Farah Al Souheil, pharmD, RPh

Lebanese International University, SOP

 Lebanese International
University School of Pharmacy
Advanced Pharmacy Practice
Experience Internal Medicine
Rotation

REMDESIVIR IN THE
MANAGEMENT OF COVID-19

June 9,
2020
EVIDENCE BASEDAPPROACH
 OUTLINE

Quick
introduction Remdesivir
about COVID- Treatment Abbreviations References
Assessment
19

• Treatment
approach
• Emerging

treatment

3
 ABOUT COVID-19

Can infect the neurological, Can be isolated from birds

Primary cases presented as
respiratory, enteric, and hepatic mammals
& (camels, bats, mice,
pneumonia of unknown etiology
system dogs & cats

Functionally inactivated with

The virus is sensitive to
ethanol (60%), ether (75%),
ultraviolet light and
and chlorine-containing 4
heat
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
 FACTS & NUMBERS
Globally,
7,200,742 cases
87% were
have been aged 30-79
The L type was reported as of 9
There are two more prevalent June, 2020
major types (or during the
strains) of the early stages of 1% were
virus (L and S) the outbreak aged ≤ 9
(More
aggressive)

1% were
Transmission aged 10-19
Detected in blood, occurs via aerosol
saliva, tears, and droplets,
conjunctival physical or close
secretions, and contact, 3% were
feces nosocomial aged
transmission, ≥80
closed spaces
Reported cases’ age
Spread from asymptomatic in years
contacts can occur
5
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
 CLINICAL PRESENTATION

Fever (Children may Patients with ARDS

be afebrile)
Dry cough (59-82%) may have tachycardia,
Dyspnea ( 18-55%) tachypnea, or cyanosis
Myalgia (38-69%)
Most with hypoxia
Fatigue (69.6%)
commo
Most Common

Anorexia Pneumonia may be present

Diarrhea, N/V on chest imaging despite
Abdominal pain having no Sx
Sputum production
Conjunctival
congestion Sore throat, Only 15% of patients
Rhinorrhea Chest pain present with fever, cough,
and dyspnea
Confusion, Headache
6
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD: Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing, Treasure Island, FL;
 LAB WORKUP

Coagulation AST and ALT

CBC-D screen Serum LDH PaO2/FiO2
ABG ( detect predict
determines
hypercarbia Procalcitonin (D-dimer, SCr Bilirubin clinical
ARDS
or acidosis) CRP PT) Amylase deterioration
to ARDS severity
Cardiac
enzymes

Expected: Leukopenia initially, thrombocytopenia, elevated CRP & liver enzymes

Common to non-survivors Ferritin, Neutrophil , D-dimer, BUN & SCr

RT-PCR for SARS-CoV-2 in all patients with suspected infection

CXR: bilateral lung infiltrates, multiple GGOs, patchy shadowing

7
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD: Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing, Treasure Island,
 Even in severe
forms of the disease,
CLINICAL CLASSIFICATION fever can be absent
or moderate

Mild Moderate Severe Critical

Cases Cases
Cases Cases
URTI Respiratory
symptoms are Fever and RR ≥ 30 failure requiring
mild respiratory breaths/min mechanical
tract ventilation
symptoms
Serious (SOB &
symptoms (i.e. tachypnea) Spo2 ≤ 93% at Septic shock
dyspnea) are Pneumonia rest
absent present
on
imaging
Pneumonia is (PaO2)/(FiO2) Other organ
absent on ≤ 300 mmHg failure
imaging

Can quickly deteriorate into > 50% lesions

progression within
severe/ critical cases 24 to 48 hours in
lung imaging
8
Cascella M, Rajnik M, Cuomo A, Dulebohn SC, Napoli RD: Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls Publishing, Treasure Island,
 Case fatality
CRITICAL CASES CLASSIFICATION rate for critical
patients is
49%

