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Development of the HPV 16 / 18 Cervical Cancer Vaccine
James P. Tursi, MD Director – Medical Affairs – N.A. Cervical Cancer Vaccines
August 3, 2006
Overview
• GSK Biologicals • Search for a cervical cancer vaccine• GSK HPV 16/18 candidate vaccine
–Novel adjuvant system resulting in strong and sustained immune responses
–Focus on cervical cancer prevention• Clinical trial data
–Efficacy data–Immunogenicity data–Broad oncogenic protection
• Current status of the GSK HPV 16/18 candidate vaccine
Wyeth-Ayerst12%
GSK23%
Chiron9%
Others11%
AP/AP-MSD26%
Merck19%
GlaxoSmithKline Biologicals: One of the World’s Leaders in Vaccines
Total market*: $8 billion
*2003
World’s Firsts
1986Recombinant hepatitis B
vaccine
Rubella 1969
1976Thermostabl
e measles vaccine
Varicella Vaccine
1984
Hepatitis A vaccine
1992
1996Combined DTPw HBV
& Hib
Combined Hepatitis A &
B1996
Combined Meningitis ACW135
2003
Long History of Innovation
1997Combined DTaP/Hib
& DTaP IPV
DTaP HBV IPV
2000
2000Combined Hepatitis A& Typhoid
Contributions to World’s Health
• In 2004, nearly one and a half billion GSK vaccines distributed– Approximately 85% delivered to the developing world– Nearly three million doses each day
• Primary Supplier to International Health Organizations– UNICEF– WHO– PAHO
• GSK provides vaccines to developing world at affordable cost– Introduce new vaccines where most needed, not where most
financially advantageous
• Every two minutes a woman dies of cervical cancer worldwide
– 10 women die every day in the U.S.
• All sexually active women are at risk of oncogenic HPV†
– Includes women over age 25
• HPV-16 / 18 / 45 / 31 are responsible for ~80% of invasive cervical cancers worldwide°
• Adenocarcinoma of the cervix is increasing despite screening effortsX
– HPV 16 / 18 / 45 / 31 responsible for 98% of cervical adenocarcinoma
Cervical Cancer – The Scope of the Problem
† Koutsky 1997 Am J Med 1997; 102(5A): 3-8°Munoz N et al. Int J Cancer 2004; 111: 278–85.XCastellsagué J Natl Cancer Inst 2006;98:303 – 15
Search for a Cervical Cancer Vaccine
• Safe• Immunogenic
–Strong immune response against oncogenic HPV
–Provide high protective levels of antibody
• Broad protection against cervical cancer –Protect women from oncogenic HPV
–Protect against the most common types
• Provide long lasting duration of protection–Sustained immune response
–Long term protection
GSK’s HPV 16/18 Cervical Cancer Vaccine
• Novel GSK Adjuvant System• AS04 (Al + MPL®)
• To enhance immune responses
• Vaccine composition• 20 µg HPV 16 L1 VLP
• 20 µg HPV 18 L1 VLP
• Administration schedule – 0, 1, 6 months
• Focus on cervical cancer prevention• Oncogenic HPV
• Directed to women
• Continuation of current cervical cancer screening methods
• 50 µg MPL®
• 500 µg AlOH3
AS04
GSK’s HPV 16/18 Cervical Cancer Vaccine
• Novel GSK Adjuvant System• AS04 (Al + MPL®)
• To enhance immune responses
• Vaccine composition• 20 µg HPV 16 L1 VLP
• 20 µg HPV 18 L1 VLP
• Administration schedule – 0, 1, 6 months
• Focused on cervical cancer prevention• Oncogenic HPV
• Directed to women
• Continuation of current cervical cancer screening methods
• 50 µg MPL®
• 500 µg AlOH3
AS04
• From latin ‘adjuvare’: to help• An adjuvant can be an immunostimulant and/or a
carrier– carrier: a compound that transports the antigen:
AlOH3– immunostimulant: a compound that acts directly
or indirectly on the immuno competent cells to increase the immune response to a given antigen : MPL®
• It is designed to increase the specific immune response intensity, quality and breadth
What is an Adjuvant?
