Learning Objective

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Learning Objective

• To know the results of the clinical trial, immune
  response and duration, and efficacy analysis for
  GARDASIL.

GARDASIL is a trademark of Merck Co., Inc.,
Whitehouse Station, NJ, USA.
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Clinical Program for GARDASILSelection of
Trial End Points13
CIN 2/3 are World Health Organization
(WHO)recommended surrogate end points for HPV
vaccine trials.1Surrogate end points are
required because it is unethical to wait for the
development of cervical cancer.1,3
HPV human papillomavirus CIN cervical
intraepithelial neoplasia GARDASIL is a trademark
of Merck Co., Inc., Whitehouse Station, NJ,
USA.
1. Pagliusi SR, Aguado T. Vaccine.
200423569578. 2. GARDASIL Worldwide Product
Circular. Merck Co., Inc., Whitehouse Station,
NJ, USA. 3. Lowy DR, Frazer IH. Chapter 16
Prophylactic human papillomavirus vaccines. J
Natl Cancer Inst Monogr. 2003111116.
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Clinical Program for GARDASIL
Ph IIP005 (N2392)1Proof of Principle 16- to
23-year-old women
Ph IIP007 (N1158)2 Dose-ranging 16- to
23-year-old women
Yr 5 Immune MemoryEvaluation
Ph IIIFUTURE I CIN/EGL (N5455)3 16- to
24-year-old women
Duration of Efficacy Registry StudyNordic Region
Ph IIIFUTURE II CIN 2/3 (N12,167)4 15- to
26-year-old women
Norwegian HPV Surveillance and Disease
Burden/Population Effectiveness Study
Ph IIIP016, P018 (N4836) Safety/immunogenicity
9- to 15-year-old boys and girls5,6
Efficacy in women up to 45 years old
Efficacy in 16- to 26-year-old men
EGL external genital lesion GARDASIL is a
trademark of Merck Co., Inc., Whitehouse
Station, NJ, USA.
1. Koutsky LA, Ault KA, Wheeler CM, et al. N Engl
J Med. 200234716451651. 2. Villa LL, Costa
RLR, Petta CA, et al. Lancet Oncol.
20056271278. 3. Garland SM, Hernandez-Avila M,
Wheeler CM, et al. New Engl J Med.
200735619281943. 4. The FUTURE II Study Group.
New Engl J Med. 200735619151927. 5. Block SL,
Nolan T, Sattler C, et al. Pediatrics.
2006118(5)21352145. 6. Reisinger K, Block S,
Lazcano-Ponce E, et al. Ped Infec Dis.
200726(3)201209.
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Combined Phase II/Phase III Efficacy Studies of
GARDASIL

• 20,541 women (1626 years of age) from the
  Americas, Europe, and Asia were enrolled in one
  of four trials.1
• In one trial, subjects were randomized to either
  a monovalent HPV 16 L1 virus-like particle (VLP)
  vaccine or placebo. In three trials, subjects
  were randomized to either quadrivalent HPV (types
  6, 11, 16, 18) L1 VLP vaccine or placebo.1
• Vaccine or placebo was administered at day 1 and
  months 2 and 6.1
• ThinPrep Pap smears and swabs for HPV DNA were
  taken at day 1, month 7, month 12 and in 6- to
  12-month intervals thereafter until month 48.23
• All Pap tests and biopsies processed/read at a
  central laboratory.3
• Expert pathology panel read all slides for
  end-point determination.3

GARDASIL is a trademark of Merck Co., Inc.,
Whitehouse Station, NJ, USA.
1. GARDASIL Worldwide Product Circular. Merck
Co., Inc., Whitehouse Station, NJ, USA. 2.
Koutsky LA, Ault KA, Wheeler CM, et al. N Engl J
Med. 200234716451651. 3. Garland SM,
Hernandez-Avila M, Wheeler CM, et al. New Engl J
Med. 200735619281943.
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Gardasil is Efficacious Against HPV 16 and
18-Related Disease
n8,462
Related Cases
100 Efficacy
99 Efficacy
n7,771
n8,492
n7,742

• PPE Population subjects were naïve to HPV types
  6, 11, 16, and/or 18

Analysis of CIN 2/3 and AIS end points included
protocol 005.
1. GARDASIL Worldwide Product Circular. Merck
Co., Inc., Whitehouse Station, NJ, USA.
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Gardasil is Efficacious Against HPV
6/11/16/18-Related Lesions
n7,900
n7,863
Related Cases
99 Efficacy
96 Efficacy
n7,899
n7,863

• PPE Population subjects were naïve to HPV types
  6, 11, 16, and/or 18

Genital Warts, VIN 1, VaIN 1.
1. GARDASIL Worldwide Product Circular. Merck
Co., Inc., Whitehouse Station, NJ, USA.
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GARDASIL Phase III Adolescent Immunogenicity
Substudy Study Rationale and Objective

• Rationale1
• Prophylactic HPV vaccines are most effective when
  given before population enters risk period for
  acquisition of infection.1
• Peak prevalence of HPV occurs among women during
  their teens and in their 20s.2
• Young adolescents represent an ideal population
  for HPV vaccination.1
• Objective
• Determine whether HPV L1 VLP vaccine-induced
  anti-HPV neutralizing antibody responses in 10-
  to 15-year-old girls and boys are comparable to
  responses in 16- to 23-year-old females.3

