ai 1 u.s. food and drug administration notice: archived document the content in this document is...

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U.S. Food and Drug AdministrationU.S. Food and Drug Administration

Notice: Archived Document

The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

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CERVARIX®CERVARIX®Human Papillomavirus Bivalent Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant(Types 16 and 18) Vaccine, Recombinant

Barbara Howe, MD Barbara Howe, MD

Vice President, DirectorVice President, Director

North American Vaccine DevelopmentNorth American Vaccine Development

GlaxoSmithKline GlaxoSmithKline

AI AI 33

Proposed IndicationProposed Indication

• Girls and women 10 - 25 years Girls and women 10 - 25 years

• Prevention of cervical cancerPrevention of cervical cancer– Squamous cell cancer and adenocarcinomaSquamous cell cancer and adenocarcinoma

– Protection against precancerous or dysplastic Protection against precancerous or dysplastic lesions and persistent/incident infectionslesions and persistent/incident infections

• HPV types 16,18 and some non-vaccine HPV types 16,18 and some non-vaccine typestypes

• 3-dose schedule: 0, 1, 6 months 3-dose schedule: 0, 1, 6 months

AI AI 44

HPV Causes a Variety of CancersHPV Causes a Variety of Cancers

• CervixCervix

• Vagina, vulva, anal canalVagina, vulva, anal canal

• PenisPenis

• Tonsil, pharynx, larynxTonsil, pharynx, larynx

Gillison, Cancer (2008)

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Burden of Cervical CancerBurden of Cervical Cancer

• 2nd most common cancer in the world

• In United States

– >11,000 women diagnosed yearly

– > 4,000 deaths yearly – 10 women die daily

– Average age of diagnosis – 48

– Adenocarcinoma – more aggressive form is increasing

Ferlay, IARC (2004); Jemal, Ca Cancer J Clin (2009); http://seer.cancer.gov/statfacts/html/cervix.html; Herzog, Am J Obstet Gynecol (2007)

AI AI 66Smith, Int J Cancer, 2007

Cumulative %

54.2

76.4

80.9

84.4

87.7

88.7

89.1

89.4

89.6

89.8

90.0

90.190.2

90.2

88% of Cervical Cancers in North America 88% of Cervical Cancers in North America Attributed to 5 Oncogenic HPV Types Attributed to 5 Oncogenic HPV Types

3.3

0

0

0.1

0.2

0.2

0.2

0.3

0.4

1

3.5

4.5

22.2

0 10 20 30 40 50 60

HPV-51

HPV-66

HPV-59

HPV-56

HPV-39

HPV-68

HPV-58

HPV-35

HPV-52

HPV-45

HPV-33

HPV-31

HPV-18

HPV-16

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Vaccine CompositionVaccine Composition

Adjuvant System

AS04

= MPL + Al(OH)3

+

Recombinant Antigens(resemble native HPV virus, non infectious)

20µg HPV-16, 20µg HPV-18 L1 VLPs 500µg Al(OH)3 and 50µg MPL

&

HPV-16 L1 VLP

HPV-18 L1 VLP

AI AI 88

Quality of BEVS Quality of BEVS Vaccine ManufacturingVaccine Manufacturing

• Recombinant technology using baculovirus expression Recombinant technology using baculovirus expression vector system – “BEVS”vector system – “BEVS”

• Robust, well-controlled, animal-free manufacturing processRobust, well-controlled, animal-free manufacturing process

• Extensive characterization, validation, QC testingExtensive characterization, validation, QC testing

AI AI 99

AS04 Components AS04 Components Well-CharacterizedWell-Characterized

• Aluminum hydroxide widely used for 80 yearsAluminum hydroxide widely used for 80 years

• MPL derived from MPL derived from Salmonella minnesotaSalmonella minnesota (gram negative bacteria) lipopolysaccharide (gram negative bacteria) lipopolysaccharide (LPS)(LPS)

• MPL is detoxified, retains adjuvant effectMPL is detoxified, retains adjuvant effect

AI AI 1010

Significant Clinical Experience with Significant Clinical Experience with GSK AS04-Containing VaccinesGSK AS04-Containing Vaccines

• Cervarix – would be first US-licensed AS04-Cervarix – would be first US-licensed AS04-containing vaccine (licensed in 98 countries WW)containing vaccine (licensed in 98 countries WW)

• Fendrix – adjuvanted HepB vaccine licensed in Fendrix – adjuvanted HepB vaccine licensed in Europe since 2005Europe since 2005

• Investigational adjuvanted HSV vaccine in late Investigational adjuvanted HSV vaccine in late Phase III (US and Canada)Phase III (US and Canada)

AI AI 1111

CERVARIX Clinical Development ProgramCERVARIX Clinical Development Program

n = number of subjects vaccinated( ) = number of subjects receiving final formulation of vaccine

HPV- 002Safety

HPV-004Adjuvant

Comparison

HPV-005Dose Range

HPV-003HPV DNA+

HPV-00815-25Y

Phase III Efficacy

HPV-01310-14Y

Immunogenicity

HPV-001/00715-25Y

Phase IIb Efficacy/Duration

6.4yrs

HPV-015>26 Y

HPV-01415-55Y

Age Bridge

HPV-01210-14Y

Age Bridge

HPV-016Final

Consistency

HPV-012Consistency

Overall Database29,953 (16,142)

Phase IIb/III

Efficacy &Immunogenicity

21,824 (10,914)

Bridging(Immunogenicity)

824 (824)

Supportive Safety5751 (2880)

Clinical Consistency

1410 (1410)

Phase I/IIa n=144 (114)

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ArgentinaChileColombiaUruguayPeruBrazilEcuadorCuracaoDominican RepNicaraguaSurinamPanamaArubaTrinidad and TobagoGuatemalaEl SalvadorGuyanaHondurasCosta RicaJamaica

EU ( 27)NorwayIcelandBelarusUkraine

KazakhstanMoldovaSerbia

MacedoniaAlbaniaRussiaBosniaCroatia

AzerbaijaGeorgia

AustraliaNew Zealand

KenyaUgandaSouth-AfricaGabonIvory CoastNigeriaNamibiaGhanaSenegalCongoTanzania

PhilippinesThailand

SingaporeMalaysiaIndonesia

Hong KongMyanmarTaiwan

South-KoreaBangladesh

VietnamIndia

PakistanCambodia**

Macau*

Mexico

UAEBahrainTurkey IsraelSaudi ArabiaMoroccoKuwaitEgyptLebanonTunisia

(*) Macau: Import permit based on Australian license

(**) Cambodia: Import permit

98 APPROVALSWHO Pre-Qualification

Worldwide Registration StatusWorldwide Registration Status

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2004

BLA Submitted Mar 2007

CR Letter Responses

Jun 2008

Class 2 Re-submission

Mar 2009

US Regulatory TimelineUS Regulatory Timeline

1998 2001

VRBPACSept 2009

PreBLA Meeting

May 2006

CR LetterReceived Dec 2007

US IND Opened Sep 1998

VRBPAC Phase III EndpointsNov 2001

PDUFA Action Date Sep 29, 2009

2005 2006 2007 2008 2009

End of Phase IIMeeting Feb 2004

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GlaxoSmithKline GlaxoSmithKline PresentationPresentation

Vaccine Design

Martine Wettendorff, PhDVice PresidentGlobal Vaccine DevelopmentAdult/Adolescent Franchise

Efficacy Gary Dubin, MDVice President, Director Global Clinical Development Center

Safety/Pharmacovigilance Plan

Thomas Verstraeten, MDVice President, HeadBiologicals Clinical Safety and Pharmacovigilance

Benefit/Risk Conclusion

Barbara Howe, MDVice President, Director North American Vaccine Development

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External Experts

• Xavier Bosch, MD, PhD Head of the Cancer Epidemiology Research Program and Chief of International Affairs Catalan Institute of Oncology

• Robert L. Brent, MD, PhD, DSc(Hon) Distinguished Professor of Pediatrics Radiology and Pathology Thomas Jefferson University

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Vaccine Design

Martine Wettendorff, Ph.DVice PresidentGlobal Vaccine DevelopmentAdult/Adolescent Franchise



Thomas Verstraeten, MDVice President, HeadBiologicals Clinical Safety and Pharmacovigilance



AI AI 1717

Vaccine DesignVaccine Design

• Cervical cancer vaccine development Cervical cancer vaccine development challenges challenges

• Vaccine design rationale Vaccine design rationale

• AS04AS04 m mode of action ode of action

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Oncogenic HPV CharacteristicsOncogenic HPV Characteristics