Early stage Middle stage Late stage

No organ failure May be Diffuse
other than the lungs
complicated by consolidation
Great chance of other mild or of both
recovery by:
moderate lungs
dysfunction of (ECMO)
Anti-viral other organs Failure of other
Anti-cytokine vital organs
Supportive care High mortality
risk
Stage Oxygenation Index Compliance of Respiratory
(mmHg) System (mL/cmH2O)
Early 100-150 ≥30
Middle 60-100 15-30
Late ≤60 ≤15
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-
 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
 SUPPORTIVE CARE
Symptom Antiviral Empirical
Oxygen Fluids
relief Treatmen Antimicrobials
t
• Target SpO₂ • Aggressive • Antipyretic/ • Shock • Antibiotics for
≥90% fluid analgesic • Respiratory secondary
• Rate of 5 resuscitation • For the relief of failure bacterial
L/min may worsen fever and pain • Other organ infection
• Patients with • Systemic failure that • Neuraminidase
severe oxygenation corticosteroids requires inhibitor until
ARDS, is not monitoring in influenza is
hypoxemia, recommended the ICU R/O
or shock to treat ARDS • Given within 1
hour if sepsis is
suspected
• De-escalate
empirical
therapy based
on test
results

11
Coronavirus disease 2019 (COVID-19). (2020, April 3). Retrieved from https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-guidance-management-patients.html
 Novel

Promising

Agents

12
INVESTIGATIONAL TREATMENT OPTIONS

13
 DATABASE SEARCH
PubMed

• Over 500 clinical trials have Clinical

trial Medline
been registered registries
• RCTs have investigated the
Database
efficacy of:
Lopinavir–ritonavir compared with standard of care
MedRxiv EMBASE
Favipiravir compared with arbidol

Lopinavir–ritonavir compared with arbidol

Cochrane
Remdesivir Librar

Hydroxychloroquine monotherapy or in combination with azithromycin

IL-6 inhibitors (tocilizumab and sarilumab)

Convalescent plasma therapy

Stem-cell transfusion

KT, LD, JP, GH, JF & EM. A real-time dashboard of clinical trials for COVID-19. Open AccessPublished:April 24, 2020DOI:https://doi.org/10.10116/4
S2589- 7500(20)30086-8. PlumX Metrics
 DATABASE SEARCH

• Remdesivir compared to:

Hydroxychloroquine Lopinavir/ritonavir

Standard of care
according to local Direct acting
COVID-19 treatment antivirals
guidelines

KT, LD, JP, GH, JF & EM. A real-time dashboard of clinical trials for COVID-19. Open AccessPublished:April 24, 2020DOI:https://doi.org/10.10116/5
S2589- 7500(20)30086-8. PlumX Metrics
 REMDISIVIR (RDV)

Broad-spectrum High genetic hurdle to

Extended intracellular
antiviral activity resistance in
half-life (>35 hours)
against RNA viruses coronaviruses

Dose: 200 mg (IV) on

day 1 followed by 100
Developed in response Highly specific for
mg IV daily for up to
to the Ebola outbreak viral polymerases
10 days, infused over
30–60 minutes

MOA: termination of
RNA synthesis by
incorporating its active
triphosphate form into
RNA

16
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)
 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
 EARLY CONFLICTING DATA

Nucleotide analogues Remdesivir was

have low efficacy against administered to the first
coronaviruses due to the US case of COVID-19
presence of the virus
exonuclease proofreading on a compassionate use
enzyme basis

Remdesivir was found to be

effective against SARS-CoV,
MERS-CoV

18
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
 EARLY CONFLICTING DATA

No apparent benefit of using IV

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
remdesivir over the placebo in
decreasing the time to clinical Positive early findings from a U.S.-
improvement, mortality, or time to designed clinical trial
clearance of virus
• Conducted in China-Japan • Conducted at 180 sites around the
Friendship Hospital and Capital world
Medical University in China
• Only enrolled half the sample size
needed due to decline in COVID-
19 cases

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
 Case Series

EARLY EXPERIENCE WITH REMDESIVIR IN SARS-COV-2

PNEUMONIA

Four critically ill

Intervention: Results: Conclusion:
COVID-19 patients
• Previously treated • IV RVD 200 mg • 3 patients showed • Although limited
with other LD followed by signs of liver by the low
antivirals 100 mg daily IV injury number of
for up to 10 days • Lymphocyte subjects studied,
• IV Tocilizumab count increased may serve as a
800 mg STAT • Nasal swab pilot study
before RVD became negative
in 3/4 of
patients on day
One patient experienced 3
TDP requiring CPR
• PCR reverted to
positive after
Dropouts: RDV
discontinuation
in 1 patient due
One died due to multiple
organ failure to a shorter
course of
therapy
20
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
 Cohort Analysis

