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Cervarix“An Innovative Vaccine

to Prevent Cervical Cancer”

Eduardo OrtegaEduardo Ortega--BarriaBarria MDMDVice President & Head Vice President & Head Clinical R&D and Medical AffairsClinical R&D and Medical AffairsLatin America & the CaribbeanLatin America & the CaribbeanGlaxoSmithKline BiologicalsGlaxoSmithKline Biologicals

®

Towards Comprehensive Cervical Cancer Prevention and ControlRegion of the Americas

Mexico City, 12-14 May 2008

Provide best possible Provide best possible primary prevention against primary prevention against cervical cancercervical cancer

•• Broad coverage against HPV Broad coverage against HPV oncogeniconcogenic types:types:

–– Most prevalent types: 16 & 18Most prevalent types: 16 & 18

–– Other Other oncogeniconcogenic types, in particular 45 & 31types, in particular 45 & 31

•• Robust Robust immunityimmunity::

–– High and sustained neutralizing antibody levelsHigh and sustained neutralizing antibody levels

–– Across broad age range (10Across broad age range (10--55 yrs)55 yrs)

GlaxoSmithKlineGlaxoSmithKline Vaccine Vaccine Development Vision Development Vision

CervarixCervarixDesigned to provide best possible primary prevention Designed to provide best possible primary prevention

against cervical canceragainst cervical cancer

Strong & sustained immune

response

Strong & sustained immune

response

Highly purified antigens

& Strongimmunogen(key genotypes, avoidinginterference)

Enhancedimmune response

AS04 = MPL + Al(OH)3

®

AS04 confers higher antibody titers in humansAS04 confers higher antibody titers in humans

Adapted from Giannini SL, Hanon E, Moris P, et al. Vaccine 2006;24:5937–49

∗

Wilcoxon’s non-Parametric (p<0.05)

* *

*

*

*

1000

600

400

200

00 8 16 32 4824 40

Vaccination

= Al(OH)3

= AS04

Anti-V5 HPV-16

GM

T an

tibod

y tit

ers

(EU

/ml) 800

* *

*

**

1000

600

400

200

00 8 16 32 4824 40

Vaccination

= Al(OH)3

= AS04

Anti-J4 HPV-18

800

*

*

months months

0

4000

8000

12000

16000

day 60 day 210

HPV-16

pre0

1000

2000

3000

day 60 day 210

HPV-18

pre

= [Al(OH)3]= AS04

Median

Median

Q3

Q1

Q3

Q1

3.6 x*

2.2 x

Freq

uenc

y of

HP

V s

peci

fic m

emor

y B

cel

ls

* statistically significant (p <0.05, Wilcoxon’s test)

vaccination vaccination

Giannini SL, et al. Vaccine 2006; 24: 5937–49

AS04 increases the memory B cell pool in humans AS04 increases the memory B cell pool in humans

Safety, efficacy and Safety, efficacy and immunogenicityimmunogenicity in in clinical trialsclinical trials

5.5 yrsInterim Analysis

6.4 yrsFirst data

HPV-008 N =18,644

15 Mo Interimanalysis

23 cases CIN2+

4.5 yrsInterim

Analysis

FinalanalysisEvent-

triggered

4 yrsExtended Follow-up

2005 2006 2007 2008 20092001 2002 2003 2004

HPV-007N = 776

HPV-001N=1,113

HPV naïve population

Broad population

HPV 023

9.5 yrsExtended Follow-up

Good safety profileGood safety profile

3.5%3.5%4.0%4.0%

3.5%3.5%4.2%4.2%

Number of women reportingNumber of women reportingNumber of Number of SAEsSAEs reportedreported

Serious Adverse Events:Serious Adverse Events:

43.6%43.6%21.8%21.8%

1.7%1.7%0.3%0.3%

42.5% 42.5% 21.3%21.3%

1.5%1.5%0.3%0.3%

All unsolicited symptoms* (Day 0All unsolicited symptoms* (Day 0––29)29)Medically significant conditions Medically significant conditions New onset chronic diseases New onset chronic diseases New onset autoimmune diseases New onset autoimmune diseases

Unsolicited Adverse Events: Unsolicited Adverse Events: % of women with at least 1 event% of women with at least 1 event

HepHep A VaccineA Vaccine(N=9,325)(N=9,325)

CervarixCervarix®

(N=9,319)(N=9,319)Safety OutcomesSafety Outcomes

*Diary card subset (3,184 HPV recipients and 3,187 HAV recipients)