• HPV evades the immune systemHPV evades the immune system

• Does not induce viremia – stays at cervix Does not induce viremia – stays at cervix

• Takes decades to progress from infection Takes decades to progress from infection to cancerto cancer

Stanley Gynecol Oncol.2008Moscicki Vaccine 2006

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Long-Lasting Protection is NeededLong-Lasting Protection is Needed

• > 80% of sexually active women infected > 80% of sexually active women infected with HPV by 50 years with HPV by 50 years

• Re-infection is common throughout lifeRe-infection is common throughout life

• Natural infection antibodies low, not reliably Natural infection antibodies low, not reliably protectiveprotective

• Most antibodies in cervix come from blood Most antibodies in cervix come from blood

Myers Am J Epi 2005Brown J Infect Dis 2005Viscidi Cancer Epidemiol Biomarkers 2004Franklin J Reproductive Immunol 1999

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Preclinical Models Demonstrate Preclinical Models Demonstrate Feasibility of VaccinationFeasibility of Vaccination

• L1 VLP induces protection against L1 VLP induces protection against Papillomavirus infection & associated lesionsPapillomavirus infection & associated lesions

• L1 VLP neutralizing antibodies sufficient for L1 VLP neutralizing antibodies sufficient for protection protection

Suzich PNAS USA 1995Breitburg J. Virol. 1995Ghim Exp. Mol. Pathol. 2000.

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Vaccine Design VisionVaccine Design Vision

• No compromise on HPV-16/18 – balance type No compromise on HPV-16/18 – balance type coverage with risk of immune interferencecoverage with risk of immune interference

• Cross-protection beyond HPV-16/18 Cross-protection beyond HPV-16/18

• Improve on natural immunityImprove on natural immunity

• Optimized combination of antigens/adjuvant Optimized combination of antigens/adjuvant

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Vaccine DesignVaccine Design

Highly pureHighly pure Resembles native virionsResembles native virions Non-infectiousNon-infectious

HPV-16 and HPV-18 Immunogens - HPV-16 and HPV-18 Immunogens - L1 VLPL1 VLP

AS04 Adjuvant System AS04 Adjuvant System

Selected for evaluation based on previously Selected for evaluation based on previously generated data (HSV/HBV)generated data (HSV/HBV)

High, broad &

sustained immune

responses

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Vaccine DesignVaccine DesignConfirmation of Immunological Benefit of AS04 with L1 VLPsConfirmation of Immunological Benefit of AS04 with L1 VLPs

Phase II Clinical TrialsPhase II Clinical Trials

*Wilcoxon’s non Parametric(p <0.05)

Giannini S, et al. Vaccine. 2006

Anti-V5 HPV-16

* *

*

*

*

1000

600

400

200

00 8 16 32 4824 40

GM

T a

nti

bod

y t

itre

s (

EU

/ml)

800

*

Anti-J4 HPV-18

* *

*

**

1000

600

400

200

00 8 16 32 4824 40

800

*

= AS04 = Al(OH)3

Time (months)Time (months)

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AS04 Mode-of-Action

VLP and AS04 need to be colocalized

induces early and transient cytokine and chemokine response

Innate ResponseInnate Response Adaptive ResponseAdaptive Response

T-cells

Lymph Node

B-cells

APC migration and maturation (costimulatory molecules) Induction of

B memory

Blood / Tissues

Induction of adaptive T and B responses, with high and persistent Ab

No direct impact of AS04 on T and B cells

Muscle

Blood

AdjuvantAntigen

Monocytes DC

Antigen Presenting Cells(APC)

Didierlaurent A. et al. J.Immunol 2009 - submitted

Direct impact of AS04 on APC

TLR4

AI AI 2525

No Evidence of Biological Mechanism for No Evidence of Biological Mechanism for Auto-Immune Disease Induction in AS04 MOAAuto-Immune Disease Induction in AS04 MOA

• MPL/AS04 activity through MPL/AS04 activity through TLR4 on specific APCTLR4 on specific APC

No IFNNo IFN

Didierlaurent A. et al. J.Immunol 2009 - submitted

Not associated with Not associated with systemic cytokine releasesystemic cytokine release

• Induces local, transient Induces local, transient innate immune responseinnate immune response

No non-specific immune No non-specific immune induction/exacerbationinduction/exacerbation

• No direct effect on effector No direct effect on effector cells (T and B)cells (T and B)

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Vaccine Design SummaryVaccine Design Summary

• No compromise on HPV 16/18 protectionNo compromise on HPV 16/18 protection

• Induce cross-protection against closely Induce cross-protection against closely phylogenetically related HPV typesphylogenetically related HPV types

• High and sustained immune response High and sustained immune response against HPV 16/18against HPV 16/18

• No basis for induction/exacerbation of No basis for induction/exacerbation of auto-immune diseaseauto-immune disease

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Vaccine Design




Thomas Verstraeten, MDVice President, Head Biologicals Clinical Safety and Pharmacovigilance



AE AE 2828

Efficacy Presentation OutlineEfficacy Presentation Outline

• EfficacyEfficacy

– Design of Clinical TrialsDesign of Clinical Trials

– Key Efficacy ResultsKey Efficacy Results

• ImmunogenicityImmunogenicity

• ConclusionsConclusions

AE AE 2929

Scope of Overall Clinical ProgramScope of Overall Clinical Program

Phase IIb (N=1,113)

• Efficacy (Proof of Concept, Long Term Follow-Up)• Immunogenicity• Safety

Key Study: HPV-001/007

Phase III (N= 28,696)

• Pivotal Efficacy (15-25yrs)• Safety• Immunogenicity / Bridging (10-14yrs) • Clinical Consistency

Key Study: HPV-008

Phase I/IIa (N=144)

• Safety• Dose Ranging• Adjuvant Selection

20041998 2001 2005 2006 2007 2008 2009

AE AE 3030

Efficacy Trial StrategyEfficacy Trial Strategy

HPV-008HPV-001/007

● Phase IIb Study ● Pivotal Phase III Study

Two Studies Conducted in 15 to 25 Year-Old WomenTwo Studies Conducted in 15 to 25 Year-Old Women

● Oncogenic HPV Naïve Population

● General Population

● 39 Months Duration● 6.4 Years Duration

● 1,113 Women ● 18,644 Women

AE AE 3131

TimeYearsMonths

Selection of a Surrogate EndpointSelection of a Surrogate Endpoint

Carcinoma Normal epithelium

HPV infectionkoilocytosis

CIN1 CIN2 CIN3

Basement membrane

CIN2+

Persistent HPV Infection

AE AE 3232

Reference: womenonce positive for relevant HPV type(s)

Reference: womennegative for relevant HPV type(s)

Association Between HPV Persistence and CIN2-3/HSIL/ICC

Author (Year) Effect Estimate (RR) and 95% CI

HPV-Negative ReferentKoutsky (1992)Wallin (1999)Cuzick (2003)Dalstein (2003)Bais (2005Kjaer (2002)Moberg (2004)Schlecht (2001)Liaw (1999)

Transient HPV Referentter Harmsel (1999)Beskow (2001)Harris (2004)Wallin (1999)Bory (2002)Cuzick (2003)Dalstein (2003)Bais (2005)Cuschieri (2005)Liaw (1999)Kjaer (2002)Mosciki (1998)

Koshiol, Koshiol, Am J. Epidemiol,Am J. Epidemiol, 2008 2008

Duration of persistence: Duration of persistence: orange: <6months, orange: <6months, green: 6-12 months, green: 6-12 months, blue: >12 months, blue: >12 months, white: unclearwhite: unclear

0.1 1 10 100 1000 1000 1000

Median Relative Risk33.3

AE AE 3333

Efficacy EndpointsEfficacy Endpoints

• CIN2+ CIN2+

• Persistent infection (6 and 12 month definitions) Persistent infection (6 and 12 month definitions)

• Other efficacy endpointsOther efficacy endpoints

– Incident infectionIncident infection

– Abnormal cytology (ASC-US, LSIL, HSIL)Abnormal cytology (ASC-US, LSIL, HSIL)

– CIN1+CIN1+

• All endpoints assessed for HPV-16/18 and All endpoints assessed for HPV-16/18 and non-vaccine oncogenic HPV types non-vaccine oncogenic HPV types

AE AE 3434

Efficacy AssessmentsEfficacy AssessmentsGeneral Methodology General Methodology

Standardization for consistency in endpoint detection Standardization for consistency in endpoint detection

• Collection of specimensCollection of specimens

• Central laboratories for cytology, histology, HPV DNA Central laboratories for cytology, histology, HPV DNA PCR testing PCR testing

