AdVac®-based vaccines against tuberculosis and malaria - Crucell

Crucell
AdVac ® -based vaccines against tuberculosis
and malaria
Maria Grazia Pau
Program Director
March 12 th , 2008
London

Products and pipeline
offering excellent scope for long-term growth
Development stage
Product Pre-clinic Phase I Phase II Phase III Marketed Comment
Quinvaxem TM
Hepavax-Gene ®
MoRuViraten ®
Epaxal ® Junior
Epaxal ®
Vivotif ®
Dukarol ®
Inflexal V ®
Flavimun ®
Fully liquid vaccine for protection against five childhood diseases
Recombinant hepatitis B vaccine
Vaccine for protection against measles and rubella (all age groups)
Unique aluminum-free hepatitis A pediatric vaccine (0.25 ml)
Unique aluminum-free hepatitis A vaccine
Unique oral anti-typhoid vaccine
Internationally licensed oral vaccine against cholera (and ETEC)
Virosomal adjuvanted influenza (all age groups)
Yellow Fever vaccine; priority given to production MoRuViraten®
Influenza seasonal Partnered with sanofi pasteur; planned submission in 2010
H9N2 (influenza pandemic) Trial completed; findings expected first half 2008
Rabies antibody cocktail Fast Track Partnered with sanofi pasteur; Phase II US trial to start in 1H 2008
Malaria Phase I trial in US on two sites; initial findings expected in 2008
Tuberculosis
Ebola
H7N1/Flupan (influenza pandemic)
Factor V L/C
Partnered with Aeras Foundation; well tolerated, response to TB antigens
Partnered with VRC of NIAID; initial indication suggest safety & immunogenicity
Developed by sanofi pasteur using Crucell’s technology
Blood coagulation Factor VL/C
HIV Partnered with Harvard; Phase I trial expected to start in Q1 2008
Antibodies against H5N1
Results demonstrating potential pandemic preparedness
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Topics
Vaccine for the prevention of
Tuberculosis
o Tuberculosis: a major health problem
Vaccine for the prevention of
o Preclinical studies AdVac ® -based vaccine against Tuberculosis
Malaria
o Clinical trials with AdVac ® -based vaccine against Tuberculosis
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Tuberculosis is a major cause of death
worldwide
Tuberculosis is endemic in large parts of
Africa, Asia and South America
Basic Facts
‣ Estimated 8.8 MM new TB
cases in 2005
‣ 7.4 MM in sub-Saharan
Africa and Asia
Estimated new TB cases per 100 000 population, 2005
0-24
100-299
25-49 300 or more
50-99 No estimate
http://www.who.int/tb/publications/global_report/2007/download_centre/en/index.html
‣ 1.6 MM people died of TB
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Extensively drug-resistant tuberculosis
(XDR-TB) is a global health threat
XDR-TB is spreading: 41 countries to date
‣ XDR-TB: germs resistant to all
most effective anti TB drugs
Countries with confirmed
XDR-TB cases to data*
*http://www.who.int/tb/xdr/xdrmap_20june_en.pps
‣ Concerns: future TB epidemic
with restricted treatment
options
Based on information provided to WHO Stop TB department
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Current TB vaccine known as BCG is used
extensively throughout the world
The Expanded Program on Immunization
Age
Birth
Vaccines
BCG, (OPV0)
6 wks OPV1, Quinvaxem TM
10 wks OPV2, Quinvaxem TM
14 wks OPV3, Quinvaxem TM
9-12 mo Measles
‣ The current TB vaccine has limited efficacy
‣ Profound need for new TB vaccines
Quinvaxem TM : Crucell’s fully liquid vaccine against diphtheria, tetanus, pertussis (whooping cough), hepatitis B and Haemophilus influenzae type b
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Market for new TB vaccines is driven by
developing and industrialized countries
‣ rBCG: the BCG replacement
vaccine (prime):
50 MM doses p.a.
‣ AdVac ® -based boost
vaccine: 60 MM doses p.a.
Estimated peak annual
market for prime-boost
combination approaches
$ 1 Billion
‣ rBCG prime- AdVac ® boost
strategy: 100 MM doses p.a.
