development of the hpv 16 / 18 cervical cancer vaccine james p. tursi, md director – medical...

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







• Focused on cervical cancer prevention• Oncogenic HPV


• 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







• Focused on cervical cancer prevention• Oncogenic HPV


• 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.

Clinical Trial Data

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


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


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



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



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



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


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


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


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.

development of the hpv 16 / 18 cervical cancer vaccine james p. tursi, md director – medical...

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