• Colposcopy referral by management algorithmColposcopy referral by management algorithm

Additionally for phase IIIAdditionally for phase III

• Independent expert panels for histopathology review, Independent expert panels for histopathology review, endpoint ascertainmentendpoint ascertainment

• Independent data monitoring committeeIndependent data monitoring committee

• Quality control program for colposcopyQuality control program for colposcopy

AE AE 3535

Efficacy Assessments Efficacy Assessments HPV DNA PCR Methodology* HPV DNA PCR Methodology*

• SPFSPF10 10 PCR and LiPA detection to detect most frequent PCR and LiPA detection to detect most frequent genital HPV typesgenital HPV types

– 14 oncogenic and 11 non-oncogenic types14 oncogenic and 11 non-oncogenic types

• High sensitivity and specificity -- even in presence High sensitivity and specificity -- even in presence of multiple infectionsof multiple infections

• HPV-16 and HPV-18 type specific PCR HPV-16 and HPV-18 type specific PCR

*Van Doorn, J Clin Microbiol, 2006

AE AE 3636

Efficacy and Immunogenicity Efficacy and Immunogenicity Presentation OutlinePresentation Outline






AE AE 3737

HPV-001/007 (15-25 years)HPV-001/007 (15-25 years)

6.4 yrs6.4 yrs FinalFinal

AnalysisAnalysis

20052005 20062006 20072007 20082008 2009200920012001 20022002 20032003 20042004

HPV-007(N = 776)

HPV-001(N=1113)

Oncogenic HPV naïve population at baselineOncogenic HPV naïve population at baseline

Screening CriteriaScreening Criteria

– Normal cytologyNormal cytology

– Seronegative for HPV-16 and HPV-18Seronegative for HPV-16 and HPV-18

– DNA negative for oncogenic HPV types (14)DNA negative for oncogenic HPV types (14)

AE AE 3838

HPV-001/007: Efficacy Against HPV-16/18 HPV-001/007: Efficacy Against HPV-16/18 Endpoints (Up to 6.4 years)Endpoints (Up to 6.4 years)

EndpointEndpoint CervarixCervarixCasesCases

ControlControlCasesCases

Vaccine EfficacyVaccine Efficacy

%% 95% CI95% CI

Incident InfectionIncident Infection 44 7070 9595 87-9987-99

6-Month Persistent Infection6-Month Persistent Infection 00 3434 100100 90-10090-100

12-Month Persistent Infection12-Month Persistent Infection 00 2020 100100 74-10074-100

CIN1+CIN1+ 00 1515 100100 62-10062-100

CIN2+CIN2+ 00 99 100100 28-10028-100

Combined analysis initial efficacy study and extended follow-upPersistent infection, CIN1+ and CIN2+ account for repeat observations of the data ATP analysis for virologic endpoints; ITT analysis for cytologic and CIN endpoints

AE AE 3939

HPV-001/007: Efficacy Irrespective of HPVHPV-001/007: Efficacy Irrespective of HPV DNA in the Lesion (Up to 6.4 years) DNA in the Lesion (Up to 6.4 years)

Combined analysis for initial efficacy study and extended follow-up

Cervical samples only; Descriptive, Conditional Exact method




%% 95% CI95% CI

CIN2+CIN2+ 55 1717 7272 21–92 21–92 52*52*

Expected Expected Prevalence of Prevalence of HPV-16/18 (%)HPV-16/18 (%)

*Smiith, Int J Cancer, 2007

AE AE 4040

HPV-001/007: Efficacy Against Individual HPV-001/007: Efficacy Against Individual Non-Vaccine Oncogenic Types (Up to 6.4 years)Non-Vaccine Oncogenic Types (Up to 6.4 years)

HPV TypeHPV Type CervarixCervarixCasesCases

ControlControl

CasesCases


%% 95% CI95% CI

HPV-31HPV-31 1313 3030 6060 21–81 21–81

HPV-45HPV-45 55 2121 7878 39–93 39–93

Incident InfectionIncident Infection

AE AE 4141

HPV-008HPV-008 (15-25 Years)(15-25 Years)

6.4 yrs6.4 yrs FinalFinal

AnalysisAnalysis

HPV-008 Pivotal Phase III StudyN =18,644

InterimInterimAnalysisAnalysis

23 cases CIN2+ 23 cases CIN2+

4 year4 yearFollow-upFollow-up

20052005 20062006 20072007 20082008 2009200920012001 20022002 20032003 20042004

HPV-007N = 776

HPV-001N=1113

Oncogenic HPV naïve population at baselineOncogenic HPV naïve population at baseline

General populationGeneral population

FinalFinalAnalysisAnalysis

≥≥36 cases CIN2+36 cases CIN2+

No Entry Criteria ForNo Entry Criteria For– CytologyCytology

– HPV-16/18 serologyHPV-16/18 serology– HPV DNAHPV DNA

AE AE 4242

HPV-008: Design Overview HPV-008: Design Overview

SerologySerology

CervicalCervicalSampleSample XX

XX

XX

XX

XXXX

XX

XXXX

XXXX

XX

XX

XX

XX

MonthMonth 0 10 1 66 77 1212 1818 2424 3030 3636 4848

• Double-blind; randomized (1:1); controlledDouble-blind; randomized (1:1); controlled

• Event-triggered efficacy analysesEvent-triggered efficacy analyses

Mean Follow-up Interim†

15 Months Post Dose 1

Mean Follow-up Final*39 Months Post Dose 1

†Paavonen, Lancet, 2007; *Paavonen, Lancet, 2009

AE AE 4343

HPV-008: Primary EndpointHPV-008: Primary EndpointProphylactic HPV-16/18 EfficacyProphylactic HPV-16/18 Efficacy

TVC (Total Vaccinated Cohort) (N = 18,644)

• Received ≥1 dose of vaccine

• Primary Endpoint: Subjects DNA negative and seronegative at baseline

• Other analyses stratified by baseline HPV DNA and serostatusATP for efficacy

(N = 16,162)• Complied with eligibility/ protocol• Received 3 doses of vaccine• Normal or low grade cytology (month 0)• Case count: Day after 3rd vaccination

TVC-1(N = 18,525)

• Received ≥1 dose of vaccine• Normal or low grade cytology (month 0)• Case count: Day after 1st vaccination

AE AE 4444

HPV-008: Geographic DistributionHPV-008: Geographic Distribution(Total Vaccinated Cohort)(Total Vaccinated Cohort)

34% 34%

15%17%

Asia Pacific

LatinAmerica

Europe

North America

AE AE 4545

HPV-008: Ethnic/Racial DistributionHPV-008: Ethnic/Racial Distribution(Total Vaccinated Cohort)(Total Vaccinated Cohort)

Caucasian10,218

Asian5,866

Hispanic1,330

Black693Other

537

AE AE 4646

HPV-008: Baseline Characteristics HPV-008: Baseline Characteristics (Total Vaccinated Cohort)(Total Vaccinated Cohort)

Mean age (years) 20

Number of sexual partners in past year 0 ≥ 1

4%96%

No evidence of current or prior infectionNo evidence of current or prior infection

Seronegative and HPV DNA negative for 16 or 18Seronegative and HPV DNA negative for 16 or 18

Evidence of current or prior infection Evidence of current or prior infection

Seropositive or HPV Seropositive or HPV DNA positive for 16 or 18

74%

26%

DNA positive for DNA positive for bothboth HPV-16 and 18 HPV-16 and 18 <1%

AE AE 4747

HPV-008: Primary Efficacy Endpoint HPV-008: Primary Efficacy Endpoint

• Vaccine efficacy in prevention of histopathologically-Vaccine efficacy in prevention of histopathologically-confirmed CIN2+ associated with HPV-16 or -18 confirmed CIN2+ associated with HPV-16 or -18 in the cervical lesion (ATP cohort)in the cervical lesion (ATP cohort)

• CIN2+ lesion confirmed by consensus diagnosis using CIN2+ lesion confirmed by consensus diagnosis using

a panel of three independent histopathologistsa panel of three independent histopathologists

• HPV-16/18 DNA detected in the lesion by sensitive HPV-16/18 DNA detected in the lesion by sensitive PCR algorithmPCR algorithm

AE AE 4848

HPV-008: Key Secondary and HPV-008: Key Secondary and Exploratory Endpoints Exploratory Endpoints

• Vaccine efficacy against CIN2+ and CIN3+ Vaccine efficacy against CIN2+ and CIN3+ irrespective of HPV type in the lesionirrespective of HPV type in the lesion

• Reduction of cervical excision proceduresReduction of cervical excision procedures

