GSK Ebola Vaccine Development An emergency response

François Roman, Clinical Research and Development Lead Presentation at Directorate-General Health and Food Safety April 29, 2015

Ebola virus disease (EVD) is a severe, often fatal illness

• Ebola virus disease (formerly known as Ebola haemorrhagic

fever) can be a severe, often fatal illness.

• The current outbreak is caused by Ebolavirus Zaire (EBOV)

• The case fatality rate of the current epidemic has been

50-74%. Case fatality rates have varied from 25% to 90% in

past outbreaks.

• Aspecific. Sudden onset of fever, intense weakness, muscle

pain, headache and sore throat are typical signs and

symptoms. This is followed by vomiting, diarrhoea, rash,

impaired kidney and liver function, and in some cases, both

internal and external bleeding.

• The incubation period, or the time interval from infection to

onset of symptoms, is from 2 to 21 days. The patients

become contagious only after they begin to show symptoms.

• Average interval from onset of symptoms to hospitalization is

5.0 days and from onset of symptoms to death or hospital

discharge is 7.5 or 16.4 days, respectively.

2 WHO Ebola Response Team, The first 9 months of the epidemic and forward projections, NEJM 2014;371(16):1481-95; http://who.int/csr/disease/ebola/faq-ebola/en; Schieffelin et al.

Clinical illness and outcomes in patients with Ebola in Sierra Leone, NEJM Online 29 October 2014. Feldmann & Geisbert, Ebola haemorrhagic fever, Lancet 2011;377:849-62.

3

Marb

252 cs

90% mor

History of EVD outbreaks

EBOV-Z

318 cs

88% mor

1979

EBOV-S

284 cs

53% mor

1976 1996 1995 2001 1994 2004

Registered as GlaxoSmithKline Biologicals SA

2000 2002 2003 2007 2008 2012 Next??

EBOV-S

34 cs

65% mor

EBOV-Z

52 cs

60% mor

EBOV-Z

315 cs

81% mor

EBOV-Z

37 cs

57% mor

EBOV-Z

60 cs

74% mor

EBOV-S

425 cs

53% mor

EBOV-Z

65 cs

82% mor

EBOV-Z

57 cs

75% mor

EBOV-Z

143 cs

89% mor

EBOV-Z

35 cs

83% mor

EBOV-S

17 cs

41% mor

EBOV-Z

264 cs

71% mor

EBOV-B

149 cs

25% mor

EBOV-Z

32 cs

47% mor

EBOV-S

11 cs

36% mor

EBOV-S

6 cs

50% mor

EBOV-B

36 cs

36% mor

1967

Marb

31 cs

23% mor

Marb

154 cs

83% mor

EVD

26159 cs until Apr 24, 2015

CFR ~40%

2014 -

2015

Cumulative epidemic curves in the three most affected WA countries

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22 April 2015

Partnership to accelerate vaccine development in response to the

WHO-declared public health emergency

- WHO statement on Western African Ebola outbreak (August 8, 2014) : “The conditions for a Public Health Emergency of

International Concern (PHEIC) are met”

- WHO virtual press conference (August 12, 2014) : “ There is unanimous agreement among the experts that given the

special circumstances of this Ebola outbreak it is ethical to offer unregistered interventions as potential treatments or

prevention”

- WHO formal request to GSK to help making a vaccine available to assist in the control of the outbreak (August 13, 2014).

Specific target: high-risk Health Care workers (HCWs).

• An international initiative – The Wellcome Trust, UK Government Department for International Development, UK Medical

Research Council, the European Commission, Swiss Government, Bill & Melinda Gates Foundation, and the US

Government (NIH, CDC, BARDA)

• WHO-sponsored meetings in September 2014 addressed the following questions:

– Prioritization of the Ebola vaccine development efforts;

– Quantity and timing of vaccine doses needed;

– Clinical studies scheduling and evaluation of efficacy;

– Financing of vaccines and vaccination programmes

7 *VRC = Vaccine Research Center of the National Institute of Allergy and Immunology (NIAID) of the US National Institutes of Health (NIH).

http://www.who.int/mediacentre/events/meetings/2014/ebola-vaccine-access/en/

Recombinant viral vectors

as delivery systems for Filovirus-derived antigens

ChAd3-GP MVA-GP

Chimpanzee derived Adenovector & Modified Vaccinia virus Ankara

Filovirus antigens

1. Ebola Zaire Glycoprotein (GP)

2. Ebola Sudan GP

3. Marburg Angola GP

Registered as GlaxoSmithKline Biologicals SA 8

&

&

Single injection for acute protection

Production on proprietary Procell92.S (mod.

