New therapeutic and preventive medicines to fight the Ebola epidemic: December 2014 Status report 16...

New therapeutic and preventive medicines to fight

the Ebola epidemic: December 2014 Status report

16 December 2014

2 |

Date of

situation report Confirmed Probable Suspected Total Deaths

Guinea 13-Dec 2,115 263 16 2,394 1,518

Liberia 9-Dec 2,946 1,801 3,050 7,797 3,290

Sierra Leone 13-Dec 6,638 79 1,556 8,273 2,033

Total 11,699 2,143 4,622 18,464 6,841

Cumulative EVD cases and deathsCumulative EVD cases and deaths

4 |

Ebola epidemiological curveEbola epidemiological curve*Data represents confirmed cases in patient database and situation report

**For Liberia, laboratory confirmed cases have been available at the country level since 03 November in the situation report

Latest Sitrep13 Dec - GN09 Dec - LB13 Dec - SL

5 |

Ebola epidemiological curveEbola epidemiological curve*Data represents confirmed cases in patient database and situation report

**For Liberia, laboratory confirmed cases have been available at the country level since 03 November in the situation report

Latest Sitrep13 Dec - GN09 Dec - LB13 Dec - SL

6 |

Cumulative EVD infections in health-care workers,as of 16 December 2014

Cumulative EVD infections in health-care workers,as of 16 December 2014

Country Case definition Total Cases* Total Deaths

Guinea Confirmed 103 50

Probable 9 9

Suspected 0 0

Total 112 59

Liberia Confirmed 197 115

Probable 66 29

Suspected 101 39

Total 364 183

Sierra Leone Confirmed 216 105

Probable 38 8

Suspected 57 21

Total 311 134

All countries Confirmed 516 270

Probable 113 46

Suspected 158 60

Total 787 376

Source: Patient database as of 15th December 2014*Includes patients for which outcome data is unavailable

Development

Testing

Licensure

Plan for use

Accelerating access to vaccines and therapeutics is a high priority

In parallel…

Accelerating access to Ebola vaccines

From research to large scale use

Dr Ana Maria Henao-Restrepo MD MSc

Group Leader, Vaccine Phase 3 trials and early deploymentExperimental Ebola therapeutics and Vaccines

▪ Is the vaccine safe and effective?▪Which of the technologies to be used?▪What is the Target Product Profile and implications?▪How can clinical trial programs be accelerated?

▪What is the benefit-risk profile and can the Vx be used at population level?▪What are the post-licensure activities / surveillance / adverse events?▪What surveillance systems are in place?▪How can we mitigate supply risks and accelerate supply scale-up?

▪What is the most likely supply map in short and long term?▪What are different supply scenarios (dosage, yield, scale-up)?▪What demand scenarios exist (age, geography, stockpile…)? ▪What to do to ensure formulation is as suited to use as possible?

▪What are vaccination strategies to use and why (e.g. ring-vaccination, cohorts, HCPs, high intensity areas, high risk countries)?

▪What are different access scenarios?▪What is the recommended use for the initial vaccine stocks?

▪Who can finance and how?▪How to best organize procurement?▪What is the right framework to think about liability?

▪Mechanism of vaccine administration in different populations?▪How to manage the cold chain and logistics of distribution?▪What are the main drivers of cost and how can they be controlled?

Key issues to consider

A comprehensive scale-up plan

Focus today

Plan

Clinical trials and

tech choice

Regulation

and safety

Supply -demand

Vaccination strategies & Access

Scale-up

Enablers

A

B

C

D

E

F

rVSV-ZEBOV Recombinant vesicular stomatitis virus

It aims to induce EVD-specific immune responses.

Merck/NewLink Pharmaceuticals/Public Health Agency of Canada

ChAd3-ZEBOV Chimpanzee adenovirus 3

It uses a chimpanzee adenovirus that does not grow, containing the gene for EVD surface protein.