Broad Population Study

Paavonen J et al. Lancet 2007;369:2161–70

nnnn

90.0 90.0 –– 100100343400Persistence: 6 Months Persistence: 6 Months

81.8 81.8 –– 100100

10010010010020200012 Months 12 Months

51.3 51.3 –– 100 100 9900CIN2+CIN2+

151500 73.4 73.4 –– 100 100

100100100100CIN1+CIN1+

95% CI95% CI%%

Vaccine EfficacyVaccine EfficacyControlControlCervarixCervarix®

Endpoints*Endpoints*

Complete protection against HPVComplete protection against HPV--16/18 persistent 16/18 persistent infections and CIN outcomes infections and CIN outcomes up to 6.4 yearsup to 6.4 years

*Combined analysis initial efficacy study and extended follow-upATP analysis for virologic endpoints; ITT analysis for CIN endpoints

Presentation Harper D, SGO 39th Annual Meeting on Women’s Cancer, Tampa, Florida, March 9-12, 2008; Gynecol Oncol 2008; 109(1):158

n = number of subjects reporting at least one event in each groupPersistence: Cervarix® N=401; Control N=372; CIN: Cervarix® N=481; Control N=470;

100% protection against HPV 16/18 CIN2+ 100% protection against HPV 16/18 CIN2+ sustained sustained up to 6.4 yearsup to 6.4 years

1.Harper et al. Lancet. 2004; 364: 1757–652.Harper et al. Lancet 2006; 367: 1247-553.Presentation Gall S, AACR, Los Angeles, April 14-18, 2007, abstract 49004.Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008; Gynecol Oncol 2008; 109(1):158

Combined analysisCombined analysisinitial efficacy initial efficacy study and study and extended followextended follow--upup

Initial efficacy Initial efficacy studystudy

6.4 yrs6.4 yrs44

5.5 yrs5.5 yrs33

4.5 yrs4.5 yrs22

27 months27 months11

95% CI95% CI%%nnnn

Vaccine EfficacyVaccine EfficacyControlControlCervarixCervarix®HPV 16/18 HPV 16/18 relatedrelated

CIN2+CIN2+0 3 100 NA

0 5 100 -8 - 100

0 7 100 33 - 100

0 9 100 51 - 100

n = number of subjects reporting at least one event in each groupITT analysis

Trials in a broad population Trials in a broad population including Latin Americaincluding Latin America

18,644 women vaccinated / 14 countries

16 %

35 %34 %

15 %

- current or prior oncogenic HPV 16/18 infection - abnormal cytology (9% low grade)- anti-HPV 16/18 serum antibodies

0

10

20

30

40

50

60

70

80

90

100

6.4 years follow-up Broad population

% E

ffica

cy C

IN2+

HPV

-16/

18

Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008; Gynecol Oncol 2008; 109(1):158; Paavonen J et al. Lancet 2007;369:2161–70

95% CI: 51.3 – 100 97.9% CI: 53.4 – 99.3

97.9% CI: 74.2 – 100

Pre-specified analysis

Causality assessment analysis*

*Based on causality assessment case assignment. The pre-specified analysis included 3 CIN2+ cases which were not considered to be causally associated with HPV-16 or HPV-18 infections acquired during the trial. Based on this analysis vaccine efficacy was 90.4% (CI 53.4–99.3)

Confirmed 100% efficacy against CIN2+Confirmed 100% efficacy against CIN2+caused by HPVcaused by HPV--16 and 1816 and 18

95% CI95% CI%%nnnn

Vaccine EfficacyVaccine EfficacyAl(OH)Al(OH)33N=497N=497

CervarixCervarix®N=505N=505EndpointEndpoint

16 16 –– 5757393993936262≥≥LSILLSIL

21 21 –– 92 92 7272171755CIN2+CIN2+

12 12 ––7373505038382020CIN1+CIN1+

18 18 –– 50 50 3535162162118118≥≥ASCUSASCUS

Protection against cytological abnormalities & CIN Protection against cytological abnormalities & CIN for any HPV types sustained for any HPV types sustained up to 6.4 Years up to 6.4 Years

Combined analysis initial efficacy study and extended followCombined analysis initial efficacy study and extended follow--upup

1 Clifford et al. Cancer Epi Biom Prev 2005;14(5); 2. Muñoz et al. N Engl J Med 2003Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008;Gynecol Oncol 2008; 109(1):158

Independent of HPV DNA statusCervical samples only; Descriptive, Conditional Exact method; ITT analysis

25–30%1

50%2

25–30%1

20–30%1

Estimated prevalence HPV 16/18

N = number of subjects included in each group; n = number of subjects reporting at least one event in each group

Cross protection against HPV 45 & 31 Cross protection against HPV 45 & 31 incident infection sustained incident infection sustained up to 6.4 years

