive ventilation (18%) compared with patients on noninvasive oxygen support (5%)
Side effects:
• The most common side events were renal impairment, rash, diarrhea, mild to moderate increase in hepatic enzymes, and
hypotension
• More common in patients on invasive ventilation
April 10., 2020
21
Grein et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. april 2020. DOI: 10.1056/NEJMoa2007016
Cohort Analysis
Discharge from the hospital OR at least a 2-point
improvement from baseline on a predefined six-
point scale

22. COMPASSIONATE USE OF REMDESIVIR
Drop outs: 4 patients (8%) terminated RDV treatment prematurely
• 1 because of deteriorating of preexisting renal failure
• 1 because of multiple organ failure
• 2 because of transaminitis, including one patient with a maculopapular rash
Limitations:
• Small sample size
• Not all patients received the 10 day course of treatment
• Not adequately powered with a randomized controlled design
• Short duration of follow-up
• Potential missing data due to the nature of the program
• Lack of control group
Conclusion:
• RDV led to clinical improvement in 68% of patients infected with Covid-19
April 10., 2020
22
Grein et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. april 2020. DOI: 10.1056/NEJMoa2007016
Cohort Analysis

23. HEALTH AUTHORITIES IN CHINA
2 RCT
Safety and efficacy of remdesivir as a potential treatment
for the coronavirus
Conducted at multiple sites in Hubei province
Gilead provided study drug at no charge and provided
input on study design and conduct
Stopped early due to low enrollment
23

24. REMDESIVIR IN ADULTS WITH SEVERE COVID-19:
A RANDOMISED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTRE TRIAL
Adults (≥18 years) admitted to hospital with lab-confirmed SARS-CoV-2
• Interval from symptom onset to enrolment (≤12 days)
• SpO2 ≤94% on room air or a ratio of arterial oxygen partial pressure to fractional inspired oxygen ≤ 300 mm Hg
• Radiologically confirmed pneumonia
• IV remdesivir (200 mg on day 1 followed by 100 mg on days 2–10 in single daily infusions) for 10 days
• Patients were permitted concomitant use of lopinavir–ritonavir, interferons, and corticosteroids.
The primary endpoint was time to clinical improvement up to day 28
Remdesivir use was not associated with a difference in time to clinical improvement (HR 1.23 [95%
CI 0.87–1.75])
When stratified to sx onset< 10 days: RDV group had a numerically faster time to clinical
improvement (HR 1.52 [0.95–2.43]) but not statistically significant
Adverse events reported in 66% (placebo) VS 64% (placebo)
• Withdrawal rate because of adverse events was 12% patients (RDV) VS 5% patients (placebo)
24
April 29, 2020
Hubei, China
Wang et al. Remdesivir in Adults With Severe COVID-19: A Randomised, Double-Blind, Placebo-Controlled, Multicentre Trial. 2020 May 16;395(10236):1569-1578. doi: 10.1016/S0140-

25. ADAPTIVE COVID-19 TREATMENT TRIAL (ACTT)
First clinical trial launched in the US to evaluate an experimental treatment for COVID-19
1063 hospitalized patients with advanced COVID-19 and lung involvement
Sponsored by NIAID, part of NIH
Reviewed & analyzed data by an independent data and safety monitoring board (DSMB)
Patients who received remdesivir had a 31% faster time to recovery than those who received placebo
(p<0.001)
The median time to recovery was 11 days (remdesivir group) compared with 15 days (placebo group)
Mortality rate was 8% for Remdesivir group versus 11.6% for the placebo group (p=0.059)
April 29, 2020
J Beigel, et al. Remdesivir for the Treatment of COVID-19 – A Preliminary Report. The New England Journal of Medicine. DOI: 10.1056/NEJMoa2007764 (2020).
25

26. FDA EMERGENCY USE APPROVAL
• Rationale:
26
The U.S. coronavirus death toll
neared 65,000
Remdesivir seems to boost recovery
among COVID-19 patients
Remdesivir shortened the time to
recovery by 31% for COVID-19
patients in the hospital
Based on review of SIMPLE &
ACTT trial
May 1, 2020
Food and Drug Administration (FDA) . Available from: https://www.fda.gov/media/137564/download Accessed May 3, 2020

27. SAFETY AND EFFICACY OF REMDESIVIR PLUS THE ANTI-
INFLAMMATORY DRUG BARICITINIB FOR COVID-19
The putative benefit of baricitinib for COVID-19 has been described in a case series of critically ill patients who
recovered from COVID-19 due to cytokine signaling inhibition
Anticipated to enroll more than 1,000 participants in 100 U.S. and international sites
Intervention:
•PO Baricitinib 4-mg oral dose (or crushed and given through a nasogastric tube, if necessary) for the duration of hospitalization up to a 14-
day total course of treatment
•IV Remdesivir 200 mg IV dose followed by a 100-mg qd IV dose for the duration of hospitalization up to a 10-day total course of
treatment
1ry end point: time to recovery
•Hospital discharge or no longer requires supplemental oxygen
•Evaluated up until 29 days
•A key secondary goal of the study is to compare patient outcomes at day 15 using an ordinal eight-point scale ranging from fully recovered
to death
Results not available yet
27
May 8., 2020
Sponsored by NIAID
RCT
NIH (may,2020) NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19 begins