• Vaccine efficacy against persistent infection and Vaccine efficacy against persistent infection and CIN2+ associated with non-vaccine oncogenic CIN2+ associated with non-vaccine oncogenic HPV typesHPV types

• Vaccine impact in women non-naïve to HPV-16/18 Vaccine impact in women non-naïve to HPV-16/18 at baseline at baseline

AE AE 4949

HPV TypesHPV TypesCervarix Cervarix CasesCases

Control Control CasesCases


%% 96.1% CI96.1% CI

HPV-16/18HPV-16/18 44 5656 9393 80-98 80-98

HPV-16HPV-16 22 4646 9696 83-10083-100

HPV-18HPV-18 22 1515 8787 40-9940-99

ATP CohortATP Cohort

HPV-008: Efficacy Against HPV-16/18 CIN2+HPV-008: Efficacy Against HPV-16/18 CIN2+ (Primary Endpoint; Seronegative Subjects) (Primary Endpoint; Seronegative Subjects)

HPV TypesHPV TypesCervarixCervarixCasesCases



%% 96.1% CI96.1% CI

HPV-16/18HPV-16/18 55 9191 9595 86-9886-98

HPV-16HPV-16 33 7373 9696 87-9987-99

HPV-18HPV-18 22 2424 9292 65-9965-99

TVC-1TVC-1

AE AE 5050

Biopsy:CIN2+ HPV-52/18

Example: CIN2+ Case in Vaccine Group

Test M0 M6 M12 M18 M24 M30 M36 M42 M48

PCR

52 52 52 52

59

52

59

52

54

52

18

45

68

52

18

06

Cytology ASC-US NL NL NL NL NA ASC-US ASC-US

ASCUS: atypical squamous cells of unknown significanceNL: NormalNA: Not available

AE AE 5151

HPV-008: Efficacy Against HPV-16/18 CIN2+ HPV-008: Efficacy Against HPV-16/18 CIN2+ Irrespective of Baseline SerostatusIrrespective of Baseline Serostatus

HPV TypesHPV TypesCervarix Cervarix CasesCases



%% 96.1% CI96.1% CI

HPV-16/18HPV-16/18 66 6565 9191 78-97 78-97

HPV-16HPV-16 44 5454 9393 79-9879-98

HPV-18HPV-18 22 1616 8888 44-9944-99


HPV TypesHPV TypesCervarixCervarixCasesCases



%% 96.1% CI96.1% CI

HPV-16/18HPV-16/18 88 104104 9292 84-97 84-97

HPV-16HPV-16 66 8686 9393 84-98 84-98

HPV-18HPV-18 22 2525 9292 66-9966-99

TVC-1TVC-1

AE AE 5252

HPV-008: Efficacy Against HPV-16/18 HPV-008: Efficacy Against HPV-16/18 Endpoints in Women with Prior Infection*Endpoints in Women with Prior Infection*

HPV-16/18HPV-16/18EndpointEndpoint

Cervarix Cervarix CasesCases



%% 96.1% CI96.1% CI

6 Month PI6 Month PI 99 4747 81 81 59-9259-92

12 Month PI12 Month PI 22 2424 9292 64-9964-99


HPV-16/18HPV-16/18EndpointEndpoint

CervarixCervarixCasesCases



%% 96.1% CI96.1% CI

6 Month PI6 Month PI 2121 7373 71 71 50-8350-83

12 Month PI12 Month PI 1313 3939 66 66 32-84 32-84

TVC-1TVC-1

PI = Persistent Infection; 6M = 6 Month; 12M = 12 MonthPI = Persistent Infection; 6M = 6 Month; 12M = 12 Month

*HPV-16/18 Seropositive and DNA negative at baseline *HPV-16/18 Seropositive and DNA negative at baseline

AE AE 5353

HPV-008: Efficacy Against HPV-16/18 HPV-008: Efficacy Against HPV-16/18 CIN2+ in Women with Current Infection* CIN2+ in Women with Current Infection*

TVCTVC

• As expected, no therapeutic effect

• No evidence that cervical disease is enhanced in DNA positive women

Paavonen, Paavonen, Lancet,Lancet, 2009 2009

*HPV-16/18 DNA positive at baseline, irrespective of serostatus *HPV-16/18 DNA positive at baseline, irrespective of serostatus

EndpointEndpoint CervarixCervarix ControlControl Vaccine EfficacyVaccine Efficacy

NN CasesCases NN CasesCases %% 96.1% CI96.1% CI

HPV-16/18HPV-16/18 641641 7474 592592 7373 66 <0-34<0-34

N = Number of women in each groupN = Number of women in each group

AE AE 5454

HPV-008: Efficacy Beyond HPV-16/18HPV-008: Efficacy Beyond HPV-16/18

Overall Vaccine Efficacy

Efficacy Against Non-Vaccine

Oncogenic Types

= +

Efficacy Against HPV-16/18

AE AE 5555

HPV-008: Cohorts for AnalysesHPV-008: Cohorts for Analyses

TVC (N = 18,644)

• Received ≥1 dose of vaccine• Case count: Day after 1st vaccination

Approximates general population: including sexually active young women with prevalent infections/lesions

These cohorts have relevance for assessing overall public health impact of the vaccine

Approximates target population for universal vaccination programs: young women before sexual debut

TVC naïve (N = 11,641)

• Received ≥1 dose of vaccine• At month 0

• Normal cytology • HPV-16/18 seronegative• HPV DNA negative all oncogenic types

• Case count: Day after 1st vaccination

AE AE 5656

HPV-008: Overall Efficacy Irrespective HPV-008: Overall Efficacy Irrespective of HPV Type in Lesion of HPV Type in Lesion




%% 96.1% CI96.1% CI

CIN2+CIN2+ 3333 110110 7070 55-8155-81

CIN3+CIN3+ 33 2323 8787 55-55-9898

TVC Naive* TVC Naive*

Smith, Smith, Int J CancerInt J Cancer, 2007, 2007

5252

Expected Expected Prevalence of Prevalence of HPV-16/18 (%)*HPV-16/18 (%)*

7070

Proportion of CIN2+ cases in control arm of HPV-008 with HPV-16/18 detected: 32-64%

*Approximates target population for universal vaccination programs (young women before sexual debut)

AE AE 5757

HPV-008: Overall Efficacy Irrespective HPV-008: Overall Efficacy Irrespective of HPV Type in Lesion (TVC)of HPV Type in Lesion (TVC)




%% 96.1% CI96.1% CI

CIN2+CIN2+ 224224 322322 3030 16-4216-42

CIN3+ CIN3+ 7777 116116 3333 9-529-52

HPVHPV

ControlControl

CIN

2+ I

nci

de

nce

(cu

mu

lati

ve)

CIN

2+ I

nci

de

nce

(cu

mu

lati

ve)

000.010.010.020.020.030.030.040.040.050.050.060.060.070.070.080.080.090.09 0.10.1

0.110.110.120.120.130.130.140.14

Separation of curvesSeparation of curves

Time (months)Time (months)00 66 1212 1818 2424 3030 3636 4242 4848 5454

AE AE 5858

HPV-008: Overall Efficacy Against HPV-008: Overall Efficacy Against Cervical Excision Procedures*Cervical Excision Procedures*

CohortCervarixCases

ControlCases

Vaccine Efficacy

% 96.1% CI

TVC Naïve 2626 8383 6969 50-8150-81

TVC 180 240 25 7-39

*LEEP, Laser, Knife or cone biopsy

TVC Naïve: Approximates target population for universal vaccination programs

TVC: Approximates general population of women

AE AE 5959





Oncogenic Types

= +

AE AE 6060

HPV-008: CIN2+ Associated with HPV-008: CIN2+ Associated with 12 Non-Vaccine Types (ATP Cohort)12 Non-Vaccine Types (ATP Cohort)

Cervarix Group Control Group

16/18 6 65

VE=54% (CI: 34-69)

50 vs 10950 10912 non-vaccine

types*

*31/33/35/39/45/51/52/56/58/59/66/68 (with or without 16/18 co-infections)

AE AE 6161

VE=37% (CI: 7-58)48 vs 77

Cervarix Group Control Group

16/18

2

12 non-vaccine types*

HPV-008: CIN2+ Exclusively Associated HPV-008: CIN2+ Exclusively Associated with 12 Non-Vaccine Types (ATP Cohort)with 12 Non-Vaccine Types (ATP Cohort)

48 77

*31/33/35/39/45/51/52/56/58/59/66/68 (without 16/18 co-infections)