HPV typeHPV typeCervarix Cervarix ® ControlControl Vaccine Vaccine EfficacyEfficacy

nn nn %% 95% CI95% CI

HPVHPV--4545 55 2121 7878 3939--9393

HPVHPV--3131 1313 3030 6060 2020--8181

ATP analysis n = number of subjects reporting at least one event in each group

Combined analysis initial efficacy study and extended follow-up

Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008

0.5 – 59.536.136.17447HPVHPV--3131

TVCTVC--E (at least 1 dose)E (at least 1 dose)OncogenicOncogenicHPV TypeHPV Type Vaccine Vaccine

(cases)(cases)Control Control (cases)(cases)

2.6 – 85.259.959.92510HPVHPV--4545

3.5 – 51.931.631.63016HPVHPV--5252

97.9% CI97.9% CIVaccine Vaccine Efficacy (%)Efficacy (%)

Confirmed Confirmed typetype--specific cspecific cross protectionross protectionagainst 6against 6--month persistent infectionmonth persistent infection


Provide best possible Provide best possible primary prevention against cervical cancerprimary prevention against cervical cancer




•• Robust immunity:Robust immunity:



GlaxoSmithKline Vaccine GlaxoSmithKline Vaccine Development Vision Development Vision

Why are Antibodi es so Important?

What we do knowHPV hides from our immune

system, therefore natural infection induces a poor immune response

Neutralising antibodies can prevent entry into cells and subsequent infection1

What we don’t know yetWil l natur al infection boost i mmune memor y i n vacci nated women?

Induction of serum neutralisingantibodies by vaccination is critical for protection1,2

1. Stanley M. HPV Today 2007; 11: 1-162. Stanley M. Vaccine 2006; 24: S106-13

Why are Antibodies so Important?Why are Antibodies so Important?

Will natural infection boost

immune memory in

vaccinated women?

Antibody levels start high and stay high

Harper D et al. Lancet 2006;367:1247–55; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007

AntiAnti--HPVHPV--16 IgG16 IgG

1,000

100

10

1

10,000

Months70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64

Seropositivity ≥98%

AntiAnti--HPVHPV--18 IgG18 IgG Seropositivity ≥98%

GM

T (E

U/m

l)G

MT

(EU

/ml) 1,000

100

10

1

10,000

Months70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64

≥11-fold higher than

natural infection


natural infection

020406080

100

month 0 month 7 month12

month18

[M25-M32]

[M33-M38]

[M39-M44]

[M45-M50]

[M51-M56]

[M57-M62]

[M63-M68]

[M69-M74]

[M75-M76]

020

4060

80100

month 0 month 7 month12

month18

[M25-M32]

[M33-M38]

[M39-M44]

[M45-M50]

[M51-M56]

[M57-M62]

[M63-M68]

[M69-M74]

[M75-M76]

ELISA

Pseudovirion(Neutra)

ELISA

Pseudovirion(Neutra)

Seropositivity HPV-16

Seropositivity HPV-18%

%

Months

Months

SeropositivitySeropositivity ≥≥98%98% at all time points at all time points up to 6.4 yearsup to 6.4 years

Presentation Harper D, SGO 39th Annual Meeting on Women’s Cancer, Tampa, Florida, March 9-12, 2008

Robust typeRobust type--specific cross reactivity against specific cross reactivity against HPVHPV--45 and 3145 and 31

HPVHPV--4545Related to HPVRelated to HPV--1818

Data on File. GSKBio-WWMA_DoF001_2007 Cut-off level for seropositivity for both HPV-45 and 31: ≥59 EU/ml*up to 4.5 yrs

1,000

100

10

1

10,000

Months70 12 25–32 33–38 39–44 45–50 51–56

8.8%

100%

100% 91.7% 85.7% 90.0% 83.7% 92.3%

GM

T (E

U/m

l)

Important cause of adenocarcinoma

HPVHPV--3131Related to HPVRelated to HPV--1616

1,000

100

10

1

10,000

Months

5.9%

100%

94.1%83.3% 80.0% 87.5% 88.4% 69.2%

70 12 25–32 33–38 39–44 45–50 51–56

GM

T (E

U/m

l)

ImmunobridgeSafety / reactogenicity

Women15–25 yrs

Women15–25 yrs

Girls10–14 yrs

Women26–55 yrs

Efficacy & Immuno Findings up to 5.5 yrs

ImmunobridgeSafety / reactogenicity

Principle of Principle of ImmunobridgingImmunobridging

Month 7 Immunogenicity: GMT and Seroconversion Rate

Seropositivity definedas titer ≥8 EU/ml HPV-16

Adapted from Pedersen C et al. J Adolesc Health 2007;40:564–71

Immune response twice as high in 10Immune response twice as high in 10––14 yr olds14 yr oldsfor HPVfor HPV--16 and 1816 and 18

Seropositivity definedas titer ≥7 EU/ml HPV-18

GM

T (E

U/m

l)