GSK/NIAID

Ebola vaccines currently under clinical evaluation

Kanapathipillai R et al. N Engl J Med 2014. DOI: 10.1056/NEJMp1412166

13

Ebola recombinant protein Protein Sciences

(1st trimester 2015 )

DNA expressing Ebola glycoprotein with electrophoration. Inovio (2015)

Oral adenovirus 5 Ebola vaccineVaxart

(1st quarter 2015) Alternate rVSV Ebola vaccine

Profectus(mid- 2015)

Recombinant rabies virusThomas Jefferson Univ. (2015)

Adenovirus, lentivirus and influenza virus based Ebola candidates. Russian candidates (2015)

Ebola recombinant nanoparticle with Matrix M adjuvant

Novovax (1st quarter 2015)

Ebola vaccines under Preclinical evaluation

Ad26/Ad35/MVA J&J/Crucell(Jan 2015)

Jan 2015 Dec 2015June 2015

Description, developer(estimated date when clinical testing will start)

HPIV-3 live attenuated Intranasal (two versions), NIAID

(March/April 2015)

Rabies Ebola gp inactivated,Intranasal, NIAID (2015)

Near-term development plan

GMP grade

vaccine

Emergency use under informed consent

Data collection

Large-scale vaccination

Non-affected areas Affected areas

Sept-Nov2014

Non-clinical eval inNHPs

Phase 1Safety and dose selection

1st Quarter 2015

Phase 2aLarge scale safety

Phase 2bPreliminary efficacy

Phase 3 Efficacy

15

Ebola vaccines in clinical testing- Phase 1 studies

VRC-USA Bivalent

20 healthy adultsDose-escalation, Safety

Sept 2014 Oct 2014

Oxford-UK Monovalent


Lausanne-SuisseMonovalent


WRAIR-USA


NIAID-USA

30 healthy adultsTwo dose schedule, Safety

Hamburg-Germany

30 healthy adultsDose-selection, Safety

Nov 2014

Lambarene-Gabon


Kilifi-Kenya


Geneva-Suisse


CVD - MaliMonovalent


rVSV: Phase 1 trials

ChAd3: Phase 1 trials

16

Ebola vaccines in clinical testing -Plans for phase 2, 3 studies

Jan- Feb 2015 2nd Q 2015

Phase 2 multisite multi-country

RCT Single common protocol -total of ?3000 including ?500 children, - other special populations?

Possible countries are Ghana, Mali, Cameroon, Nigeria, Senegal, Cote d’Ivoire

Safety, Immunogenicity

Liberia-MonroviaNIH- ChAd3 + rVSV

RCTs3 arm study

Efficacy, Safety

Sierra LeoneCDC(rVSV-ChAd3) Stepped Wedged

Efficacy, Safety

GuineaConsortium (rVSV and?or

ChAd3)Ring Vaccination and FLWs

Efficacy, Safety

Early results of vaccine efficacy

17

Initiation of Phase 1 trials for the two most advanced

vaccines

Ebola Vaccines - Key milestones

Sept - Oct 2015 2nd Q 2015Nov-Dec 2015

Agreed protocols (including Phase 3) trials across sites

Preparation started of sites for Phase 3 studies

in Ebola affected countries

Initial safety and immunogenicity

from Phase 1 trials available

Start of Phase 3 trials in Ebola affected

countries

1st quarter 2015

Early results of vaccine efficacy

18 |

There is consensus that the use of whole blood and convalescent blood

serums needs to be considered as

a matter of priority.

Use of convalescent whole blood or plasma collected from patients who have recovered from Ebola virus disease for transfusion as an empirical treatment during outbreaks

Whole blood and convalescent plasmaWhole blood and convalescent plasma

WHO guideline (Sept 2014):Identification of patients recovered from EVD as potential blood donorsInformed consent and selection of donorsDonor’s blood grouping and screening for transfusion-transmissible infectionsBlood collection and donor careLabelling, storage, and transportation of blood and plasma products to sites where transfusion is givenSelection of EVD patients for this interventionClinical transfusion processData collection at the transfusion siteAssessment of effectiveness of this empirical treatment

http://apps.who.int/iris/bitstream/10665/135591/1/WHO_HIS_SDS_2014.8_eng.pdf

http://apps.who.int/iris/bitstream/10665/135591/1/WHO_HIS_SDS_2014.8_eng.pdf

19 |

Other Adjacent countries – strengthening preparedness: mtg end FebExpatriated patients – receiving convalescent plasma

Blood ProductsBlood Products

Guinea

Guinea/Belgium/UK/France Guinea/Belgium/UK/France

Deploying imminentlyDeploying imminently

Whole BloodPlasma

Liberia

GovernmentUS (Clin RM/BMFG)

RunningRunning

Whole bloodPlasma

Sierra Leone

GovernmentOthers

RunningPlanning

Whole BloodPlasma

Nigeria

Clin RM To be deployed TBC (IgG?)