32

4 33

10950

AE AE 6262

HPV-008: Expected Impact of Efficacy HPV-008: Expected Impact of Efficacy Against Non-Vaccine Types Against Non-Vaccine Types

• True vaccine efficacy against non vaccine CIN2+ is True vaccine efficacy against non vaccine CIN2+ is between 37% - 54%between 37% - 54%

• 30% cervical cancers caused by non-vaccine 30% cervical cancers caused by non-vaccine oncogenic typesoncogenic types

• 11%-16% additional protection against cervical 11%-16% additional protection against cervical cancer beyond HPV-16/18cancer beyond HPV-16/18

AE AE 6363





Oncogenic Types

= +

AE AE 6464

HPV-008: Contribution of Individual HPV-008: Contribution of Individual

Non-Vaccine Oncogenic Types Non-Vaccine Oncogenic Types • CIN2+ endpoints CIN2+ endpoints

– Useful, but frequent detection of multiple HPV Useful, but frequent detection of multiple HPV types complicates evaluationtypes complicates evaluation

• Persistent infection endpointsPersistent infection endpoints

– Predict risk of progression to pre-cancer and cancerPredict risk of progression to pre-cancer and cancer

– NotNot complicated by infection with multiple HPV types complicated by infection with multiple HPV types

AE AE 6565

HPV-008: Efficacy Against Individual HPV-008: Efficacy Against Individual Non-Vaccine Oncogenic TypesNon-Vaccine Oncogenic Types

CIN2+CIN2+

Values with LLCI > 0 in yellowValues with LLCI > 0 in yellow

* In subjects HPV DNA negative at baseline* In subjects HPV DNA negative at baseline

Type Cohort

Includes 16/18 Co-infections Excludes 16/18 Co-infections

Cervarix/Control

Efficacy (%) Cervarix/Control

Efficacy (%)

31

ATP 2/25 92 2/19 89

TVC Naive 0/20 100 0/13 100

TVC* 11/35 68 11/24 54

33

ATP 12/25 52 12/21 43

TVC Naive 5/18 72 5/15 67

TVC* 17/34 50 16/26 38

45

ATP 0/4 100 0/1 100

TVC Naive 0/5 100 0/1 100

TVC* 0/6 100 0/2 100

AE AE 6666

HPV-008: Efficacy Against Individual HPV-008: Efficacy Against Individual Non-Vaccine Oncogenic TypesNon-Vaccine Oncogenic Types

Values with LLCI > 0 in yellowValues with LLCI > 0 in yellow

* In subjects HPV DNA negative at baseline* In subjects HPV DNA negative at baseline

Type Cohort

6 Month Persistent Infection 12 Month Persistent Infection

Cervarix/Control

Efficacy (%) Cervarix/Control

Efficacy (%)

31

ATP 46/215 79 21/102 79

TVC Naive 32/140 78 17/62 73

TVC* 94/285 67 52/139 63

33

ATP 67/123 46 31/50 38

TVC Naive 53/93 44 30/41 27

TVC* 101/168 40 50/77 35

45

ATP 23/94 76 10/27 63

TVC Naive 12/64 81 4/19 79

TVC* 35/125 72 19/43 56

Persistent Infection

AE AE 6767

Significance of HPV-31, Significance of HPV-31, HPV-33 and HPV-45HPV-33 and HPV-45

• Phylogenetically related to HPV-16 or 18 Phylogenetically related to HPV-16 or 18 – HPV-31 and 33 HPV-31 and 33 →→ HPV-16 HPV-16

– HPV-45 HPV-45 →→ HPV-18 HPV-18

• 3 most common types after HPV-16/18*3 most common types after HPV-16/18*– Account for 12% of cervical cancers in NA Account for 12% of cervical cancers in NA

• HPV-45 is commonly associated with adenocarcinomaHPV-45 is commonly associated with adenocarcinoma– Often escapes detection by screeningOften escapes detection by screening

*Smith, Int J Cancer, 2007

AE AE 6868







AE AE 6969

Immunogenicity OverviewImmunogenicity Overview

• Immune responses sustained at high levels for Immune responses sustained at high levels for both HPV-16 and HPV-18 for up to 6.4 yearsboth HPV-16 and HPV-18 for up to 6.4 years

• High correlation between antibody levels in High correlation between antibody levels in serum and cervico-vaginal secretions (site of serum and cervico-vaginal secretions (site of infection)infection)

• Successful immunological bridge to younger Successful immunological bridge to younger age group (10-14 years)age group (10-14 years)

AE AE 7070Total follow-up time (Months)Total follow-up time (Months)

1

10

100

1000

10000

0 7 12 18 [25-32] [33-38] [39-44] [45-50] [51-56] [57-62] [63-68]

GM

Ts

(EL

U/m

l)

[69-74] [75-76]

6%

100% 100% 99% 99% 99% 100% 100% 100% 100% 100% 99% 100%

Natural Infection (Women in HPV-008 who were DNA negative and seropositive at baseline)Natural Infection (Women in HPV-008 who were DNA negative and seropositive at baseline)

1

10

100

1000

10000

0 7 12 18 [25-32] [33-38] [39-44] [45-50] [51-56] [57-62] [63-68] [69-74] [75-76]

10%

100% 100% 99% 99% 99% 99% 100% 100% 100% 100% 99% 100%

Total follow-up time (Months)Total follow-up time (Months)

1

10

100

1000

10000

100000

0 7 12 18 [25-32] [33-38] [39-44] [45-50] [51-56] [57-62] [63-68]

GM

Ts

(ED

50)

[69-74] [75-76]

2.3%

100% 100% 100% 100% 100% 98% 98% 100% 98% 100% 100% 100%

HPV-001/007: Immune Responses Sustained HPV-001/007: Immune Responses Sustained at High Levels Through 6.4 yearsat High Levels Through 6.4 years

1

10

100

1000

10000

100000

0 7 12 18 [25-32] [33-38] [39-44] [45-50] [51-56] [57-62] [63-68] [69-74] [75-76]

0%

100% 100% 100% 100% 100% 98% 98% 100% 100% 100% 100% 100%

HPV-16 HPV-18(ELISA)

(PBNA)

AE AE 7171

Immunobridge to Younger Age GroupImmunobridge to Younger Age GroupHPV-012: Blinded, randomized, multicenter study in Europe HPV-012: Blinded, randomized, multicenter study in Europe N=N=532 (15-25 years); 150 (10-14 years)532 (15-25 years); 150 (10-14 years)

HPV-16 HPV-16 HPV-18 HPV-18

1

10

100

1000

10000

100000

15-25 years 10-14 years1

10

100

1000

10000

15-25 years 10-14 years

GM

Ts

(E

U/m

l)G

MT

s (

EU

/ml)

● Non-inferiority of immune response demonstrated for 10-14 years Non-inferiority of immune response demonstrated for 10-14 years

● GMTs in 10-14 years > 2-fold higher than 15-25 years GMTs in 10-14 years > 2-fold higher than 15-25 years

AE AE 7272







AE AE 7373

Immunogenicity and Efficacy Immunogenicity and Efficacy SummarySummary

• Cervarix induces immune responses which are sustained at Cervarix induces immune responses which are sustained at high levels for both HPV-16 and HPV-18high levels for both HPV-16 and HPV-18

• Cervarix is highly efficacious against HPV-16/18 pre-Cervarix is highly efficacious against HPV-16/18 pre-cancers in HPV-16/18 seronegative womencancers in HPV-16/18 seronegative women

• Efficacy demonstrated against clinically relevant endpoints in Efficacy demonstrated against clinically relevant endpoints in previously exposed womenpreviously exposed women

• Significant overall impact driven by:Significant overall impact driven by:

– Efficacy against HPV-16/18 endpoints Efficacy against HPV-16/18 endpoints

– Efficacy against some non-vaccine oncogenic types Efficacy against some non-vaccine oncogenic types

• Consistent efficacy pattern against HPV-31Consistent efficacy pattern against HPV-31, , 33, 45 using 33, 45 using persistent infection and CIN2+ endpointspersistent infection and CIN2+ endpoints

• Reduction in cervical excision proceduresReduction in cervical excision procedures

AE AE 7474

Overall ConclusionOverall Conclusion

Cervarix provides significant overall protection Cervarix provides significant overall protection against cervical pre-cancers – resulting from against cervical pre-cancers – resulting from efficacy against vaccine types and some non-efficacy against vaccine types and some non-vaccine typesvaccine types

