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Cervarix“An Innovative Vaccine
to Prevent Cervical Cancer”
Eduardo OrtegaEduardo Ortega--BarriaBarria MDMDVice President & Head Vice President & Head Clinical R&D and Medical AffairsClinical R&D and Medical AffairsLatin America & the CaribbeanLatin America & the CaribbeanGlaxoSmithKline BiologicalsGlaxoSmithKline Biologicals
®
Towards Comprehensive Cervical Cancer Prevention and ControlRegion of the Americas
Mexico City, 12-14 May 2008
Provide best possible Provide best possible primary prevention against primary prevention against cervical cancercervical cancer
•• Broad coverage against HPV Broad coverage against HPV oncogeniconcogenic types:types:
–– Most prevalent types: 16 & 18Most prevalent types: 16 & 18
–– Other Other oncogeniconcogenic types, in particular 45 & 31types, in particular 45 & 31
•• Robust Robust immunityimmunity::
–– High and sustained neutralizing antibody levelsHigh and sustained neutralizing antibody levels
–– Across broad age range (10Across broad age range (10--55 yrs)55 yrs)
GlaxoSmithKlineGlaxoSmithKline Vaccine Vaccine Development Vision Development Vision
CervarixCervarixDesigned to provide best possible primary prevention Designed to provide best possible primary prevention
against cervical canceragainst cervical cancer
Strong & sustained immune
response
Strong & sustained immune
response
Highly purified antigens
& Strongimmunogen(key genotypes, avoidinginterference)
Enhancedimmune response
AS04 = MPL + Al(OH)3
®
AS04 confers higher antibody titers in humansAS04 confers higher antibody titers in humans
Adapted from Giannini SL, Hanon E, Moris P, et al. Vaccine 2006;24:5937–49
∗
Wilcoxon’s non-Parametric (p<0.05)
* *
*
*
*
1000
600
400
200
00 8 16 32 4824 40
Vaccination
= Al(OH)3
= AS04
Anti-V5 HPV-16
GM
T an
tibod
y tit
ers
(EU
/ml) 800
* *
*
**
1000
600
400
200
00 8 16 32 4824 40
Vaccination
= Al(OH)3
= AS04
Anti-J4 HPV-18
800
*
*
months months
0
4000
8000
12000
16000
day 60 day 210
HPV-16
pre0
1000
2000
3000
day 60 day 210
HPV-18
pre
= [Al(OH)3]= AS04
Median
Median
Q3
Q1
Q3
Q1
3.6 x*
2.2 x
Freq
uenc
y of
HP
V s
peci
fic m
emor
y B
cel
ls
* statistically significant (p <0.05, Wilcoxon’s test)
vaccination vaccination
Giannini SL, et al. Vaccine 2006; 24: 5937–49
AS04 increases the memory B cell pool in humans AS04 increases the memory B cell pool in humans
Safety, efficacy and Safety, efficacy and immunogenicityimmunogenicity in in clinical trialsclinical trials
5.5 yrsInterim Analysis
6.4 yrsFirst data
HPV-008 N =18,644
15 Mo Interimanalysis
23 cases CIN2+
4.5 yrsInterim
Analysis
FinalanalysisEvent-
triggered
4 yrsExtended Follow-up
2005 2006 2007 2008 20092001 2002 2003 2004
HPV-007N = 776
HPV-001N=1,113
HPV naïve population
Broad population
HPV 023
9.5 yrsExtended Follow-up
Good safety profileGood safety profile
3.5%3.5%4.0%4.0%
3.5%3.5%4.2%4.2%
Number of women reportingNumber of women reportingNumber of Number of SAEsSAEs reportedreported
Serious Adverse Events:Serious Adverse Events:
43.6%43.6%21.8%21.8%
1.7%1.7%0.3%0.3%
42.5% 42.5% 21.3%21.3%
1.5%1.5%0.3%0.3%
All unsolicited symptoms* (Day 0All unsolicited symptoms* (Day 0––29)29)Medically significant conditions Medically significant conditions New onset chronic diseases New onset chronic diseases New onset autoimmune diseases New onset autoimmune diseases