20 |

Effective community engagementEffective community engagement

Draft WHO document on key considerations for effective community engagement in blood donation for compassionate use and clinical trials

Document outlines a draft model and key considerations to enable national health authorities, blood transfusion services and trial investigators to effectively engage with communities to prepare EVD survivors and the communities for blood donation and the clinical trials

Aims to help to ensure informed participation of survivors and communities and avoid the additional pressure and anxiety inappropriate and/or insufficient community engagement can place to already vulnerable groups.

WHO Ebola Blood and Plasma Working Group

21 |

Strengthening NBTSStrengthening NBTS

In-depth assessment of BTS conducted in affected countries

The NBTS in affected countries have suffered from a decade of under resourcing; in staff recruitment, staff development, facility maintenance, effective consumables procurement, equipment provision and maintenance

The services were unable to meet the nations’ needs prior to the outbreak - for this emergency the services are not in a position to support either the compassionate use or the clinical trials

Substantial investment is needed to refresh and resource the services during the recovery phase

Country specific plans for system strengthening are developed - training needs are identified – meeting planned for mid-Jan 2015

WHO Ebola Blood and Plasma Working Group

2- Interferes with viral productionTKM 100802Ebola Target two essential viral genes to stop the Ebola from replicating.

AVI 7537 Sarepta Molecules that bind viral RNA, blocking gene function.

Favipiravir T705 Disrupts enzymes that the virus uses to make copies of himself.

BCX4430 Biocryst Disrupts enzymes that the virus uses to make copies of himself.

Brincidofovir Disrupts enzymes that the virus uses to make copies of himself.

4- Bolsters human cellsInterferons - Induce an antiviral state in exposed cells and regulates the immune system

6- Whole blood transfusions and convalescent plasma

Experimental therapies used to treat Ebola Prioritized for consideration based on the availability of NHP efficacy data with a

filovirus challenge and justification for a human dose based on clinical data of the product or comparable products within that class.

Source: Adapted from the Washington Post, Oct 7, 2014

5- Testing existing drugs approved for other purposesAll drugs Screening all licensed drugs.

3- Prevents virus from exiting host cells

1- Targets the virus before it enters the cellZmapp A cocktail of three monoclonal antibodies, which block or neutralises the virus by binding to or coating a different site on the covering or “envelope” of the virus

Hyperimune globulin Antibodies that can neutralize the different EVD strains.

23 |

Zmapp (Mapp)

siRNA/ AVI-7537 (Serepta)

siRNA/ TKM-100802 (Tekmira)

rNAPc2 (ARCA biopharma)

BCX4430 (Biocryst)

Favipirivir/T705 (Fuji/Toyama)

Brincidofovir (Chimerix)

Toremifene

Inteferons

Lamivudine (GSK)

Amiodarone

New Potential Interventions

TherapeuticsTherapeutics

24 |

The ‘stuff’ that is being proposed to WHO for testing in the field…

The ‘stuff’ that is being proposed to WHO for testing in the field…

Vulture Gastric Fluid

Chamomile tea

Ayurvedic oils

Silver suspensions

Bath salts

HIV therapies

Homeopathy

CrystalsVitamins

Micronutrients

Root extracts

Magnets

Electromagnetic waves

25 |

Expert training

Funding for development

Equipment deployment

Integrating development into trials

Understanding the needs

Health System Building/Repair/Development

Health System Building/Repair/Development

26 |

17 tests under investigation (1 approved for procurement)

Others being received

4 main purposes– Identification/ Confirmation– Field test– Entry/Exit tests– Detailed test for data gathering

Need for standards/ standard testing

DiagnosticsDiagnostics

27 |

Ensure there are emergency use regulatory pathways in place;

Ensure there is rapid and proactive cooperation and collaboration between regulators, and also with WHO, to help accelerate development and evaluation of investigational treatments and vaccines;

Drive innovative clinical trial design for situations like the current EVD emergency where traditional clinical trial designs may not be feasible.