AI AI 7575


Vaccine Design







AS AS 7676

Safety Presentation OutlineSafety Presentation Outline

• Overview of clinical safety database Overview of clinical safety database

• Post-marketing experiencePost-marketing experience

• Pharmacovigilance planPharmacovigilance plan

AS AS 7777

Overview of Safety Data in BLAOverview of Safety Data in BLA

• Total of 57,323 girls and womenTotal of 57,323 girls and women– > 130,000 person years total> 130,000 person years total

• 29,953 girls and women in original submission 29,953 girls and women in original submission – 16,142 at least one dose of Cervarix16,142 at least one dose of Cervarix

• Meta-analysis AS04 vaccines: 68,512 people Meta-analysis AS04 vaccines: 68,512 people

• Post-marketing experience following Post-marketing experience following ~~ 7 million 7 million doses distributeddoses distributed

AS AS 7878

Overview of Data Collection forOverview of Data Collection forSafety ReportingSafety Reporting

Solicited Solicited symptomssymptoms

7 days7 days 7 days7 days 7 days7 days

Unsolicited Unsolicited symptomssymptoms

30 days30 days 30 days30 days 30 days30 days

Dose 1Dose 1Month 0Month 0

Dose 2Dose 2Month 1Month 1

Dose 3Dose 3Month 6Month 6 Month 7Month 7 Month 12Month 12

* Pregnancies followed up until outcome* Pregnancies followed up until outcome

SAEs, Ms SAEs, Ms conditionsconditions& NOCDs & NOCDs

Pregnancies*Pregnancies*

Up to 7.4 yearsUp to 7.4 years(130,000 person years)(130,000 person years)

AS AS 7979

Age Distribution:Age Distribution: Pooled Safety Analysis Pooled Safety Analysis

29,953 girls and women 10 to 72 years29,953 girls and women 10 to 72 years

15,171

6,240 8,54210-17 years

18-25 years

> 25 years

11 studies reported in BLA; DLP depending on study

AS AS 8080

Ethnic/Racial Distribution:Ethnic/Racial Distribution:Pooled Safety AnalysisPooled Safety Analysis

Others = Mixed Ethnicities, Aboriginal, American Indian, Native American, Native Canadian, Cape Colored, First Nations, Gipsy

16,899

7,739

973

3,651691

Overall population(number of women)

US population(number of women)

11 studies reported in BLA; DLP depending on study

White/Caucasians Asians Blacks Hispanics Others

2,883

87

487

542

179

AS AS 8181

1.2%0.6%7.0%

0.2%0.0%1.8% 0.2%0.1%0.8% 0.0%0.1%

7.8%

0

10

20

30

40

50

60

70

80

90

100

Grade 3 Pain Grade 3 Redness Grade 3 SwellingPain Redness Swelling

Solicited Local Symptoms:Solicited Local Symptoms:Pooled Safety Analysis 10-25 Year OldsPooled Safety Analysis 10-25 Year Olds

Overall/Dose- 7 Days of Vaccination (Total Vaccinated CohortOverall/Dose- 7 Days of Vaccination (Total Vaccinated Cohort))

Grade 3 pain = pain that prevents normal activityGrade 3 pain = pain that prevents normal activityGrade 3 redness/swelling = redness/swelling greater than 50 mmGrade 3 redness/swelling = redness/swelling greater than 50 mm

%

Cervarix

HAV 720

Al(OH)3

HAV 360

11 studies reported in BLA; DLP depending on study11 studies reported in BLA; DLP depending on study

AS AS 8282

Solicited General Symptoms:Solicited General Symptoms: Pooled Safety Analysis 10-25 Year Olds Pooled Safety Analysis 10-25 Year Olds

Overall/Dose - 7 Days of Vaccination (Total Vaccinated Cohort)Overall/Dose - 7 Days of Vaccination (Total Vaccinated Cohort)

%

0

10

20

30

40

50

60

70

80

90

100

Fatigue Fever GI* Headache Rash Arthralgia** Myalgia** Urticaria**

** GI = Gastrointestinal, including nausea, vomiting, diarrhea, and/or abdominal pain GI = Gastrointestinal, including nausea, vomiting, diarrhea, and/or abdominal pain ** Arthralgia, myalgia and urticaria not solicited in Phase II study using Al(OH)** Arthralgia, myalgia and urticaria not solicited in Phase II study using Al(OH) 33 as control as control

11 studies reported in BLA; DLP depending on study11 studies reported in BLA; DLP depending on study

Cervarix

HAV 720

Al(OH)3

HAV 360

AS AS 8383

Compliance with Dosing: Studies HPV-008 and HPV-013 10-25 Year Olds

Number of Women Receiving Study Vaccine Doses

0

1000

2000

3000

4000

Dose 1 Dose 2 Dose 3

CervarixHAV720

0

300

600

900

1200

1500

Dose 1 Dose 2 Dose 3

CervarixHAV360

10-14 years 15-25 years

AS AS 8484

Analysis of Deaths:Analysis of Deaths:All Studies with CervarixAll Studies with Cervarix

Cause of Death

HPV Vaccine

N = 33,623

Control*

N = 23,700

n Per 1000 n Per 1000

Road traffic accident 5 0.16 5 0.21

Suicide 2 0.06 5 0.21

Homicide 2 0.06 1 0.04

Neoplasm 3 0.10 2 0.08

Autoimmune disease 3 0.10 1 0.04

Infectious disease 3 0.10 1 0.04

Cardiovascular disorders 2 0.06 0 0.00

Unknown 0 0.00 2 0.08

TOTAL 20 0.64 17 0.72

* One death occurred in subject not vaccinated* One death occurred in subject not vaccinated

DLP August 31, 2008DLP August 31, 2008

AS AS 8585

Overall Safety Results:Overall Safety Results: Pooled Safety Analysis Pooled Safety Analysis

Entire observation period

Percentage With ≥ 1 Event (Total Vaccinated Cohort)

29.0%

5.5%

0.7%

31.4%

6.8%

0.8%0

5

10

15

20

25

30

35

Medically SignificantConditions

SAEs New Onset of AutoimmuneDisorders

100

DLP August 31, 2008

HPV vaccinePooled Control(Al(OH)3, HAV 360, HAV 720)

%

AS AS 8686

Safety Events of Specific Interest

• Events of potential autoimmune origin– Neuroinflammatory events

– Musculoskeletal events

• Pregnancy outcomes– Spontaneous pregnancy loss

– Congenital abnormalities

AS AS 8787* 95% CI = 95% confidence interval for relative risk (Exact Stratified Conditional to total number of cases)

Relative Risk (AS04 vs non-AS04) with 95% CI*Relative Risk (AS04 vs non-AS04) with 95% CI*

Events of Potential Autoimmune Origin: Events of Potential Autoimmune Origin: Meta-Analysis of All HPV Vaccine TrialsMeta-Analysis of All HPV Vaccine Trials

DLP: Jun 30, 2007; Verstraeten, Vaccine, 2008

0 1 2 3 4 5 6

At Least OneSymptom Overall

Number of Diagnoses (HPV / Control)

96 / 1040.92

Thyroid Disease

Skin Disorders

Others

Neuroinflammatory

Musculoskeletal

Gastrointestinal 10 / 10

19 / 15

2 / 3

11 / 12

48 / 57

7 / 8

0.97

1.24

0.67

0.88

0.92

0.85

RR

AS AS 8888

* 95% CI = 95% confidence interval for relative risk (Exact Stratified Conditional to total number of cases)

Relative Risk (AS04 vs non-AS04) with 95% CI*Relative Risk (AS04 vs non-AS04) with 95% CI*

Potential Autoimmune Disorders: Meta-analysis of All AS04 Vaccine Trials*

* AS04-containing vaccines: HPV, HSV and adjuvanted Hepatitis B

DLP: Jun 30, 2007; Verstraeten, Vaccine, 2008

At Least OneSymptom Overall

0 1 2 3 4 5 6

191 / 1710.98

Thyroid Disease

Skin Disorders

Others

Neuroinflammatory

Musculoskeletal

Gastrointestinal 16 / 17

45 / 34

5 / 4

27 / 22

81 / 78

19 / 17

0.85

1.16

1.00

0.98

1.07

0.92

RR Number of Diagnoses (AS04 / Control)

AS AS 8989

Role of Expert Panels:Role of Expert Panels:Rheumatologists and NeurologistsRheumatologists and Neurologists

• Blinded reviewBlinded review

• Individual assessment ofIndividual assessment of – Immune mediated nature of eventImmune mediated nature of event

– Appropriate diagnosisAppropriate diagnosis

• Consensus diagnosis if opinion differedConsensus diagnosis if opinion differed

• Determination of onset date Determination of onset date

Expert panels: 12 months following first dose* – highest Expert panels: 12 months following first dose* – highest theoretical risktheoretical risk