Unsolicited Adverse Events: Unsolicited Adverse Events: % of women with at least 1 event% of women with at least 1 event
HepHep A VaccineA Vaccine(N=9,325)(N=9,325)
CervarixCervarix®
(N=9,319)(N=9,319)Safety OutcomesSafety Outcomes
*Diary card subset (3,184 HPV recipients and 3,187 HAV recipients)
Broad Population Study
Paavonen J et al. Lancet 2007;369:2161–70
nnnn
90.0 90.0 –– 100100343400Persistence: 6 Months Persistence: 6 Months
81.8 81.8 –– 100100
10010010010020200012 Months 12 Months
51.3 51.3 –– 100 100 9900CIN2+CIN2+
151500 73.4 73.4 –– 100 100
100100100100CIN1+CIN1+
95% CI95% CI%%
Vaccine EfficacyVaccine EfficacyControlControlCervarixCervarix®
Endpoints*Endpoints*
Complete protection against HPVComplete protection against HPV--16/18 persistent 16/18 persistent infections and CIN outcomes infections and CIN outcomes up to 6.4 yearsup to 6.4 years
*Combined analysis initial efficacy study and extended follow-upATP analysis for virologic endpoints; ITT analysis for CIN endpoints
Presentation Harper D, SGO 39th Annual Meeting on Women’s Cancer, Tampa, Florida, March 9-12, 2008; Gynecol Oncol 2008; 109(1):158
n = number of subjects reporting at least one event in each groupPersistence: Cervarix® N=401; Control N=372; CIN: Cervarix® N=481; Control N=470;
100% protection against HPV 16/18 CIN2+ 100% protection against HPV 16/18 CIN2+ sustained sustained up to 6.4 yearsup to 6.4 years
1.Harper et al. Lancet. 2004; 364: 1757–652.Harper et al. Lancet 2006; 367: 1247-553.Presentation Gall S, AACR, Los Angeles, April 14-18, 2007, abstract 49004.Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008; Gynecol Oncol 2008; 109(1):158
Combined analysisCombined analysisinitial efficacy initial efficacy study and study and extended followextended follow--upup
Initial efficacy Initial efficacy studystudy
6.4 yrs6.4 yrs44
5.5 yrs5.5 yrs33
4.5 yrs4.5 yrs22
27 months27 months11
95% CI95% CI%%nnnn
Vaccine EfficacyVaccine EfficacyControlControlCervarixCervarix®HPV 16/18 HPV 16/18 relatedrelated
CIN2+CIN2+0 3 100 NA
0 5 100 -8 - 100
0 7 100 33 - 100
0 9 100 51 - 100
n = number of subjects reporting at least one event in each groupITT analysis
Trials in a broad population Trials in a broad population including Latin Americaincluding Latin America
18,644 women vaccinated / 14 countries
16 %
35 %34 %
15 %
- current or prior oncogenic HPV 16/18 infection - abnormal cytology (9% low grade)- anti-HPV 16/18 serum antibodies
0
10
20
30
40
50
60
70
80
90
100
6.4 years follow-up Broad population
% E
ffica
cy C
IN2+
HPV
-16/
18
Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008; Gynecol Oncol 2008; 109(1):158; Paavonen J et al. Lancet 2007;369:2161–70
95% CI: 51.3 – 100 97.9% CI: 53.4 – 99.3
97.9% CI: 74.2 – 100
Pre-specified analysis
Causality assessment analysis*
*Based on causality assessment case assignment. The pre-specified analysis included 3 CIN2+ cases which were not considered to be causally associated with HPV-16 or HPV-18 infections acquired during the trial. Based on this analysis vaccine efficacy was 90.4% (CI 53.4–99.3)
Confirmed 100% efficacy against CIN2+Confirmed 100% efficacy against CIN2+caused by HPVcaused by HPV--16 and 1816 and 18
95% CI95% CI%%nnnn
