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AI AI 11
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 It was current when produced, but is no longer maintained and may be outdated.
AI AI 22
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)
AI AI 55
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
AI AI 77
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)
AI AI 1212
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
AI AI 1313
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
AI AI 1414
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
AI AI 1515
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
AI AI 1616
GlaxoSmithKline GlaxoSmithKline PresentationPresentation
Vaccine Design
Martine Wettendorff, Ph.DVice 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
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
AI AI 1818
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
AI AI 1919
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
AI AI 2020
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.
AI AI 2121
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
AI AI 2222
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
AI AI 2323
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)
AI AI 2424
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)
AI AI 2626
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
AI AI 2727
GlaxoSmithKline GlaxoSmithKline PresentationPresentation
Vaccine Design
Martine Wettendorff, Ph.DVice PresidentGlobal Vaccine DevelopmentAdult/Adolescent Franchise
Efficacy Gary Dubin, MDVice President, Director Global Clinical Development Center
Safety/Pharmacovigilance Plan
Thomas Verstraeten, MDVice President, Head Biologicals Clinical Safety and Pharmacovigilance
Benefit/Risk Conclusion
Barbara Howe, MDVice President, Director North American Vaccine Development
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
• EfficacyEfficacy
– Design of Clinical TrialsDesign of Clinical Trials
– Key Efficacy ResultsKey Efficacy Results
• ImmunogenicityImmunogenicity
• ConclusionsConclusions
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
EndpointEndpoint CervarixCervarixCasesCases
ControlControlCasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
Vaccine EfficacyVaccine Efficacy
%% 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
Vaccine EfficacyVaccine Efficacy
%% 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
ControlControlCasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
Control Control CasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
ATP CohortATP Cohort
HPV TypesHPV TypesCervarixCervarixCasesCases
ControlControlCasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
Control Control CasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
ATP CohortATP Cohort
HPV-16/18HPV-16/18EndpointEndpoint
CervarixCervarixCasesCases
ControlControlCasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
EndpointEndpoint CervarixCervarixCasesCases
ControlControlCasesCases
Vaccine EfficacyVaccine Efficacy
%% 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)
EndpointEndpoint CervarixCervarixCasesCases
ControlControlCasesCases
Vaccine EfficacyVaccine Efficacy
%% 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
HPV-008: Efficacy Beyond HPV-16/18HPV-008: Efficacy Beyond HPV-16/18
Efficacy Against HPV-16/18
Overall Vaccine Efficacy
Efficacy Against Non-Vaccine
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
HPV-008: Efficacy Beyond HPV-16/18HPV-008: Efficacy Beyond HPV-16/18
Efficacy Against HPV-16/18
Overall Vaccine Efficacy
Efficacy Against Non-Vaccine
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
Efficacy and Immunogenicity Efficacy and Immunogenicity Presentation OutlinePresentation Outline
• EfficacyEfficacy
– Design of Clinical TrialsDesign of Clinical Trials
– Key Efficacy ResultsKey Efficacy Results
• ImmunogenicityImmunogenicity
• ConclusionsConclusions
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
Efficacy and Immunogenicity Efficacy and Immunogenicity Presentation OutlinePresentation Outline
• EfficacyEfficacy
– Design of Clinical TrialsDesign of Clinical Trials
– Key Efficacy ResultsKey Efficacy Results
• ImmunogenicityImmunogenicity
• ConclusionsConclusions
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
GlaxoSmithKline GlaxoSmithKline PresentationPresentation
Vaccine Design
Martine Wettendorff, Ph.DVice PresidentGlobal Vaccine DevelopmentAdult/Adolescent Franchise
Efficacy Gary Dubin, MDVice President, Director Global Clinical Development Center
Safety/Pharmacovigilance Plan
Thomas Verstraeten, MDVice President, Head Biologicals Clinical Safety and Pharmacovigilance
Benefit/Risk Conclusion
Barbara Howe, MDVice President, Director North American Vaccine Development
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
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
GlaxoSmithKline GlaxoSmithKline PresentationPresentation
Vaccine Design
Martine Wettendorff, Ph.DVice PresidentGlobal Vaccine DevelopmentAdult/Adolescent Franchise
Efficacy Gary Dubin, MDVice President, Director Global Clinical Development Center
Safety/Pharmacovigilance Plan
Thomas Verstraeten, MDVice President, Head Biologicals Clinical Safety and Pharmacovigilance
Benefit/Risk Conclusion
Barbara Howe, MDVice President, Director North American Vaccine Development
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