* or 6 months after last dose for delayed/incomplete dosing

AS AS 9090

Relative Risks of Immune-Mediated Events

AS04*AS04* Control*Control*

AS04 over ControlAS04 over Control

RRRR95% CI95% CI

LLLL ULUL

All reports, any All reports, any TTOTTO

Level 1Level 1 77 33 2.32.3 0.50.5 14.014.0

Level 2Level 2 1010 55 1.7 1.7 0.50.5 6.56.5

* Level 1 (includes Cervarix and investigational HPV vaccines): AS04 group N = 25,580; non-AS04 group N = 25,438Level 2: AS04 group N = 42,600; non-AS04 group N = 37,769

Neuro-Inflammatory EventsNeuro-Inflammatory Events

Confirmed, risk Confirmed, risk periodperiod

Level 1Level 1 00 22 0.00.0 0.00.0 5.35.3

Level 2Level 2 11 33 0.20.2 0.00.0 3.03.0

DLP: August 31, 2008 for all reports and December 31, 2007 for adjudicated reportsDLP: August 31, 2008 for all reports and December 31, 2007 for adjudicated reports

AS AS 9191

Relative Risk of Immune-Mediated EventsRelative Risk of Immune-Mediated Events

AS04*AS04* Control*Control*

AS04 over ControlAS04 over Control

RRRR95% CI95% CI

LLLL ULUL

All reports, any All reports, any TTOTTO

Level 1Level 1 3939 2929 1.31.3 0.80.8 2.22.2

Level 2Level 2 7676 5959 1.11.1 0.80.8 1.61.6

** Level 1 (includes Cervarix and investigational HPV vaccines): AS04 group N = 25,580; non-AS04 group N = 25,438Level 1 (includes Cervarix and investigational HPV vaccines): AS04 group N = 25,580; non-AS04 group N = 25,438Level 2: AS04 group N = 42,600; non-AS04 group N = 37,769 Level 2: AS04 group N = 42,600; non-AS04 group N = 37,769

Musculoskeletal EventsMusculoskeletal Events

Confirmed, risk Confirmed, risk periodperiod

Level 1Level 1 33 11 3.03.0 0.20.2 157.4157.4

Level 2Level 2 55 33 1.61.6 0.30.3 10.310.3

DLP: August 31, 2008 for all reports and December 31, 2007 for adjudicated reportsDLP: August 31, 2008 for all reports and December 31, 2007 for adjudicated reports

AS AS 9292

All Pregnancy Outcomes:All Pregnancy Outcomes: Pooled Safety Analysis* Pooled Safety Analysis*

Pregnancy OutcomesPregnancy Outcomes

Cervarix Cervarix 19,871 Women19,871 Women

Pooled ControlPooled Control17,548 Women17,548 Women

N = 3696N = 3696 N = 3580N = 3580

nn %% nn %%

Normal infantNormal infant 23002300 62.262.2 22402240 62.662.6

Pregnancy ongoingPregnancy ongoing 490490 13.313.3 459459 12.812.8

Spontaneous lossSpontaneous loss 408408 11.011.0 388388 10.910.9

Elective terminationElective termination 216216 5.95.9 217217 6.16.1

Infant peri-natal conditions**Infant peri-natal conditions** 105105 2.92.9 114114 3.23.2

Premature birthPremature birth 7373 2.02.0 6262 1.71.7

Congenital anomalyCongenital anomaly 3030 0.80.8 2828 0.80.8

Lost to follow-upLost to follow-up 2424 0.70.7 2525 0.70.7

Ectopic pregnanciesEctopic pregnancies 2222 0.60.6 2121 0.60.6

Still birthStill birth 2020 0.50.5 1919 0.50.5

Therapeutic abortionTherapeutic abortion 44 0.10.1 44 0.10.1

Molar pregnancyMolar pregnancy 44 0.10.1 33 0.10.1

* Including NCI sponsored study HPV-009; DLP August 31, 2008** not congenital anomaly

AS AS 9393

Pregnancy Around Vaccination:* Pooled Safety Analysis

Pregnancy Outcomes

Cervarix19,871 Women

Pooled Control17,548 Women

N = 396 N = 365

n % n %

Normal infant 258 65.2 253 69.3

Spontaneous loss 54 13.6 35 9.6

Elective termination 39 9.9 35 9.6

Infant peri-natal conditions** 20 5.1 17 4.7

Premature birth 10 2.5 9 2.5

Congenital anomaly 7 1.8 5 1.4

Lost to follow-up 4 1.0 5 1.4

Ectopic pregnancies 2 0.5 1 0.3

Still birth 1 0.3 3 0.8

Therapeutic abortion 1 0.3 1 0.3

Pregnancy ongoing 0 0.0 1 0.3

* defined as last menstrual period from 30 days before until 45 days post-vaccination** not congenital anomaly

DLP August 31, 2008

PEROMY00

Highlight spont ab in circle

AS AS 9494

Pregnancy Around Vaccination: Additional Analyses

• Detailed analyses of HPV-008

• Review of other trials

• Comparison to background rates

• Assessment of biological plausibility

• Independent NCI analysis

AS AS 9595

Spontaneous Loss by Time of Pregnancy OnsetSpontaneous Loss by Time of Pregnancy Onset(NCI Analysis on Completed Pregnancies: HPV-008 and HPV-009) (NCI Analysis on Completed Pregnancies: HPV-008 and HPV-009)

AS AS 9696

Additional Assessment of Pregnancy Loss in HPV-008

• No difference between groups in gestational age at time of pregnancy loss

• No relationship to dosing

• Potential misreporting of elective terminations and spontaneous losses in several countries

AS AS 9797

0

5

10

15

20

25

30

35

40

45

50

Brazil

Mex

ico

Philip

pine

s

Austra

lia

Unite

d Kin

gdom

Unite

d Sta

tes

Canad

a

Finlan

d

Germ

any

Spain

Taiwan

Thaila

nd

%

Spontaneous loss

Elective termination

DLP August 31, 2008

Spontaneous Pregnancy Loss and Elective Termination Rates by Country (HPV-008)

All PregnanciesAll Pregnancies

AS AS 9898

0

5

10

15

20

25

30

35

40

45

50

Brazil

Mex

ico

Philip

pine

s

Austra

lia

Unite

d Kin

gdom

Unite

d Sta

tes

Canad

a

Finlan

d

Germ

any

Taiwan

Thaila

nd

%

Spontaneous loss

Elective termination

DLP August 31, 2008

Spontaneous Pregnancy Loss and Elective Termination Rates by Country (HPV-008)

Pregnancies Around VaccinationPregnancies Around Vaccination

AS AS 9999

Additional Assessment of Pregnancy Loss in HPV-008

• No difference between groups in gestational age at time of pregnancy loss

• No relationship to dosing

• Potential misreporting of elective terminations and spontaneous losses in several countries

• Additional considerations– Imbalance of 13 cases – No randomization on pregnancies– Many potential confounding factors

AS AS 100100

Background rates1

1 Zinaman, Fertil Steril, 1996; Goldhaber, Epidemiology,1991; Goldhaber, Am J Epidemiol, 2000; Swan, Epidemiology, 1998; Li, Epidemiology, 2002; Massad, AIDS, 2004; Jones, Stud Fam Plann, 2007; Wilcox, Am J Epidemiol, 1981; Savitz, Epidemiology, 2008; Wilcox, N Engl J Med, 1988; Harlap, Human embryonic and fetal death, 1980; Ellish, Hum Reprod, 1996; Eskenazi, Am J Ind Med, 1995; Hakim, Am J Obstet Gynecol, 1995; Sweeney, Am J Epidemiol, 1988

Spontaneous Loss by Study Pregnancies Around Vaccination

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

HPV-008

%

HPVHAV

n=22 n=9

Gardasil studiesspontaneous loss rate

HPV-009

n=27 n=19

Pooling without HPV-008-009

n=5 n=7

AS AS 101101

No Mechanism for Biological Plausibility

• No teratogenic effect of Cervarix – no mutagenic effect of MPL in preclinical toxicology – At doses 24-54 fold higher than human dose

• Chromosomal abnormalities? – No mutagenicity observed

• Interference with embryonic development?– No imbalance in congenital abnormalities– No decrease in birthweight

• Immunological effect?– No dose effect– Not seen in women who became pregnant later despite

sustained immune reponse

AS AS 102102

Evaluation of CausalityVaccine Specific Bradford-Hill Criteria*

* Weekly Epidemiological Review 2001 76: 85-89

No evidence of a causal association between Cervarix and spontaneous pregnancy loss