Vaccine EfficacyVaccine EfficacyAl(OH)Al(OH)33N=497N=497
CervarixCervarix®N=505N=505EndpointEndpoint
16 16 –– 5757393993936262≥≥LSILLSIL
21 21 –– 92 92 7272171755CIN2+CIN2+
12 12 ––7373505038382020CIN1+CIN1+
18 18 –– 50 50 3535162162118118≥≥ASCUSASCUS
Protection against cytological abnormalities & CIN Protection against cytological abnormalities & CIN for any HPV types sustained for any HPV types sustained up to 6.4 Years up to 6.4 Years
Combined analysis initial efficacy study and extended followCombined analysis initial efficacy study and extended follow--upup
1 Clifford et al. Cancer Epi Biom Prev 2005;14(5); 2. Muñoz et al. N Engl J Med 2003Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008;Gynecol Oncol 2008; 109(1):158
Independent of HPV DNA statusCervical samples only; Descriptive, Conditional Exact method; ITT analysis
25–30%1
50%2
25–30%1
20–30%1
Estimated prevalence HPV 16/18
N = number of subjects included in each group; n = number of subjects reporting at least one event in each group
Cross protection against HPV 45 & 31 Cross protection against HPV 45 & 31 incident infection sustained incident infection sustained up to 6.4 years
HPV typeHPV typeCervarix Cervarix ® ControlControl Vaccine Vaccine EfficacyEfficacy
nn nn %% 95% CI95% CI
HPVHPV--4545 55 2121 7878 3939--9393
HPVHPV--3131 1313 3030 6060 2020--8181
ATP analysis n = number of subjects reporting at least one event in each group
Combined analysis initial efficacy study and extended follow-up
Presentation Harper D, SGO, Tampa, Florida, March 9-12, 2008
0.5 – 59.536.136.17447HPVHPV--3131
TVCTVC--E (at least 1 dose)E (at least 1 dose)OncogenicOncogenicHPV TypeHPV Type Vaccine Vaccine
(cases)(cases)Control Control (cases)(cases)
2.6 – 85.259.959.92510HPVHPV--4545
3.5 – 51.931.631.63016HPVHPV--5252
97.9% CI97.9% CIVaccine Vaccine Efficacy (%)Efficacy (%)
Confirmed Confirmed typetype--specific cspecific cross protectionross protectionagainst 6against 6--month persistent infectionmonth persistent infection
Paavonen J et al. Lancet 2007;369:2161–70
Provide best possible Provide best possible primary prevention against cervical cancerprimary prevention against cervical cancer
•• Broad coverage against HPV Broad coverage against HPV oncogeniconcogenic types:types:
–– Most prevalent types: 16 & 18Most prevalent types: 16 & 18
–– Other Other oncogeniconcogenic types, in particular 45 & 31types, in particular 45 & 31
•• Robust immunity:Robust immunity:
–– Across broad age range (10Across broad age range (10--55 yrs)55 yrs)
–– High and sustained neutralizing antibody levelsHigh and sustained neutralizing antibody levels
GlaxoSmithKline Vaccine GlaxoSmithKline Vaccine Development Vision Development Vision
Why are Antibodi es so Important?
What we do knowHPV hides from our immune
system, therefore natural infection induces a poor immune response
Neutralising antibodies can prevent entry into cells and subsequent infection1
What we don’t know yetWil l natur al infection boost i mmune memor y i n vacci nated women?
Induction of serum neutralisingantibodies by vaccination is critical for protection1,2
1. Stanley M. HPV Today 2007; 11: 1-162. Stanley M. Vaccine 2006; 24: S106-13
Why are Antibodies so Important?Why are Antibodies so Important?
Will natural infection boost
immune memory in
vaccinated women?