COMPASSIONATE USE OF REMDESIVIR FOR

PATIENTS WITH SEVERE COVID-19
April 10., 2020

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 Discharge from the hospital OR at least a 2-
• 57% were extubated point improvement from baseline on a
predefined six- point scale
• 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

2
1
 Cohort Analysis

COMPASSIONATE USE OF REMDESIVIR

April 10., 2020

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
22
Grein et al. Compassionate Use of Remdesivir for Patients with Severe Covid-19. april 2020. DOI:
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
 REMDESIVIR IN ADULTS WITH SEVERE COVID-
19: A RANDOMISED, DOUBLE-BLIND, PLACEBO-
CONTROLLED, MULTICENTRE TRIAL April 29, 2020
Hubei, China

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)
2
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-
4
 ADAPTIVE COVID-19 TREATMENT TRIAL (ACTT)
April 29, 2020

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)
25
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).
 FDA EMERGENCY USE APPROVAL
May 1, 2020

• Rationale:

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

26
Food and Drug Administration (FDA) . Available from: https://www.fda.gov/media/137564/download Accessed May 3, 2020
 RCT

SAFETY AND EFFICACY OF REMDESIVIR PLUS THE ANTI-

INFLAMMATORY DRUG BARICITINIB FOR COVID-19
May 8., 2020

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

Sponsored by NIAID 27
NIH (may,2020) NIH clinical trial testing antiviral remdesivir plus anti-inflammatory drug baricitinib for COVID-19
 RCT

ADAPTIVE COVID-19 TREATMENT TRIAL:

ACTT May 22, 2020
TRIAL
Mortality rate:
The median
RVD group: time to
1063
Double- 7.1% recovery was
hospitalized 31%
blind,
randomized,
patients with
Preliminary Placebo group: quicker
advanced
placebo-
COVID-19 results 11.9% (RVD group)
controlled and lung compared to
trial (p=0.059) placebo
involvement (HR for death: group (11 vs
0.70 (0.47, 15 days) (
1.04) p<0.001)

Metric often
First clinical trial launched in the used in
United States to evaluate an influenza
Recovery: Hospital trials
experimental treatment for COVID-19
discharge or the return
to normal activity level

Sponsored by NIAID
28

Beigel et al. (may,2020). Remdesivir for the Treatment of Covid-19: Preliminary Report DOI: 10.1056/NEJMoa2007764
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
GILEAD-INITIATED “SIMPLE” TRIALS

• The first of the two SIMPLE studies is evaluating the

• The second SIMPLE study is evaluating the safety and
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
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
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
 Open-label, Phase 3
Trial

Placebo
SIMPLE TRIAL
May 27, 2020

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

In patients with severe Covid-19 not requiring mechanical

ventilation, there’s no significant difference between a 5-day
Conducted by Gilead course and a 10-day course of remdesivir

31
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
 IN PROGRESS RCT’S

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

Gilead Sciences, Inc.

32
PENDING QUESTIONS

Does earlier
treatment with
remdesivir
have better
outcomes?
Is the five-day
course non
inferior to
the10-day
course?

34
 OVERALL EVALUATION

The inclusion/ exclusion criteria and the

Remdesivir inhibits coronavirus and improve Evidence in patients with COVID-19 remains outcome measurements do not include CXR
pulmonary functions limited and sparse (key element for disease diagnosis and recovery
assessment according to guidelines

Remdesivir was effective only when it was Current evidence is insufficient to support the
administered at the early stage of infection No predefined plans of trial designs or statistical safety of remdesivir even though some
(before the initiation of the immunopathological analyses are given in their protocols cytotoxicity tests suggest that remdesivir could
phase of pneumonia) 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
 CONCLUSION

Remdesivir might be Safety and efficacy in

crucial for ensuring an humans requires high-
efficient treatment, quality evidence from well-
decrease mortality and designed and adequately-
allow early discharge in powered clinical trials for
relation to Covid-19 further clarification

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