28. ADAPTIVE COVID-19 TREATMENT TRIAL:
ACTT TRIAL
28
Sponsored by NIAID
RCT
May 22, 2020
Recovery: Hospital
discharge or the return to
normal activity level
Metric often
used in
influenza
trials
Double-
blind,
randomized,
placebo-
controlled
trial
1063
hospitalized
patients with
advanced
COVID-19
and lung
involvement
Preliminary
results
Mortality rate:
RVD group:
7.1%
Placebo group:
11.9%
(p=0.059)
(HR for death:
0.70 (0.47,
1.04)
The median
time to
recovery was
31% quicker
(RVD group)
compared to
placebo
group (11 vs
15 days) (
p<0.001)
First clinical trial launched in the
United States to evaluate an
experimental treatment for COVID-19
Beigel et al. (may,2020). Remdesivir for the Treatment of Covid-19: Preliminary Report DOI: 10.1056/NEJMoa2007764

29. MANUFACTURING COMPANY TRIALS
Gilead is conducting
two Phase 3 clinical
trials of remdesivir,
the SIMPLE studies,
in countries with
high prevalence of
COVID-19
Target population
• Patients with severe
disease
• Patients with moderate
disease
29

30. GILEAD-INITIATED “SIMPLE” TRIALS
Two randomized, open-label,
multicenter, Phase 3 clinical studies
to evaluate the safety and efficacy of
two dosing durations – 5 days and 10
days – of remdesivir in adults
diagnosed with COVID-19
• The first of the two SIMPLE studies is evaluating the
safety and efficacy of both a 5-day and a 10-day dosing
duration of remdesivir, in addition to standard of care, for
patients with severe manifestations of COVID-19
• Published on April 29, 2020
• The second SIMPLE study is evaluating the safety and
efficacy of the same dosing regimens of remdesivir in
addition to standard of care for patients with moderate
manifestations of COVID-19, compared with standard of
care alone
• Results from this study are still not available
30

31. SIMPLE TRIAL
Objective: Evaluation of 5-day dosing (group 1) and 10-day dosing durations (group 2) of Remdesivir
Target population: Hospitalized patients with severe COVID-19: pneumonia and reduced oxygen levels that did
not require mechanical ventilation
Results:
Comparable improvement in clinical status between study groups (OR: 0.75 [95% CI 0.51 – 1.12] on Day 14) P=0.14
The time to clinical improvement for 50% of patients was 10 days in group 1 and 11 days in group 2
More than 50% of patients in both treatment groups were discharged from the hospital by Day 14 (group 1: 60.0% vs. group 2: 52.3% p=0.14)
At Day 14, 64.5% of patients in group 1 and 53.8% of patients in group 2 achieved clinical recovery
The overall mortality rate at Day 14 was 7% across both treatment groups
No observed side effects in both group
Gilead Announces Results From Phase 3 Trial of Investigational Antiviral Remdesivir in Patients with Severe COVID-19 . Foster City, CA; April 29, 2020: Gilead Sciences. Available from
https://www.gilead.com/news-and-press/press-room/press-releases/2020/4/gilead-announcesresults-from-phase-3-trial-of-investigational-antiviral-remdesivir-in-patients-with-severe-covid19. Accessed April 29, 2020
31
May 27, 2020
Open-label, Phase 3
Trial
Conducted by Gilead
In patients with severe Covid-19 not requiring mechanical
ventilation, there’s no significant difference between a 5-day
course and a 10-day course of remdesivir
Placebo

32. IN PROGRESS RCT’S
Severe 2019-
nCoV
Remdesivir
RCT China-
Japan
Friendship
Hospital -
Beijing,
China
Mild/Modera
te 2019-nCoV
Remdesivir
RCT Jin Yin-
tan Hospital -
Wuhan,
China
Adaptive
COVID-19
Treatment
Trial Universi
ty of
Nebraska
Medical
Center -
Omaha NE,
USA
Expanded
Access
Remdesivir:
U.S. Army
Medical
Research and
Development
Command
Study to
Evaluate the
Safety and
Antiviral
Activity of
Remdesivir in
Participants
With Severe
COVID-19
Study to
Evaluate the
Safety and
Antiviral
Activity of
Remdesivir in
Participants
With Moderate
COVID-19
Compared to
Standard of
Care
Adaptive
COVID-19
Treatment
Trial by
NIAID
32
Gilead Sciences, Inc.

33. PENDING QUESTIONS
Does earlier
treatment with
remdesivir
have better
outcomes?
Is the five-day
course non
inferior to
the10-day
course?
34

34. OVERALL EVALUATION
Remdesivir inhibits coronavirus and improve
pulmonary functions
Evidence in patients with COVID-19 remains
limited and sparse
The inclusion/ exclusion criteria and the
outcome measurements do not include CXR
(key element for disease diagnosis and recovery
assessment according to guidelines
Remdesivir was effective only when it was
administered at the early stage of infection
(before the initiation of the immunopathological
phase of pneumonia)
No predefined plans of trial designs or statistical
analyses are given in their protocols
Current evidence is insufficient to support the
safety of remdesivir even though some
cytotoxicity tests suggest that remdesivir could
be safe
In patients with Ebola virus disease, the overall
mortality was even higher in remdesivir group
(53%) than the control group (a triple
monoclonal antibody agent; 50%), although
without significance
35

35. CONCLUSION
Remdesivir might be
crucial for ensuring an
efficient treatment,
decrease mortality and
allow early discharge in
relation to Covid-19
Safety and efficacy in
humans requires high-
quality evidence from well-
designed and adequately-
powered clinical trials for
further clarification
36

36. ABBREVIATIONS
• RDV: remdesivir
• S/Sx: signs and symptoms
• N/V: nausea and vomiting
• ARDS: acute respiratory distress syndrome
• RCT: randomized clinical trial
• WHO: world health organization
• NIAID: national institute of allergy & infectious diseases
• NIH: national institute of health
• STAT: immediately
• R/O: rule out
• HR: hazard ratio
• ECMO: extracorporeal membrane oxygenation
• GGO: ground glass opacities
• URTI: upper respiratory tract infection
• MSC: mesenchymal stem cell
• SOB: shortness of breath
37