1. Development of the HPV 16 / 18 Cervical Cancer Vaccine
James P. Tursi, MD Director – Medical Affairs – N.A Cervical Cancer Vaccines
August 3, 2006

2. 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

3. GlaxoSmithKline Biologicals: One of the World’s Leaders in Vaccines
Total market*: $8 billion
Merck
19%
AP/AP-MSD
26%
Wyeth-Ayerst
12%
Others
11%
GSK
23%
Chiron 9%
*2003

4. Long History of Innovation
World’s Firsts
Varicella Vaccine
1984
Hepatitis A vaccine
1992
Combined Hepatitis A & B
1996
Combined Meningitis ACW135
2003
Rubella
1969
DTaP HBV IPV
2000
1976
Thermostable measles vaccine
1986
Recombinant hepatitis B vaccine
1996
Combined DTPw HBV & Hib
1997
Combined DTaP/Hib & DTaP IPV
2000
Combined Hepatitis A & Typhoid

5. 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

6. Cervical Cancer – The Scope of the Problem
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
† 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

7. 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
Natural infection issues.

8. 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
Why we chose two types.

9. 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
Why we chose two types.

10. What is an Adjuvant? 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

11. 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

12. Enhanced and Sustained Immunogenicity Over 4 Years
AS04 versus Aluminum
Neutralizing Antibody *
Anti-V5 (HPV-16) *
Anti-J4 (HPV-18)
Al(OH) 3
AS04
Al(OH) 3
AS04 * * *
GMT (EU/ml) * * * * * * *
Time (months)
Enhanced and Sustained Immunogenicity Over 4 Years
* Statistically significant
Giannini SL et al. Vaccine 2006

13. 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

14. 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

15. HPV Types in Cervical Cancer
HPV genotype 16
53.5
53.5%
Vaccine
types 18
17.2
70.7% 45
6.7
77.4% 31
2.9
80.3% 33
2.6 52
2.3 58
2.2 35
1.4 59
1.3 56
1.2 51
1.0 39
0.7 68
0.6 73
Multiple types vs. two
0.5 82
0.3
Other
1.2 X
4.4 10 20 30 40 50 60 70 80 90
100
Cancer cases attributed to the most frequent HPV genotypes (%)
Munoz N et al. Int J Cancer 2004; 111: 278–85.

16. HPV Types in Cervical Adenocarcinoma
HPV genotype 16
52.1
52.1%
Vaccine
types 18
39.0
91.1% 45
6.2
97.3% 31
0.7
98.0 10 20 30 40 50 60 70 80 90
100
Adenocarcinoma cases attributed to the listed HPV genotypes (%)
Castellsague X et al. JNCI 2006; 98: 303–15.

17. 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.

18. Clinical Trial Data

19. Study HPV 001 HPV-16/18 associated Vaccine efficacy (%) 6M Persistent
92%
100%
100%
93%
100%
ATP
ATP
ATP
ITT
ITT
6M Persistent
Infection
12M Persistent
Infection post
hoc analysis
Cytology
CIN
Incident
Figure based on Harper et al. Lancet ; 364: 1757

20. Study HPV 007 HPV-16/18 associated Vaccine efficacy (%) 6M Persistent
92%
100%
100%
93%
100%
97%
94%
100%
96%
100%
Sustained Protection up to 4.5 years
ATP
ATP
ATP
ITT
ITT
ATP
ATP
ATP
ITT
ITT
6M Persistent
Infx
12M Persistent
Infection post
hoc analysis
Cytology
CIN
Incident
Infection
Figure based on Harper et al. Lancet ; 364: 1757
Harper et al. Lancet ; 367 : 124.