• Consistency of observation

•Strength of association/ Dose response relationship

• Specificity

•Temporal relationship with study vaccination

• Biological plausibility

Not met

Not met

Not met

Partially met

Not met

Not met

Not met

Not met

Partially met

Not met

AS AS 103103

Congenital Anomalies:Congenital Anomalies: Pooled Safety Analysis Pooled Safety Analysis

DLP August 31, 2008

• 60 reports60 reports

• Equal rates HPV vaccine vs control Equal rates HPV vaccine vs control – Also in sub-analysis of women pregnant around Also in sub-analysis of women pregnant around

vaccination vaccination

• No specific pattern or cluster on type of defects No specific pattern or cluster on type of defects reportedreported

• Expert panel concluded data did not indicate Expert panel concluded data did not indicate increased risk following vaccinationincreased risk following vaccination

AS AS 104104

Post-Marketing ExperiencePost-Marketing Experience

• Registered in 98 countriesRegistered in 98 countries

• ~7 million doses distributed worldwide since ~7 million doses distributed worldwide since launchlaunch

• Over 70% coverage of 12-13 year olds in UKOver 70% coverage of 12-13 year olds in UK

• 1,680 reports received since launch* 1,680 reports received since launch*

– Most from Most from UK (37%), Italy (14%) Germany (9%)UK (37%), Italy (14%) Germany (9%)– 7% of reported events - serious7% of reported events - serious– Most events recognized in currently approved labelsMost events recognized in currently approved labels

* DLP May 18, 2009

AS AS 105105

Frequency Most Common Events/ 1,000,000 Frequency Most Common Events/ 1,000,000 Doses Distributed Since Launch: Doses Distributed Since Launch:

Spontaneous CasesSpontaneous Cases

12

15

17

18

24

25

28

33

36

37

0 5 10 15 20 25 30 35 40

Fatigue

Syncope

Rash

Malaise

Nausea

Pain in extremity

Dizziness

Pyrexia

Injection site pain

Headache

DLP May 18, 2009DLP May 18, 2009

AS AS 106106

Events of Interest:Events of Interest:Spontaneous CasesSpontaneous Cases

• Pregnancy ReportsPregnancy Reports– 65 prospective pregnancy reports65 prospective pregnancy reports

– 5 cases spontaneous loss -- no congenital anomalies5 cases spontaneous loss -- no congenital anomalies

• Autoimmune Diseases Autoimmune Diseases – No clusters autoimmune disorders – similar to literatureNo clusters autoimmune disorders – similar to literature

– 2 reports Guillain-Barré Syndrome (GBS) from UK 2 reports Guillain-Barré Syndrome (GBS) from UK

• MHRA - no evidence vaccine increases frequency of MHRA - no evidence vaccine increases frequency of GBS vs. occurring naturally in population*GBS vs. occurring naturally in population*

* www.mhra.gov.uk

AS AS 107107

Pharmacovigilance PlanPharmacovigilance Plan

• Enhanced pharmacovigilanceEnhanced pharmacovigilance

• Follow-up of autoimmune disease Follow-up of autoimmune disease – Phase IV trial in US Phase IV trial in US

– Phase IV trial in FinlandPhase IV trial in Finland

• Follow-up of pregnanciesFollow-up of pregnancies– Phase IV trial in USPhase IV trial in US

– US/UK Pregnancy Registries US/UK Pregnancy Registries

– Ongoing clinical trialsOngoing clinical trials

• Additional clinical trials: HIV+, co-administration, Additional clinical trials: HIV+, co-administration, long-term immunogenicity, efficacy and safety long-term immunogenicity, efficacy and safety

AS AS 108108

U.S. Safety Study

• ObjectivesObjectives– Assess autoimmune diseasesAssess autoimmune diseases– Assess pregnancy outcomesAssess pregnancy outcomes

• Observational study in existing databasesObservational study in existing databases

• Follow-up of 100,000 women 10-25 year oldsFollow-up of 100,000 women 10-25 year olds – Screen for AID in 12 months after 1st vaccinationScreen for AID in 12 months after 1st vaccination– Follow all women vaccinated during pregnancy or up to 45 days Follow all women vaccinated during pregnancy or up to 45 days

before LMPbefore LMP

• Control group: women not receiving CervarixControl group: women not receiving Cervarix– Matching on propensity scoreMatching on propensity score

• RR that can be detected with 80% powerRR that can be detected with 80% power– 1.6 and 3.7 for aggregate AID endpoints1.6 and 3.7 for aggregate AID endpoints– 2.0 for spontaneous pregnancy loss2.0 for spontaneous pregnancy loss

AS AS 109109

U.S. and UK Pregnancy Registry

• To monitor spontaneous pregnancy loss in addition to other pregnancy outcomes

• Measures to encourage enrollment of women

• Enroll women with LMP up to 45 days after vaccination

• Compare to background rates for comparable population -- maternal age and gestational age

AS AS 110110

Overall Safety ConclusionsOverall Safety Conclusions

• Large safety database (130,000 person years of follow-up)Large safety database (130,000 person years of follow-up)

• Comparable AE/SAE rates in vaccine and control groupsComparable AE/SAE rates in vaccine and control groups

• No significant increase in relative risk of potential No significant increase in relative risk of potential autoimmune events in meta-analysisautoimmune events in meta-analysis

• Similar overall rates of pregnancy outcomesSimilar overall rates of pregnancy outcomes

• No safety concerns in post-marketing surveillanceNo safety concerns in post-marketing surveillance

• Comprehensive Pharmacovigilance plan to cover events of Comprehensive Pharmacovigilance plan to cover events of specific interestspecific interest

The safety profile is clinically acceptable and indicates that Cervarix can be used with confidence

in the target population

The safety profile is clinically acceptable and indicates that Cervarix can be used with confidence

in the target population

AI AI 111111


Vaccine Design







AC AC 112112

Efficacy ConclusionsEfficacy Conclusions

• Cervarix is highly efficacious against HPV-16/18 Cervarix is highly efficacious against HPV-16/18 pre-cancers in HPV-16/18 seronegative women pre-cancers in HPV-16/18 seronegative women

• Efficacy demonstrated against clinically relevant Efficacy demonstrated against clinically relevant endpoints in previously exposed womenendpoints in previously exposed women

• Significant overall impact irrespective of HPV types, Significant overall impact irrespective of HPV types, indicates efficacy beyond HPV-16/18indicates efficacy beyond HPV-16/18

– 70% against all CIN2+ lesions70% against all CIN2+ lesions

• Consistent efficacy pattern against HPV-31,33,45 Consistent efficacy pattern against HPV-31,33,45 using persistent infection and CIN2+ endpointsusing persistent infection and CIN2+ endpoints

AC AC 113113

• Immune responses sustained at high levels for both HPV-16, 18

• Good correlation between antibody levels in serum and at site of infection

• Successful immunological bridge to 10-14 year olds

Cervarix is Highly ImmunogenicCervarix is Highly Immunogenic

AC AC 114114

• Large safety database – 57,323 women, 130,000 person years

• Comparable rates (vaccine vs control)– AEs/SAEs

– Pregnancy outcomes

– Autoimmune events

• No safety concerns in post-marketing database– ~7 million doses distributed

• Extensive Pharmacovigilance Plan

Cervarix Has a Favorable Cervarix Has a Favorable Safety ProfileSafety Profile

AC AC 115115

• 5 HPV types = ~88% cervical cancers 5 HPV types = ~88% cervical cancers – HPV-16 ,18 , 31, 33, 45HPV-16 ,18 , 31, 33, 45

• 11,270 diagnosed / 4,070 die from cervical cancer11,270 diagnosed / 4,070 die from cervical cancer

• Cervarix versus vaccine without cross-protectionCervarix versus vaccine without cross-protection

– EEstimated global incremental benefit in efficacy of 11-16% due to cross-protection

– Potential to prevent more cancers and save more livesPotential to prevent more cancers and save more lives

Smith, Int J Cancer (2007); Jemal, Ca Cancer J Clin (2009); Herzog, Am J Obstet Gynecol (2007)

Cervarix Addresses a Medical Need Cervarix Addresses a Medical Need

AC AC 116116

ConclusionConclusion

Cervarix is expected to provide a significant Cervarix is expected to provide a significant public health benefit to American girls and public health benefit to American girls and women 10-25 years of agewomen 10-25 years of age

AC AC 117117

CERVARIX®CERVARIX®Human Papillomavirus Bivalent Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant(Types 16 and 18) Vaccine, Recombinant

GlaxoSmithKline GlaxoSmithKline

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