Novel Adjuvant: Why AS04 for HPV?
• Prevention of HPV infection requires presence of neutralizing antibodies at the site of potential infection (cervix)
• High serum antibody concentrations that then transudate to the site of the infection
• AS04 versus traditional aluminum*– Higher and more persistent humoral antibody
response
– Higher frequency of memory B cells
* Giannini S et al. Vaccine 2006
0 8 16 24 32 40 480
100
200
300
400
800
1000 anti-J4 HPV18
0 8 16 24 32 40 480
100
200
300
400
800
1000 anti-V5 HPV16Anti-V5 (HPV-16)Anti-J4 (HPV-18)
****
** ** **
**
**
**
** ** **
**
* Statistically significant
GM
T (
EU
/ml)
Al(OH)3
AS04 Al(OH)3
AS04
Time (months)
Giannini SL et al. Vaccine 2006
Neutralizing Antibody
Enhanced and Sustained Immunogenicity Over 4 Years
AS04 versus Aluminum
Clinical Experience with AS04 Adjuvant
• AS04 used in several vaccines developed by GSK
– Superiority of immune profile induced by AS04 vs alum formulations
– 16,000 subjects received ~43,000 doses of AS04 in 40 completed and 4 ongoing studies
– gD-AS04 (genital HSV vaccine)- Now in large-scale phase III trials including NIH collaboration)
– FENDrix™- adjuvanted HBsAg for use in hemodialysis patients; recently approved in EU (2005)
– Generally well tolerated
GSK’s HPV 16/18 Cervical Cancer Vaccine
• Novel GSK Adjuvant System• AS04 (Al + MPL®)
• To enhance immune responses
• Vaccine composition• 20 µg HPV 16 L1 VLP
• 20 µg HPV 18 L1 VLP
• Administration schedule – 0, 1, 6 months
• Focused on cervical cancer prevention• Oncogenic HPV
• Directed to women
• 50 µg MPL®
• 500 µg AlOH3
AS04
HPV Types in Cervical Cancer
Cancer cases attributed to the most frequent HPV genotypes (%)
HPV genotype
Vaccine types
2.32.21.41.31.21.00.70.60.50.31.2
4.4
53.5
2.6
17.26.7
2.9
0 10 20 30 40 50 60 70 80 90 100
XOther
827368395156593558523331451816 53.5%
70.7%77.4%80.3%
Munoz N et al. Int J Cancer 2004; 111: 278–85.
HPV Types in Cervical Adenocarcinoma
Adenocarcinoma cases attributed to the listed HPV genotypes (%)
HPV genotype
Vaccine types
52.1
39.0
6.2
0.7
0 10 20 30 40 50 60 70 80 90 100
31
45
18
16 52.1%
91.1%
97.3%
98.0
Castellsague X et al. JNCI 2006; 98: 303–15.
HPV – The Disease Burden in Women
• 90.3% of cancers attributable to oncogenic HPV occur solely in women
–Cervix – 86.5%
–Vulva / Vagina – 3.8%
• This does not include other sites of cancer attributable to oncogenic HPV
–Anal
–Oro-pharyngeal
–Mouth
Parkin DM et al. Int J Cancer 2006; 118: 3030–44.