21. Sustained Seropositivity and High Antibody Levels up to 4.5 Years
log (ELU/ml)
HPV-16
10000 6%
100%
99%
99.7%
% seropositive
Vaccine HPV-16 IgG
Placebo IgG
1000
100
17 fold higher
Natural
Infection 10 0%
17%
12%
11%
10% 1
month 0
month 7
month 12
month 18
[M25-M32]
[M33-M38]
[M39-M44]
[M45-M50]
[M51-M53]
HPV-001
HPV-007
Months follow up time
Figure based on Harper et al. Lancet ; 364: 1757

22. Sustained Seropositivity and High Antibody Levels up to 4.5 Years
log (ELU/ml)
HPV-18
10000
% seropositive
Vaccine HPV-18 IgG
100%
99%
99.7%
10%
Placebo IgG
1000
100
14 fold higher
Natural
Infection 10 0%
17% 9%
13%
16%
12% 7% 1
month 0
month 7
month 12
month 18
[M25-M32]
[M33-M38]
[M39-M44]
[M45-M50]
[M51-M53]
HPV-001
HPV-007
Months follow up time
Figure based on Harper et al. Lancet ; 364: 1757

23. Estimated prevalence of
GSK studies 001 & 007 up to 4.5 years First Evidence of Broader Protection
Independent of HPV DNA status
Endpoint
Vaccine
Placebo
Vaccine efficacy (%)
(95% CI)
p-values
50%2
25-30%1
20-30%1
Estimated prevalence of
HPV-16/18 N n N n
ASCUS
505 90
497
138
39.8 ( )
<0.001
LSIL
505 41
497 70
44.6 ( )
0.003
CIN1+
481 12
470 24
51.5 ( )
0.042
CIN2+
481 3
470 11
73.3 ( )
0.033
Harper et al. Lancet ; 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

24. Incident infection with most common oncogenic types beyond 16 & 18
GSK studies 001 & 007 up to 4.5 years First evidence of cross protection types 45 & 31
Incident infection with most common oncogenic types beyond 16 & 18
HPV Type
Vaccine
Placebo
Vaccine Efficacy (%)
(95% CI)
Event rate
(rate per 100)
(95% CI)
Event rate
(rate per 100)
(95% CI) N n
Rate N n
Rate
HPV-45
528 1
0.1 ( )
518 17
1.2 ( )
94.2 ( )
HPV-31
528 14
0.9 ( )
516 30
2.1 ( )
54.5 ( )
HPV-33
529 12
0.8 ( )
519 13
0.9 ( )
8.6 ( )
HPV-52
524 40
2.8 ( )
515 48
3.5 ( )
18.6 ( )
HPV-58
529 14
0.9 ( )
517 16
1.1 ( )
14.0 ( )
Study not powered to evaluate cross protection against all individual types
Harper et al. Lancet ; 367 : 124.
Combined initial efficacy and extended follow up studies

25. GSK studies HPV-001 & 007 Major 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 et al. Lancet ; 367 : 124.
*Harper April 6, 2006 Lancet Online

26. GSK study HPV-007 Safety Profile during Extended Follow Up
Vaccine
N (%)
Placebo
N (%)
Adverse events
Women with at least one adverse event reported
54 (15.4%)
81 (23.5%)
Adverse events reported 65 98
New Onset Chronic Disease (NOCD)*
Women with at least one NOCD event reported
10 (2.9%)
18 (5.2%)
NOCD events reported 10 19
Serious adverse events
Women with at least one SAE reported
16 (4.6%)
19 (5.5%)
SAEs reported 21 19
Harper et al. Lancet ; 367 : *Including auto immune diseases
ATP Safety analysis

27. Age Bridging Trials Pre-teen/adolescent girls
HPV-012 Immunological bridge yrs and yrs Safety/reactogenicity
Women >25 years
HPV-014
Immunological bridge yrs and yrs
Safety

28. HPV-012 Results
HPV-16 and -18 ELISA GMTs (Month 7)
Solicited symptoms within 7 days (ATP cohort)
15-25 yrs
10-14 yrs
Geometric Mean Titer (EU/ml)
% Doses followed by symptoms
HPV HPV-18
Any symptom General symptoms Local symptoms
100% of initially seronegative subjects seroconverted to both HPV-
16 and HPV-18 positive
GMTs in yr olds >2-fold higher than yr olds
Dubin G, et al. Poster 4042, ICAAC, 2005, Washington, D.C. ,USA

29. Age Bridging Trials Pre-teen/adolescent girls
HPV-012 Immunological bridge yrs and yrs Safety/reactogenicity
Women >25 years (HPV-014)
HPV-014
Immunological bridge yrs and yrs
Safety