Source: Global Vaccine Market Outlook (2007-2010) RNCOS, November 2007
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AdVac ® -based boost vaccine contains the
gene for highly immunogenic antigens
Ag85A
Ag85B
TBS gene
Ag85A Ag85B 10.4
TB10.4
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Ad35.TBS: AdVac ® -based boost vaccine
for the prevention of tuberculosis
Ag85A Ag85B 10.4
TBS gene
Transfer to Ad35
adenoviral vector
ΔE1 Ad35
Ad35.TBS
Infection of
PER.C6 cells
PER.C6 ®
Vaccination
Tuberculosis vaccine
Manufacturing of Ad35.TBS
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Ad35.TBS induces a T-cell immune
response providing protection against TB
Mouse model
Immunogenicity
Ad35.TBS Challenge
0 6 12 weeks
IFNγ SFU/10 6 cells
500
250
0
T-cell response
CD8 CD4 CD8 CD4
control
Ad35.TBS
colony forming units
x 1,000
2000
1500
1000
500
0
Protection
control
Ad35.TBS
INFECTION AND IMMUNITY, Aug 2007 Vol 75; p4105-4115
40%
Protection
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Ad35.TBS vaccine induces T cell immunity
to the antigens 85A, 85B and 10.4
Non-human primate model
Group 1:
Group 2:
BCG prime
rBCG prime
Ad35.TBS boost
Ad35.TBS boost
0 14 15 16
pre boost
weeks
post boost
1000
Ag85A
1000
Ag85B
1000
TB10.4
T cell response
100
10
T cell response
100
10
T cell response
100
10
1
BCG/Ad35
rBCG/Ad35
1
BCG/Ad35
rBCG/Ad35
1
BCG/Ad35
rBCG/Ad35
Note: T cell response expressed as IFNγ pg/ml
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Ad35.TBS boost vaccine to protect infants
against tuberculosis
Tuberculosis vaccine and the Expanded Program on Immunization
Age
Birth
Vaccines
BCG, (OPV0)
6 wks OPV1, Quinvaxem TM
Ad35.TBS
10 wks OPV2, Quinvaxem TM
Ad35.TBS
14 wks OPV3, Quinvaxem TM
9-12 mo Measles
‣ Efficacy of Ad35.TBS above 50%
‣ Efficacy of BCG is highly variable (0-80%)
Quinvaxem TM : Crucell’s fully liquid vaccine against diphtheria, tetanus, pertussis (whooping cough), hepatitis B and Haemophilus influenzae type b
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TB clinical trial US (C-001-402): design
Open label phase I study
Start: Oct. 2006 (PRA, Clinical Pharmacology Center, Lenexa, US)
Ad35.TBS Ad35 Boost: group 4 only
0
//
2 months
day 2, 7, 14, 28, 42, 84, 182 follow up
‣ Primary endpoint:
• Adverse events
(systemic and locally)
‣ Secondary endpoint:
• Immunogenicity
(T cell responses)
10 8 VP
(n=8)
prime
10 9 VP
(n=8)
prime
10 10 VP
(n=8)
prime
10 10 VP
(n=8)
Group 1 Group 2 Group 3 Group 4
All volunteers were BCG naive
Prime
Boost
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TB clinical trial US (C-001-402): status
Open label phase I study
Start: Oct. 2006 (PRA, Clinical Pharmacology Center, Lenexa, US)
• Follow up completed: safe at all doses tested
• Tuberculosis specific T cell responses following two
doses in the higher dose groups
• Data to be presented at the conference ‘TB Vaccines
for the world’ (9-11 April, 2008, Atlanta, US)
14

TB clinical trial SA (C-003-402): design
Randomized, double-blind, placebo-controlled phase I study
Start: May 2007 (University of Cape Town, South Africa)
Ad35.TBS Ad35.TBS Boost:group 4 only
10 10 VP
(n=7)
10 10 VP
(n=8)
0
//
2 months
10 9 VP
(n=7)
Placebo
(n=3)
Placebo
(n=2)
day 2, 7, 14, 28, 42, 84, 182 follow up
‣ Primary endpoint:
• Adverse events
(systemic and locally)
‣ Secondary endpoint:
• Immunogenicity
(T cell responses)
10 8 VP
(n=7)
Placebo
(n=3)
Placebo
(n=3)
Group 1 Group 2 Group 3 Group 4
All volunteers were BCG vaccinated at birth
(SATVI: South African Tuberculosis Vaccine Initiative)
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TB clinical trial SA (C-003-402): status
Randomized, double-blind, placebo-controlled phase I study
Start: May 2007 (University of Cape Town, South Africa)
• Dose cohorts fully enrolled
• Immunological assessments ongoing
• Results available in H2 2008
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TB clinical trial US (C-008-402 & C-009-402)
Randomized, double-blind, placebo-controlled phase I study
Start: December 2007 (St. Louis Un. Center for Vaccine Development)
Group 1 (n=8)
Group 2 (n=8)
BCG
All volunteers were BCG naive
Ad35.TBS
3x10 10 vp
Ad35.TBS
3x10 10 vp
BCG Placebo Placebo
‣ Primary endpoint:
• Adverse events
‣ Secondary endpoint:
• Immunogenicity
C-008-402
0
84 days 112 days
Ad35.TBS boost expected in Q2, 2008
Preliminary results by end of 2008
C-009-402
0 168 days 196 days
Ad35.TBS boost in Q3 and Q4,08
Preliminary results by H1 2009
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Topics
Vaccine for the prevention of
malaria
o Malaria: a major health problem
o Preclinical studies AdVac ® -based vaccine against Malaria
o Clinical trial with AdVac ® -based vaccine against Malaria
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Malaria is one of the world’s most common
and most deadly parasitic diseases
Malaria is endemic in large parts of Africa,
Asia and South America
Basic facts
‣ 2.5 B people at risk
‣ 500 MM people infected
per year
Increasing malaria endemicity
‣ Between 1 and 2 MM
deaths/year, mainly
children under 5
Source: WHO, World malaria report, 2005
Source: Market assessment for malaria vaccines, January 2005
The Boston consulting group
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The Plasmodium falciparum parasite is
responsible for most of the malaria deaths
Malaria deaths
P. Falciparum is increasing
5%
‣ Sub-Saharan Africa
0.1%
85%
8%
‣ >90% P.falciparum
‣ SE Asia
‣ 80% P. falciparum
‣ India
1%
‣ 45% Pl. falciparum
‣ Eastern Europe, SA
Increasing malaria endemicity
% of malaria
deaths
‣ P.vivax predominates
Source: WHO, World malaria report, 2005 Source: Market assessment for malaria vaccines, January 2005
The Boston consulting group
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Potential malaria vaccine market largely driven
by developing world
‣ Endemic market
~20-30 MM people p.a.