Study HPV 001
0
10
2030
4050
60
7080
90100
Initial efficacy study (001) 001 / 007 combined analyses
Figure based on Harper et al. Lancet. 2004; 364: 1757
6M Persistent Infection
12M Persistent Infection post hoc analysis
Cytology CINIncident Infection
HPV-16/18 associatedVaccine efficacy (%)
92%100% 93%100%100%
ATP
ATP
ITT ITTATP
0
1020
30
4050
60
7080
90
100
Initial efficacy study (001) 001 / 007 combined analyses
Study HPV 007
ATPATP ATP ITT ITT
94%97% 100%96%100%
Harper et al. Lancet. 2006; 367 : 124.Figure based on Harper et al. Lancet. 2004; 364: 1757
6M Persistent Infx
12M Persistent Infection post hoc analysis
Cytology CINIncident Infection
HPV-16/18 associatedVaccine efficacy (%)
92%100% 93% 100%
100%
ATP
ATP
ITT ITTATP
Sustained Seropositivity andHigh Antibody Levels up to 4.5 Years
0%17%
0% 0%12%11%12%10%10%6%
100%100%
100%99%99%99.7%
100%
100%
1
10
100
1000
10000
month 0 month 7 month 12month 18[M25-M32][M33-M38][M39-M44][M45-M50][M51-M53]
Vaccine HPV-16 IgGPlacebo IgG
% seropositive
log (ELU/ml)
Months follow up timeHPV-001 HPV-007
NaturalInfection
HPV-16
17 fold higher
Figure based on Harper et al. Lancet. 2004; 364: 1757
1
10
100
1000
10000
month 0 month 7 month 12month 18[M25-M32][M33-M38][M39-M44][M45-M50][M51-M53]
log (ELU/ml)
Months follow up timeHPV-001 HPV-007
0%17%
0% 0%9%13%16%12%7%
100%100%
99%99%99%99.7%
100%
100%
10%
Vaccine HPV-18 IgGPlacebo IgG
% seropositive
HPV-18
NaturalInfection
14 fold higher
Sustained Seropositivity andHigh Antibody Levels up to 4.5 Years
Figure based on Harper et al. Lancet. 2004; 364: 1757
p-values
0.033
0.042
0.003
<0.001
CIN2+
CIN1+
LSIL
ASCUS
Endpoint
GSK studies 001 & 007 up to 4.5 yearsFirst Evidence of Broader Protection
Independent of HPV DNA status
Harper et al. Lancet. 2006; 367 : 124. ITT analysis, Conditional Exact method
1Clifford et al. Cancer Epidemiol Biomarkers Prev 2005; 14(5). 2Muñoz et al. N Engl J Med 348;6
50%2
25-30%1
25-30%1
20-30%1
Estimated prevalence of
HPV-16/18
73.3 (-1.0-95.2)
51.5 (-0.9-77.9)
44.6 (17.4-63.3)
39.8 (20.9-54.4)
114703481
2447012481
7049741505
13849790505
nNnN
Vaccine efficacy (%)(95% CI)
PlaceboVaccine
GSK studies 001 & 007 up to 4.5 yearsFirst evidence of cross protection types 45 & 31
Study not powered to evaluate cross protection against all individual types
Harper et al. Lancet. 2006; 367 : 124.Combined initial efficacy and extended follow up studies
Incident infection with most common oncogenic types beyond 16 & 18
14.0 (-87.9-61.1)1.1 (0.6-1.8)165170.9 (0.5-1.6)14529HPV-58
18.6 (-26.5-47.8)3.5 (2.6-4.6)485152.8 (2.0-3.8)40524HPV-52
8.6 (-117.3-61.9)0.9 (0.5-1.5)135190.8 (0.4-1.4)12529HPV-33
54.5 (11.5-77.7)
2.1 (1.4-3.0)305160.9 (0.5-1.6)14528HPV-31
94.2 (63.3-99.9)
1.2 (0.7-1.9)175180.1 (0.0-0.4)1528HPV-45
RatenNRatenN
HPV Type
Event rate(rate per 100)
(95% CI)
Event rate(rate per 100)
(95% CI)
Vaccine Efficacy (%)
(95% CI)
PlaceboVaccine
GSK studies HPV-001 & 007Major findings
• Duration of protection– Sustained efficacy against HPV 16 / 18 infections and
associated lesions for up to 4.5 years – Longest peer-reviewed efficacy follow up for any
commercial formulation • Sustained immune response
– Persistent antibody levels in virtually 100% of patients over 4.5 years
• Broad oncogenic protection– Efficacy beyond 16/18 (broader protection) largely due
to cross protection against HPV types 31 and 45
*Harper April 6, 2006 Lancet OnlineHarper et al. Lancet. 2006; 367 : 124.
