Therapeutic options for Ebola patients

Clinical management training:

Module 5 June 2018

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Objectives
By the end of this module, participants should be able to:
1. describe the Monitored Emergency Use of Unregistered
and Investigational Interventions (MEURI) for Ebola
Virus Disease (EVD); and
2. describe the various investigational therapeutics that are
being considered for MEURI as of 30 May 2018.

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MEURI ethical framework
§ In the context of an outbreak characterized by high mortality, the
Monitored Emergency Use of Unregistered and Investigational
Interventions (MEURI) guideline provides a framework for
selection of investigational therapeutics in an ethical manner.
– Chapter 9: http://www.who.int/ethics/publications/infectious-disease-outbreaks/en/

§ WHO convened an international expert panel to discuss use of

therapeutics under MEURI
– http://www.who.int/emergencies/ebola/MEURI-Ebola.pdf

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Principles of MEURI framework (1/2)
§ No proven effective treatment exists.

§ It is not possible to initiate clinical studies immediately.

§ Data providing preliminary support of the intervention’s efficacy and

safety are available:
– at least from laboratory or animal studies; and
– use of the intervention outside clinical trials has been suggested
by an appropriately qualified scientific advisory committee on
the basis of a favourable risk–benefit analysis.

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Principles of MEURI framework (2/2)
§ The relevant country authorities, as well as an appropriately
qualified ethics committee, have approved such use.
§ Adequate resources are available to ensure that risks can be
minimised.

§ The patient’s informed consent is obtained.

§ The emergency use of the intervention is monitored and the

results are documented and shared in a timely manner with the
wider medical and scientific community.
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 Overview of investigational therapeutic options
Type Examples Pharmacological structure
Monoclonal ZMapp Combination of three chimeric human/murine
antibodies monoclonal antibodies against EBOV surface
glycoproteins
mAb114 Fully human monoclonal antibody against
EBOV
Regeneron (REGN3470- Cocktail of 3 human IgG1 monoclonal
3471-3479) antibodies targeting separate epitope

Antiviral Favipiravir RNA-dependent polymerase inhibitor

Remdesivir (GS-5734) Single diastereomer monophosphoramidate
prodrug of a adenosine nucleoside analogue
Galidesivir (BCX4430) Indirect RNA polymerase inhibitor
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 ZMapp
Evidence/Benefits Challenges
• Highest quality evidence available to • Requires cold chain.
date for efficacy, trend towards • Limited global supply.
improvement when compared to • High resource requirements (infusion
standard of care. time, monitoring).
• Risk of infusion-related adverse
• Established safety in pregnant events.
women. • Risk of hyponatremia during infusion.

Group PIW, Multi-National PIIST, Davey RT, Jr., Dodd L, Proschan MA, Neaton J, et al. A
Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med.
2016;375(15):1448-56.
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 PREVAIL II trial
§ Randomized, open-label control trial
– ZMapp + standard of care vs standard of
care
– n=72, 4 countries, 8 sites.

§ Primary end-point: mortality at 28 days.

§ Results suggest trend towards improved

survival, but trial did NOT reach target
enrolment.

§ Mild-moderate infusion-related adverse

events
– Requires close monitoring.
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Remdesivir (GS-5734)
Evidence
• Available data on
animal models.
• Multiple ongoing
Phase I studies to
assess safety.
Feasibility Challenges
• Lyophilised formulation • Safety profile not
available that does not studied in pregnant
require cold chain. women.
• Need for ALT/AST
monitoring.

Warren TK, Jordan R, Lo MK, Ray AS, Mackman RL, Soloveva V, et al. Therapeutic efficacy of the small
molecule GS-5734 against Ebola virus in rhesus monkeys. Nature. 2016;531(7594):381-5.

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Regeneron (REGN3470-3471-3479)
Evidence Benefits/Feasibility Risks/challenges
• Available data from • Possible to use as • Infusion-related
animal models of single-dose therapy. adverse events.
Ebola infection; • Generally well tolerated. • Higher resources
results similar to needed for monitoring
Zmapp. during infusion.
• Early phase 1 studies • Avoidance
report headache and recommended if
myalgia as common doxycycline allergy.
side effects.

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Favipiravir
Evidence Feasibility Challenges
• Proof of concept • Oral formulation • Uncertainty for benefits
study, single arm available - requires less based on available
compared to historical resources to administer data.
control. than IV formulation. • Doses originally
• Very high morality in described in trial
patients with high viral shown to not reach
load. therapeutic level.
Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, et al. Experimental
Treatment with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm
Proof-of-Concept Trial in Guinea. PLoS Med. 2016;13(3).
Nguyen TH, Guedj J, Anglaret X, Laouenan C, Madelain V, Taburet AM, et al. Favipiravir
pharmacokinetics in Ebola-Infected patients of the JIKI trial reveals concentrations lower than targeted.
PLoS Negl Trop Dis. 2017;11(2).
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 JIKI trial

§ Multi-centre, non-randomized proof-of-

concept trial
– Favipiravir higher dose used for inhibition of
EBOV
– n = 111, 3 sites in Guinea.
§ Primary endpoint – mortality at 14 days.
§ Exclusion of pregnant and age <1 year,
inability to tolerate PO.
§ Results suggest mortality benefit in those
with Ct > 20 (low viral load), but very high
mortality in those with higher viral load.

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mAb114
Evidence Challenges
• Available data from animal models • Early stage of development.
of Ebola infection. • Currently at phase 1; results not
• Fully human monoclonal antibody. available.

Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, et al. Protective monotherapy against
lethal Ebola virus infection by a potently neutralizing antibody. Science. 2016;351(6279):1339-42.

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Summary
§ Various therapeutic agents for EVD are
investigational and unregistered.
§ Use of such agents during an outbreak operate
under the MEURI framework until clinical trials can
be conducted.
§ It is important to design and conduct approved
clinical trials for evaluation of such agents as soon
as possible.
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Acknowledgements
This training course has been adapted from materials developed by
the IMAI-IMCI Alliance.

It is based on:
§ WHO. Notes for the record: Consultation on Monitored Emergency Use of Unregistered
and Investigational Interventions for Ebola Virus Disease (EVD). 2018.
http://www.who.int/emergencies/ebola/MEURI-Ebola.pdf?ua=1
§ WHO. Managing Ethical Issues in Infectious Disease Outbreaks. 2016.
http://www.who.int/ethics/publications/infectious-disease-outbreaks/en/

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Key contact

EDCARN
Health Emergencies Programme
WHO Geneva
edcarn@who.int
Photo credits: Sissoko D, Laouenan C, Folkesson E, M'Lebing AB, Beavogui AH, Baize S, et al. Experimental Treatment
with Favipiravir for Ebola Virus Disease (the JIKI Trial): A Historically Controlled, Single-Arm Proof-of-Concept Trial in
Guinea. PLoS Med. 2016;13(3); Group PIW, Multi-National PIIST, Davey RT, Jr., Dodd L, Proschan MA, Neaton J, et al. A
Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med. 2016;375(15):1448-56.

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