~250-300 MM€
• Infants in endemic countries
• Adults in endemic countries
Short term catch up will generate an additional 300 MM€ p.a.
during first 5-7 years
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Potential malaria vaccine market for travelers
and military
‣ Travel/military market
~8-9 MM people (US &EU) p.a.
~300-400 MM€
• People traveling to areas at risk
• People stationed in areas at risk
International tourism to malaria endemic regions projected to
increase over the next 15 years
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AdVac ® -based malaria vaccine contains the
full length gene for the protective antigen
CS gene
Vol 10:4 2004
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Ad35.CS: Crucell’s malaria vaccine for the
prevention of severe clinical malaria
Malaria CS gene
Transfer to Ad35
adenoviral vector
ΔE1 Ad35
Ad35.CS
Infection of
PER.C6 cells
PER.C6 ®
Vaccination
Crucell’s Malaria vaccine
Manufacturing of Ad35.CS
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Ad35.CS vaccine induces immune response
and protect against malaria challenge
Mouse model: Plasmodium yoelii
Ad35.CS
0
days
Immunogenicity
Challenge
14 +42 h
Antibody response
CS antibody titer
10000
1000
100
10
SFU / 10 6 splenocytes
T-cell response
6000
4000
2000
0
% protection
Protection
100
75
50
25
0
Protection
INFECTION AND IMMUNITY, Jan. 2006, p. 313-320
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Ad35.CS induces CS-specific antibody and
T-cell response
Non-human primate model: Plasmodium falciparum
Antibody response
T-cell response
1000
400
Ad35.CS
Ad35.CS
EU
100
SFU / 10 6 PBMC
300
200
100
10

Malaria vaccine to protect infants against
severe clinical malaria in endemic regions
Malaria vaccine and The Expanded Program on Immunization
Age
Birth
Vaccines
BCG, (OPV0)
6 wks OPV1, Quinvaxem TM 1
Ad35.CS
10 wks OPV2, Quinvaxem TM 2
Ad35.CS
14 wks OPV3, Quinvaxem TM 3
Ad35.CS
9-12 mo Measles
Infants in endemic regions
‣ Efficacy
• Reduction of severe clinical malaria > 50%
• Duration of protection should be > 2 years
Quinvaxem TM : Crucell’s fully liquid vaccine against diphtheria, tetanus, pertussis (whooping cough), hepatitis B and Haemophilus influenzae type b
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Malaria vaccine to protect travelers and
military against malaria
‣ Administration
• Single, intramuscular dose of Ad35.CS followed by one (two) boost
‣ Efficacy
• Protection needed above 85%
• Duration of protection at least 12 months
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Malaria clinical trial: design
Randomized double-blind, placebo-controlled phase I study
Start: December 2006 (Vanderbilt and Stanford University)
Ad35.CS
Ad35.CS Boost
10 11 VP
(n=15)
10 10 VP
(n=15)
Placebo n=3
0
1
‣ Primary endpoint:
• Adverse events
(systemic and locally)
6 months
‣ Secondary endpoint:
• Immunogenicity
(antibody and T cell responses)
10 8 VP
(n=15)
Placebo n=3
10 9 VP
(n=15)
Placebo n=3
Placebo n=3
Group 1 Group 2 Group 3 Group 4
Boost
vaccinations ongoing
Start Feb, 2008
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Take home
Vaccine for the prevention of Tuberculosis
o Crucell’s vaccine is one of the most advanced and promising in industry
o Manufacturing process suited to provide the entire world’s need
o Distribution infrastructure in place to maximize the vaccine reach
Vaccine for the prevention of malaria
o Crucell’s vaccine showed superior T cell responses over competition
o Vaccine proven safe and tolerated in clinical trial
o Program will profit from the the TB experience
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