1921SAEs reported
19 (5.5%)16 (4.6%)Women with at least one SAE reported
Serious adverse events
1910NOCD events reported
18 (5.2%)10 (2.9%)Women with at least one NOCD event reported
New Onset Chronic Disease (NOCD)*
9865Adverse events reported
81 (23.5%)54 (15.4%)Women with at least one adverse event reported
Adverse events
PlaceboN (%)
VaccineN (%)
GSK study HPV-007Safety Profile during Extended Follow Up
Harper et al. Lancet. 2006; 367 : 124. *Including auto immune diseasesATP Safety analysis
• Pre-teen/adolescent girls
– HPV-012 Immunological bridge 10-14 yrs and 15-25 yrs Safety/reactogenicity
• Women >25 years
– HPV-014
Immunological bridge 15-25 yrs and 26-55 yrs Safety
Age Bridging Trials
0
10
20
30
40
50
60
70
80
90
100
Any Symptoms General Symptoms Local Symptoms
• 100% of initially seronegative subjects seroconverted to both HPV-
16 and HPV-18 positive • GMTs in 10-14 yr olds >2-fold higher than 15-25 yr olds
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
HPV-16 HPV-18
15-25 yrs10-14 yrs
HPV-012 Results
Solicited symptoms within 7 days (ATP cohort)
HPV-16 and -18 ELISA GMTs (Month 7)
Any symptom General symptoms Local symptomsHPV-16 HPV-18
Geo
met
ric M
ean
Tite
r (E
U/m
l)
% D
oses
fol
low
ed b
y sy
mpt
oms
Dubin G, et al. Poster 4042, ICAAC, 2005, Washington, D.C. ,USA
• Pre-teen/adolescent girls
– HPV-012 Immunological bridge 10-14 yrs and 15-25 yrs Safety/reactogenicity
• Women >25 years (HPV-014)– HPV-014
Immunological bridge 15-25 yrs and 26-55 yrs Safety
Age Bridging Trials
HPV-014 - Results
• Month 7–100% of subjects were seropositive to both HPV-16 and
HPV-18 with high GMTs at month 7
–Age dependent decrease in GMTs but absolute values were high
HPV-16 Antibody Levels – Efficacy Study 001 / 007
1
10
100
1000
10000
0 7 12 18 45-5033-38
Month
Natural Infection
15 – 25 y.o.
Efficacy study
Harper et al. Lancet 2006; 367: 1247-55
HP
V-1
6 G
MC
E
U/m
l
1
10
100
1000
10000
0 7 12 18 45-50
15-25y
33-38
Efficacy study
Natural Infection
15 – 25 y.o.
Month
HP
V-1
6 G
MC
E
U/m
l
HPV 16 Antibody Levels by Age Group Study 014
Harper et al. Lancet 2006; 367: 1247-55Shwarz, T, et al. ASCO, 2006, Atlanta,USA
1
10
100
1000
10000
0 7 12 18 45-50
15-25y26-35y
33-38
Efficacy study
Natural Infection
15 – 25 y.o.
Month
HP
V-1
6 G
MC
E
U/m
l
Harper et al. Lancet 2006; 367: 1247-55Shwarz, T, et al. ASCO, 2006, Atlanta,USA
HPV 16 Antibody Levels by Age Group Study 014
1
10
100
1000
10000
0 7 12 18 45-50
36-45y
15-25y26-35y
33-38
Efficacy study
Natural Infection
15 – 25 y.o.