17,2727,439

1

10

100

1,000

10,000

100,000

10–14 y 15–25 y1

10

100

1,000

10,000

100,000

10–14 y 15–25 y

6,864

3,070

GM

T (E

U/m

l)

100%100% 100%

100%

Efficacy study in women 15Efficacy study in women 15––25 yrs of age shows25 yrs of age showshigh and sustained antibody levelshigh and sustained antibody levels

Immunobridging to girls 10Immunobridging to girls 10––14 yrs14 yrsshows even stronger immune responseshows even stronger immune response

Harper D et al. Lancet 2006;367:1247–1255; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007; Rombo L, ESPID, Porto, Portugal, May 2-4,2007


1,000

100

10

1

10,000

Total follow-up time (months)70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64


1,000

100

10

1

10,000

Total follow-up time (months)70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64

10–14 Year old girls


natural infection


natural infection G

MT

(EU

/ml)

GM

T (E

U/m

l)

Keam SJ & Harper DM. Drugs. 2008;68 (3):359-72;

1

10

100

1,000

10,000

100% 100%100%100%100% 100% 100%100%

ATP cohort, Seronegative at entry, month 7 results

GM

T (E

U/m

l)

HPV-16 HPV-18

15–25 years

26–35 years

36–45 years

46–55 years

Schwarz TF. J Clin Oncol 2006;24(18S):1008

Consistently high immune response Consistently high immune response across all agesacross all ages

Natural Infection

Seroconversion Seroconversion

N=437

High and sustained antibody levels in a broad High and sustained antibody levels in a broad age group over timeage group over time

Assay cut-off: 8 EU/mlATP analysisSeronegative prior to vaccination

Months

NaturalInfection

1

10

100

1,000

10,000

0 7 12 18 24 39–44 51–56 63–64

15–25 years (Efficacy study)

15–25 years26–35 years36–45 yearsAt least

8-fold higher than

natural infection

46–55 years

Keam SJ & Harper DM. Drugs. 2008;68 (3):359-72; Presentation Gall S. AACR 2007; Presentation Schwarz TF Eurogin, 2007

10,000At least 8-fold higher than

natural infection

1

10

100

1,000

0 7 12 18 24 39–44 51–56 63–64

GM

T (E

U/m

l)

HPV-16 HPV-18

0

0.5

1

1.5

2

2.5

3

0 0.5 1 1.5 2 2.5 3

R = 0.9031 R = 0.7280 R = 0.8753

-1

-0.5

0

0.5

1

1.5

2

2.5

-0.5 0 0.5 1 1.5 2 2.5

15-25 years 26-45 years 46-55 years

Strong correlation between serum and Strong correlation between serum and cervical mucosa antibody levelscervical mucosa antibody levels

Log

ratio

(ant

i-HPV

-16/

tota

l IgG

) in

CVS

Log

ratio

(ant

i-HPV

-18/

tota

l IgG

) in

CVS

- Log ratio (anti-HPV-16/total IgG) in serum - Log ratio (anti-HPV-18/total IgG) in serum

Month 24

Schwarz T. EuroGIN 2007 presentation; Stanley M, et al. Vaccine 2006;24(Suppl 3):S106–13; Giannini SL, et al. Vaccine 2006;24:5937–49

AntiAnti--HPVHPV--1616 AntiAnti--HPVHPV--1818

Higher serum Ab levels à Higher Ab levels at the mucosa -where they are most needed

15–25 years R=0.903126–45 years R=0.728046–55 years R=0.8753

15–25 years R=0.911426–45 years R=0.823546–55 years R=0.9328

Provide best possible Provide best possible primary prevention against cervical cancerprimary prevention against cervical cancer




•• Robust immunity:Robust immunity:



GlaxoSmithKline Vaccine GlaxoSmithKline Vaccine Development Vision Development Vision

665 (=100%)665 (=100%)30.2%30.2%40.6%40.6%0.6%0.6%2.3%2.3%9.9%9.9%13.1%13.1%1.5%1.5%

Cervarix Cervarix ®(N=9,319)(N=9,319)

685 (=100%)685 (=100%)34.0%34.0%38.5%38.5%1.2%1.2%2.5%2.5%7.4%7.4%13.6%13.6%1.9%1.9%

Number of pregnanciesNumber of pregnancies

Pregnancy ongoingPregnancy ongoingNormal infantNormal infant

Abnormal infantAbnormal infant

Premature birthsPremature births

Spontaneous abortionSpontaneous abortionElective termination Elective termination

Lost to followLost to follow--upup

HepHep A VaccineA Vaccine(N=9,325)(N=9,325)

Pregnancies/Pregnancy Pregnancies/Pregnancy outcomes*outcomes*

Pregnancy outcomesPregnancy outcomes

*Totals do not include blinded outcomes, ectopic pregnancies

Broad Population Study


Documents

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