Antibody levels start high and stay high
Harper D et al. Lancet 2006;367:1247–55; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007
AntiAnti--HPVHPV--16 IgG16 IgG
1,000
100
10
1
10,000
Months70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64
Seropositivity ≥98%
AntiAnti--HPVHPV--18 IgG18 IgG Seropositivity ≥98%
GM
T (E
U/m
l)G
MT
(EU
/ml) 1,000
100
10
1
10,000
Months70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64
≥11-fold higher than
natural infection
≥11-fold higher than
natural infection
020406080
100
month 0 month 7 month12
month18
[M25-M32]
[M33-M38]
[M39-M44]
[M45-M50]
[M51-M56]
[M57-M62]
[M63-M68]
[M69-M74]
[M75-M76]
020
4060
80100
month 0 month 7 month12
month18
[M25-M32]
[M33-M38]
[M39-M44]
[M45-M50]
[M51-M56]
[M57-M62]
[M63-M68]
[M69-M74]
[M75-M76]
ELISA
Pseudovirion(Neutra)
ELISA
Pseudovirion(Neutra)
Seropositivity HPV-16
Seropositivity HPV-18%
%
Months
Months
SeropositivitySeropositivity ≥≥98%98% at all time points at all time points up to 6.4 yearsup to 6.4 years
Presentation Harper D, SGO 39th Annual Meeting on Women’s Cancer, Tampa, Florida, March 9-12, 2008
Robust typeRobust type--specific cross reactivity against specific cross reactivity against HPVHPV--45 and 3145 and 31
HPVHPV--4545Related to HPVRelated to HPV--1818
Data on File. GSKBio-WWMA_DoF001_2007 Cut-off level for seropositivity for both HPV-45 and 31: ≥59 EU/ml*up to 4.5 yrs
1,000
100
10
1
10,000
Months70 12 25–32 33–38 39–44 45–50 51–56
8.8%
100%
100% 91.7% 85.7% 90.0% 83.7% 92.3%
GM
T (E
U/m
l)
Important cause of adenocarcinoma
HPVHPV--3131Related to HPVRelated to HPV--1616
1,000
100
10
1
10,000
Months
5.9%
100%
94.1%83.3% 80.0% 87.5% 88.4% 69.2%
70 12 25–32 33–38 39–44 45–50 51–56
GM
T (E
U/m
l)
ImmunobridgeSafety / reactogenicity
Women15–25 yrs
Women15–25 yrs
Girls10–14 yrs
Women26–55 yrs
Efficacy & Immuno Findings up to 5.5 yrs
ImmunobridgeSafety / reactogenicity
Principle of Principle of ImmunobridgingImmunobridging
Month 7 Immunogenicity: GMT and Seroconversion Rate
Seropositivity definedas titer ≥8 EU/ml HPV-16
Adapted from Pedersen C et al. J Adolesc Health 2007;40:564–71
Immune response twice as high in 10Immune response twice as high in 10––14 yr olds14 yr oldsfor HPVfor HPV--16 and 1816 and 18
Seropositivity definedas titer ≥7 EU/ml HPV-18
GM
T (E
U/m
l)
17,2727,439
1
10
100
1,000
10,000
100,000
10–14 y 15–25 y1
10
100
1,000
10,000
100,000
10–14 y 15–25 y
6,864
3,070
GM
T (E
U/m
l)
100%100% 100%
100%
Efficacy study in women 15Efficacy study in women 15––25 yrs of age shows25 yrs of age showshigh and sustained antibody levelshigh and sustained antibody levels
Immunobridging to girls 10Immunobridging to girls 10––14 yrs14 yrsshows even stronger immune responseshows even stronger immune response
Harper D et al. Lancet 2006;367:1247–1255; Presentation Gall S, AACR, Los Angeles, April 14–18, 2007; Rombo L, ESPID, Porto, Portugal, May 2-4,2007
AntiAnti--HPVHPV--16 IgG16 IgG
1,000
100
10
1
10,000
Total follow-up time (months)70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64
AntiAnti--HPVHPV--18 IgG18 IgG
1,000
100
10
1
10,000
Total follow-up time (months)70 12 18 25–32 33–38 39–44 45–50 51–56 57–62 63–64
10–14 Year old girls
≥11-fold higher than
natural infection
≥11-fold higher than
natural infection G
MT
(EU
/ml)
GM
T (E
U/m
l)
Keam SJ & Harper DM. Drugs. 2008;68 (3):359-72;