Regulators: ICDRA recommendations to Member States

Regulators: ICDRA recommendations to Member States

28 |

Rapidly provide scientific information on the potential therapies and vaccines for EVD, and ensure the information is regularly updated;

Establish and lead a network of regulators globally to address the response to EVD

Facilitate collaborations between regulators in countries where products are being developed and those in countries where the products will be evaluated and, if found safe, used

Regulators: ICDRA recommendations to WHO

Regulators: ICDRA recommendations to WHO

29 |

Research fields include; Therapeutics, Diagnostics, Vaccines, Epidemiology, Virology and Behavioural dynamics

Trans-disciplinary approach

Better future response– Investigating what we could understand about disease

immunopathogenesis, viral progression and viral shedding– This could benefit patient care, infection prevention and control

and contact management– What can we learn about the behavioural dynamics– This could benefit every level of our intervention in country, with

all actions being impacted

ResearchResearch

30 |

Rumours

Interventions without evidential basis

Community engagement (large and small scale)

Awareness

Safety

In the fieldIn the field

“Any man's death diminishes me,Because I am involved in mankind”John Donne

31 |

Back-up slidesBack-up slides

32

8. Considerations on operational (non-vaccine) financial needs

33

Considerations on operational (non-vaccine) financial needs for roll out of vaccination

strategies

Type of vaccination

strategy

SpecialconsiderationsEbola vaccine

Typicalcampaign

costs

Planning, management and coordination

Possible Ebola Vaccination Strategies

34

Mobile teams Ring vaccination

Similar to measles campaigns Health care centre

HCWs in ETCsCommunity basedEbola

responders

Contacts of Ebola

patientsHome-based care takers of

Ebola patients

Target age groups:

Children < 15 yo

Target age groups:

Adults older than 15 yo

Pregnant women

People living

with HIV

Ebola vaccination campaignsPlanning, management, and coordination

35Before campaign During campaign After campaign

High quality microplanning/preparation to identify target population, and to identify logistical and funding requirements

Campaign “readiness dashboards” might be considered

Availability of data for decision making on an hour by hour basis to identify and manage issues and bring reinforcements

Real time tracking and reporting of vaccination team supervision.

Vaccine coverage monitoring

Coordination of data managers at district, regional, national levels

Assessment of vaccine coverage

Evaluation of lessons learned

Drafting guidelines for Ebola vaccination campaign management

36

0.2

2.0

Polio Measles HPV

0.6

3.0 3.0

5.0

Estim

ated

co s

t per

pe r

son

vacc

inat

ed (U

SD)

Medical volunteers travel house to house to identify and vaccinate children aged <5 years with oral polio vaccine

Trained health workers work at permanent, temporary or

field posts to vaccinate children aged <5 years with injectable measles vaccine

Trained health workers travel to schools to vaccinate adolescent girls with

injectable HPV vaccine

Typical operational costs of other types

of vaccination campaigns5

4

3

2

1

0

Operational costs of an Ebola vaccine campaign are likely to be higher than those

of other campaigns

Category

Social mobilisation to explain target populationsTraining and supervision for a new “special” vaccineMore human resource requirements may be neededTransport to access remote locations

Immunisation session supplies for vaccine monitoring

Other

Special considerations for an Ebola vaccine campaign plan are pertinent

Category

Cold chain equipment/special logistics

Security and crowd control

Infection control programme and suppliesMonitoring of Adverse Events

Waste management

Stockpiling challenges are more than financing and vaccine supply future outbreaks might involve other strainsphysical/behavioural interventions may continue to be the mainstay of outbreak controltiming of outbreaks is somewhat unpredictableneed international mechanism to manage stockpile

39

40

African Vaccine Regulators Forum (AVAREF): Review of IND application: Protocols, IB, Ethics and informant consentWHO Advisory Committee on Regulatory Emergency Authorization of unlicensed Ebola Vaccines: Review of GMP, evidence on safety and efficacy, programmatic suitability. Time limited authorization for use.

WHO Ebola Vaccines Risk Assessment Group and WHO Global Advisory Committee on Vaccine Safety: Evaluation of safety data and opinion on potential risks and benefits

Strategic and Technical Advisory Committee on Experimental Ebola Therapeutics and Vaccines (STAC-EE): Review of development plan, expert opinion on protocol design, and interpretation of data emerging from trials.

Strategic Advisory Group of Experts: Review of evidence to inform policy considerations for large scale use, if appropriate

Oversight

"The vaccine is not the magic bullet. But when ready, they may be a good part of the effort to turn the tide of this epidemic.”

41

Acknowledgements

42

New therapeutic and preventive medicines to fight the Ebola epidemic: December 2014 Status report 16...

Documents

Transcript of New therapeutic and preventive medicines to fight the Ebola epidemic: December 2014 Status report 16...