Month
HP
V-1
6 G
MC
E
U/m
l
Harper et al. Lancet 2006; 367: 1247-55Shwarz, T, et al. ASCO, 2006, Atlanta,USA
HPV 16 Antibody Levels by Age Group Study 014
1
10
100
1000
10000
0 7 12 18 45-50
36-45y46-55y
15-25y26-35y
33-38
Efficacy study
Natural Infection
15 – 25 y.o.
Month
HP
V-1
6 G
MC
E
U/m
l
26 fold higher
Harper et al. Lancet 2006; 367: 1247-55Shwarz, T, et al. ASCO, 2006, Atlanta,USA
HPV 16 Antibody Levels by Age Group Study 014
1
10
100
1000
10000
0 7 12 18 33-38
MonthHarper et al. Lancet 2006; 367: 1247-55
HP
V-1
8 G
MC
EU
/ml
Efficacy study15-25y
36-45y46-55y
26-35y
16 fold higher
Natural Infection
15 – 25 y.o.
0 7 12 18 45-5033-38
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
HPV 18 Antibody Levels by Age Group Study 014
Study HPV 014 - Conclusions
1 Harper et al. Lancet 2006; 367: 1247-55
In all age groups, the vaccine was:• Generally well tolerated
• Highly immunogenic :– Seroconversion : 100% for both antigens as early as the 2nd
dose of vaccine
– Antibody levels
– at least 16-26 times higher than those associated with natural HPV infection
– ≥ levels of antibodies associated with protection against HPV infection and its associated outcomes 1
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Safety profile in women 15-55 years of age%
pa
rtic
ipa
nts
ov
era
ll d
os
e
0
20
40
60
80
100
Pain Redness Swelling Myalgia Fever
15-25 years
26-35 years
36-45 years
46-55 years
>95% study compliance
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Phase III Efficacy Program
GSK efficacy study (HPV 008)
NCI supportive study (HPV 009)
Double blind, randomised, controlled
Double blind, randomised, controlled
Multi-centre (90+) Population-based
Multi-country (14) > 6 centres in Costa Rica
18,665 women aged 15–25 years
7465 women aged 18–25 years
CIN II+ CIN II+
China
South Korea
Denmark
The Philippines
France
Germany
Honduras
Panama
Colombia
Australia
Norway Sweden
Czech Republic
Taiwan
Brazil
Canada
Mexico
Thailand
Spain
Italy
Belgium
Finland
Costa Rica
Greece
EstoniaUnited Kingdom
Russia
Poland
USA
Peru
Portugal
Lithuania
India
Japan
Malaysia
Hong Kong
The Netherlands
South Africa
Senegal
Nigeria
GSK HPV 16/18 Vaccine Global Clinical Development Plan
Timings: Ongoing Trials
2005 2006 2007 2008 2009
HPV-009: CIN2+ efficacy-Costa Rica (N = 7,467)
Y1
HPV-014 (immuno 15-55y)
Y2 Y3
HPV-007 Efficacy Y2 Y3
HPV-012 (immuno 10-25y)
HPV-008: CIN2+ efficacy- global (N = 18,668)
Y1*
LT follow-up
LT follow-up
*4 yrs of follow-up
>30,000 subjects enrolled in ongoing trials
LT follow-up
Long term immunogenicity
HPV-013 (adol. safety)
Conclusions
• GSK’s commitment to those in need–Worldwide and the U.S.
• Search for a cervical cancer vaccine–Novel adjuvant – AS04
• Stronger immune response compared to our vaccine formulated with Al adjuvant
–Focused on cervical cancer
• HPV 16 / 18
–Directed to women
Conclusions (Cont’d)
• Safety profile–Well tolerated in clinical trials
• Immunogenic–No evidence of waning immunity to HPV 16 / 18 through
4.5 years• Broad protection against oncogenic HPV
–Efficacy beyond HPV 16 and 18 due to protection against HPV types 45 and 31
• Long duration of protection–Sustained efficacy against HPV 16 and 18 for up to 4.5
years–Persistent antibody levels in nearly 100% of patients
Harper et al. Lancet. 2006; 367 : 124.