1
10
100
1,000
10,000
100% 100%100%100%100% 100% 100%100%
ATP cohort, Seronegative at entry, month 7 results
GM
T (E
U/m
l)
HPV-16 HPV-18
15–25 years
26–35 years
36–45 years
46–55 years
Schwarz TF. J Clin Oncol 2006;24(18S):1008
Consistently high immune response Consistently high immune response across all agesacross all ages
Natural Infection
Seroconversion Seroconversion
N=437
High and sustained antibody levels in a broad High and sustained antibody levels in a broad age group over timeage group over time
Assay cut-off: 8 EU/mlATP analysisSeronegative prior to vaccination
Months
NaturalInfection
1
10
100
1,000
10,000
0 7 12 18 24 39–44 51–56 63–64
15–25 years (Efficacy study)
15–25 years26–35 years36–45 yearsAt least
8-fold higher than
natural infection
46–55 years
Keam SJ & Harper DM. Drugs. 2008;68 (3):359-72; Presentation Gall S. AACR 2007; Presentation Schwarz TF Eurogin, 2007
10,000At least 8-fold higher than
natural infection
1
10
100
1,000
0 7 12 18 24 39–44 51–56 63–64
GM
T (E
U/m
l)
HPV-16 HPV-18
0
0.5
1
1.5
2
2.5
3
0 0.5 1 1.5 2 2.5 3
R = 0.9031 R = 0.7280 R = 0.8753
-1
-0.5
0
0.5
1
1.5
2
2.5
-0.5 0 0.5 1 1.5 2 2.5
15-25 years 26-45 years 46-55 years
Strong correlation between serum and Strong correlation between serum and cervical mucosa antibody levelscervical mucosa antibody levels
Log
ratio
(ant
i-HPV
-16/
tota
l IgG
) in
CVS
Log
ratio
(ant
i-HPV
-18/
tota
l IgG
) in
CVS
- Log ratio (anti-HPV-16/total IgG) in serum - Log ratio (anti-HPV-18/total IgG) in serum
Month 24
Schwarz T. EuroGIN 2007 presentation; Stanley M, et al. Vaccine 2006;24(Suppl 3):S106–13; Giannini SL, et al. Vaccine 2006;24:5937–49
AntiAnti--HPVHPV--1616 AntiAnti--HPVHPV--1818
Higher serum Ab levels à Higher Ab levels at the mucosa -where they are most needed
15–25 years R=0.903126–45 years R=0.728046–55 years R=0.8753
15–25 years R=0.911426–45 years R=0.823546–55 years R=0.9328
Provide best possible Provide best possible primary prevention against cervical cancerprimary prevention against cervical cancer
•• Broad coverage against HPV Broad coverage against HPV oncogeniconcogenic types:types:
–– Most prevalent types: 16 & 18Most prevalent types: 16 & 18
–– Other Other oncogeniconcogenic types, in particular 45 & 31types, in particular 45 & 31
•• Robust immunity:Robust immunity:
–– Across broad age range (10Across broad age range (10--55 yrs)55 yrs)
–– High and sustained neutralizing antibody levelsHigh and sustained neutralizing antibody levels
GlaxoSmithKline Vaccine GlaxoSmithKline Vaccine Development Vision Development Vision
665 (=100%)665 (=100%)30.2%30.2%40.6%40.6%0.6%0.6%2.3%2.3%9.9%9.9%13.1%13.1%1.5%1.5%
Cervarix Cervarix ®(N=9,319)(N=9,319)
685 (=100%)685 (=100%)34.0%34.0%38.5%38.5%1.2%1.2%2.5%2.5%7.4%7.4%13.6%13.6%1.9%1.9%
Number of pregnanciesNumber of pregnancies
Pregnancy ongoingPregnancy ongoingNormal infantNormal infant
Abnormal infantAbnormal infant
Premature birthsPremature births
Spontaneous abortionSpontaneous abortionElective termination Elective termination
Lost to followLost to follow--upup
HepHep A VaccineA Vaccine(N=9,325)(N=9,325)
Pregnancies/Pregnancy Pregnancies/Pregnancy outcomes*outcomes*
Pregnancy outcomesPregnancy outcomes
*Totals do not include blinded outcomes, ectopic pregnancies
Broad Population Study
Paavonen J et al. Lancet 2007;369:2161–70