HEK 293)

Heterologous boost for long-term protection

Production on CEF

Emergency Use

Single dose of ChAd3-EBO-Z

Monovalent Zaire

Studies for Chimpanzee Adenovirus Type 3 Ebola Zaire vaccine candidate

08/14 09/14 10/14 11/14 12/14 01/15 02/15 03/15 04/15 05/15 06/15 07/15

VRC 207, Phase 1, VRC/NIAID, US

EBL01, Phase 1, Oxford Univ, UK

EBL03, CVD-Mali, Phase 1, Maryland Univ, Mali

Phase 1/2, Univ Lausanne (WHO), Switzerland

Phase 3 study (PREVAIL, sponsor NIH)

Phase 2 studies

WHO call

8 August Ph.I data evaluation

10

The ChAd3-EBO-Z vaccine candidate:

Clinical development

Confidential - GSK proprietary

information

Pre-clinical evidence for the ChAd3-EBO-Z

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• Infected by human filoviruses (Ebola, Marburg)

• Similar kinetics and type of disease compared to humans (faster onset)

• 100% mortality rate (higher than humans)

• Immunological assays available

• 100% protection at short term after single vaccination (using 1010vp dose)

Cynomolgus macaques:

ChAd3-EBO-Z clinical development overview

Phase 1 (US, UK, Mali, Switzerland) data available mid-January 2015

for dose selection. Multiple Sponsors. GSK-supported

Phase 2 controlled trials in adults (n=3000) and children (n=600) in

Mali, Ghana, Nigeria, Senegal and Cameroon. GSK-sponsored. EC-

funded.

Phase 3 program in collaboration with NIH in Liberia (PREVAIL).

Sponsor NIH. GSK-supported

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Overall timings – Regulatory

Oct-2014 Nov-2014 Dec-2014 Jan-2015 2015

AVAREF

Discussions on pathways

for local CTA appprovals

WHO-

coordinated Joint

Review

GSK/EMA & US FDA interactions on Ph.2/3

CTA submission

Ph.2 study start

Ph.3 PREVAIL

Ph.I data evaluation

CTA approvals

Inclusion of the

dose in the

pharmacy manual

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Phase 1 studies

Confidential - GSK proprietary

information

Phase 1 Ebola trials: planned and ongoing

Trial Site PI Product (dose) Phase N Start Date

VRC 207 NIH Ledgerwood Bivalent

2e10 & 2e11 1 20 2 Sept 2014

VRC 207 Part 2 Emory and VRC Ledgerwood/ Mulligan

Bivalent

2e11 (n=100)

+ n=10 (VRC)

Boost DNA WT EBO (VRC

206)

1b 100 +10 30 Oct 2014

VRC 207 Part 2 UMD Ledgerwood/

Lyke

Monovalent

1e10 & 1e11 (rando) 1 20 31 Oct 2014

EBL01 Oxford - UK Hill Monovalent

1e10 & 2.5e10 & 5e10 1 60 17 Sept 2014

EBL03 CVD-1000 Mali Sow/Levine

Monovalent

1e10 (n=10) & 2.5e10 &

5e10

1 80 8 Oct 2014

cAd3-EBOZ Lau Lausanne Genton Monovalent

2.5e10 & 5e10 (rando) 2a 120 31 Oct 2014

RV422 MUWRP - Uganda Kibuuka

Bivalent

2e10 & 2e11

Monovalent

1e10 & 1e11

1 90 Feb 2015

CVD-Mali 2000 UMD - Mali Sow Bivalent

2e10 & 2e11 1b 30 Mar 2015

15

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PREVAIL, NIH sponsor, Liberia

Confidential - GSK proprietary

information

PREVAIL, Liberia

• Randomized 1:1:1 to ChAd3-EBO-Z, VSVDG-ZEBOV or saline placebo.

• Adults aged ≥ 18 yrs without a history of EVD, pregnancy, breast-feeding or fever ≥ 38°C. All eligible volunteers providing informed consent are randomized to vaccine or control.

• Primary endpoint is lab-confirmed EVD occurring 21 days or more after vaccination. Monthly follow-up per subject.

• 9390 subjects per study arm will provide >90% power to detect VE>50% (assuming EVD incidence of 1% per year, 112 EVD cases are required for each of the two vaccines)

• In-study procedures kept to a minimum. Subjects followed for outcome (occurrence of EVD). In the event of suspected EVD, blood for RT-PCR for diagnosis.

• Subset assessed for reactogenicity and immunogenicity, biochemistry, haematology, D-dimer, PT, HIV and syphilis testing

• Predefined event-driven efficacy assessment by DSMB with appropriate alpha adjustment

• Study continues until either VE or futility is confirmed using conditional power calculations to guide DSMB

• Enrolment started on Feb 2.

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Percent with Ebola after 12

Months in the Control Group (%)

Combined Sample Size

(number per arm)

0.75 37,560 (12,520)

1.0 28,170 (9,390)

1.3 21,660 (7,220)

1.6 17,580 (5,860)

1.9 14,790 (4,930)

2.2 12,780 (4,260)

2.5 11,250 (3,750)

Combined sample size (and number per group) for comparing each vaccine versus placebo for EVD

(90% power to detect 50% vaccine efficacy; 0.025 (2-sided) level of significance).

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Phase 2 studies

Confidential - GSK proprietary

information

Sites selected for the Phase 2 studies

adult

paediatric

Conclusions and perspectives

• Single ChAd3-EBO-Z vaccination approach as a response to the Ebola Zaire epidemic in

Western Africa

• Phase 1 studies conducted with ChAd3-EBO-Z in US, UK, Switzerland and Mali to select the

dose for phase 2 and phase 3 studies; dose selection made Mid-January 2015

• Fast deployment of phase 3 intervention in Liberia

• Phase 2 program to support licensure of the single ChAd3-EBO-Z vaccination approach (safety

and immunogenicity data in African populations)

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Thank you