gsk ebola vaccine development an emergency response · 2015-04-29 · - who formal request to gsk...
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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).
18
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