30. HPV 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
Of note: 100% seropositive one month after 2nd dose
Of note: GMTs in 46 to 55 yr age group higher than those achieved during the plateau phase of HPV-001/007

31. HPV-16 Antibody Levels – Efficacy Study 001 / 007
10000
1000
HPV-16 GMC EU/ml
100
Natural
Infection
15 – 25 y.o. 10 1 7 12 18
33-38
45-50
Month
Harper et al. Lancet 2006; 367:

32. HPV 16 Antibody Levels by Age Group Study 014
Efficacy study
10000
15-25y
1000
HPV-16 GMC EU/ml
100
Natural
Infection
15 – 25 y.o. 10 1 7 12 18
33-38
45-50
Month
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Harper et al. Lancet 2006; 367:

33. HPV 16 Antibody Levels by Age Group Study 014
Efficacy study
10000
15-25y
26-35y
1000
HPV-16 GMC EU/ml
100
Natural
Infection
15 – 25 y.o. 10 1 7 12 18
33-38
45-50
Month
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Harper et al. Lancet 2006; 367:

34. HPV 16 Antibody Levels by Age Group Study 014
Efficacy study
10000
15-25y
26-35y
36-45y
1000
HPV-16 GMC EU/ml
100
Natural
Infection
15 – 25 y.o. 10 1 7 12 18
33-38
45-50
Month
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Harper et al. Lancet 2006; 367:

35. HPV 16 Antibody Levels by Age Group Study 014
Efficacy study
10000
15-25y
26-35y
36-45y
46-55y
1000
HPV-16 GMC EU/ml
26 fold higher
100
Natural
Infection
15 – 25 y.o. 10 1 7 12 18
33-38
45-50
Month
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Harper et al. Lancet 2006; 367:

36. HPV 18 Antibody Levels by Age Group Study 014
10000
Efficacy study
15-25y
26-35y
36-45y
46-55y
1000
HPV-18 GMC EU/ml
16 fold higher
100
Natural
Infection
15 – 25 y.o. 10 1 7 12 18
33-38
45-50 7 12 18
33-38
Month
Shwarz, T, et al. ASCO, 2006, Atlanta,USA
Harper et al. Lancet 2006; 367:

37. Study HPV 014 - Conclusions
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 times higher than those associated with natural HPV infection
≥ levels of antibodies associated with protection against HPV infection and its associated outcomes 1
1 Harper et al. Lancet 2006; 367:
Shwarz, T, et al. ASCO, 2006, Atlanta,USA

38. Safety profile in women 15-55 years of age
100 80 60
% participants overall dose 40 20
Pain
Redness
Swelling
Myalgia
Fever
>95% study compliance
Shwarz, T, et al. ASCO, 2006, Atlanta,USA

39. Phase III Efficacy Program
GSK efficacy study (HPV 008)
NCI supportive study (HPV 009)
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+

40. GSK HPV 16/18 Vaccine Global Clinical Development Plan
Denmark
Norway
Sweden
Finland
Canada
United Kingdom
Estonia
Russia
The Netherlands
China
Lithuania
Belgium
Poland
South Korea
Germany
Czech Republic
Japan
France
Taiwan
Spain
Hong Kong
Portugal
USA
Italy
Greece
Mexico
Honduras
The Philippines
Panama
GSK HPV 16/18 vaccine global development plan
This slide shows the global development plan currently underway with the HPV 16/18 vaccine, including the phase III efficacy trials.
Costa Rica
India
Senegal
Colombia
Thailand
Nigeria
Peru
Malaysia
Brazil
Australia
South Africa

41. Timings: Ongoing Trials
2005
2006
2007
2008
2009 Y2 Y3
HPV-007 Efficacy
Y1*
HPV-012 (immuno 10-25y)
LT follow-up Y1 Y2 Y3
HPV-013 (adol. safety)
LT follow-up
Long term immunogenicity
HPV-014 (immuno 15-55y)
LT follow-up
HPV-008: CIN2+ efficacy- global (N = 18,668)
HPV-009: CIN2+ efficacy-Costa Rica (N = 7,467)
>30,000 subjects enrolled in ongoing trials
*4 yrs of follow-up

42. 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

43. Conclusions (Cont’d) Safety profile Immunogenic
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 ; 367 : 124.