GARDASIL is a trademark of Merck Co., Inc.,
Whitehouse Station, NJ, USA. 1. Schiller JT,
Davies P. Nature Rev. 20042343347. 2.
Schiffman M, Castle PE. N Engl J Med.
200535321012104. 3. Block SL, Nolan T, Sattler
C, et al. Pediatrics. 200611821352145.
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Immune Response to GARDASIL Neutralizing
Anti-HPV GMTs at Month 7
GMTs in adolescents were statistically
noninferior to those in young adult females
(Plt0.001)
Females 1015 Years of Age Males 1015 Years of
Age Females 1623 Years of Age
GARDASIL is a trademark of Merck Co., Inc.,
Whitehouse Station, NJ, USA. GMTs geometric
mean titers
A P value lt0.025 supports a conclusion that the
specific type anti-HPV response in 10- to
15-year-old adolescents was noninferior to the
response in 16- to 23-year-old females. Block SL,
Nolan T, Sattler C, et al. Pediatrics.
200611821352145.
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Neutralizing Antibodies After Vaccination
Relation to Age at Enrollment
Per-protocol immunogenicity (PPI) population
(ages 926) Neutralizing anti-HPV 6 GMTs at
month 7

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Inclusive of five study protocols (all GMTs
measured using cLIA) cLIA competitive
Luminex immunoassay
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Immunologic Persistence With GARDASIL One Year
Postdose 3
Seropositive is defined as anti-HPV serum cLIA
levels 20, 16, 20, 24 mMU/mL for HPV types 6,
11, 16, and 18, respectively.

• In both boys and girls, GMTs at month 18 were
  approximately 4- to 7-fold lower than the GMTs
  observed at month 7.

In the per-protocol population GARDASIL is a
trademark of Merck Co., Inc., Whitehouse
Station, NJ, USA.
Reisinger KS, Block SL, Lazcano-Ponce E, et al.
Pediatr Infect Dis J. 200726(3)201209.
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GARDASIL (20/40/40/20 µg) Neutralizing Anti-HPV
Immunogenicity
In a double-blind, placebo-controlled,
dose-ranging study of quadrivalent HPV (types 6,
11, 16, 18) L1 VLP vaccine
Per-Protocol Subjects (GARDASIL)
1000
1000
HPV 6
HPV 11
100
100
10
10






1
1

7
12
18
24
30
36
54
60

7
12
18
24
30
36
54
60
GMT with 95 CI
mMU/mL (Log Scale)
10,000
1000
HPV 18
HPV 16
1000
100
100
10
10






1

7
12
18
24
30
36
54
60

7
12
18
24
30
36
54
60
Time Since Vaccination (Months)
Vaccination GARDASIL is a trademark of Merck
Co., Inc., Whitehouse Station, NJ, USA. Adapted
from Olsson S-E, Villa LL, Costa RLR, et al.
Vaccine. 20072549314939.
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GARDASIL Demonstrated Immune Memory
Vaccination series for GARDASIL V Vaccination at
day 0, month 2, and month 6
Antigen challenge A Antigen challenge at month 60
When tested by antigen challenge, vaccinated
subjects demonstrated classic immune memorythe
hallmark of long-term protection.1
Antibody levels stabilized through at least five
years and counting.1
Antibodies were built up during the
3-dose vaccination series.
Minimum protective level of antibodies is defined
through breakthrough cases. Through five years,
there were no breakthrough cases for GARDASIL,
while there were continuing infections for
placebo.
GARDASIL is a trademark of Merck Co., Inc.,
Whitehouse Station, NJ, USA.
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1. Data on file, MSD.
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GARDASIL Durable Protection Through Five Years
PPE population subjects were naïve to HPV types
6, 11, 16, and/or 18
A total of 241 subjects were entered into the
five-year extension phase of protocol 007. One
case of confirmed persistent infection HPV 18
DNA detected at months 12 and 18 only (not a case
in the five-year extension). One case of HPV 16
DNA detected at the last visit (month 36) not a
subject in the five-year extension
phase. GARDASIL is a trademark of Merck Co.,
Inc., Whitehouse Station, NJ, USA. Villa LL,
Costa R, Petta R, et al. Br J Cancer.
20069514591466.
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Follow-Up Through Nordic Registries Provides a
Sentinel Cohort
Vaccination
Registry-Based Follow-Up
FUTURE II Study
Efficacy Reports
5 years
7 years
9 years
3.5 years
4 years
6 years
2 years
Launch
2003
2004
2005
2006
2007
2008
2013
2010
2011
2012
2009
FUTURE Females United To Unilaterally Reduce
Endo/Ectocervical Disease Multiple countries
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Nordic Cancer Registry Extension Long-Term
Efficacy of Vaccination

• Nordic European countries have organized
  mass-screening programs.
• Compulsory reporting of Paps, biopsies,
  CIN/cancer
• Registries are sources for prospective studies
• Through these registries, we can evaluate
• Duration of effectiveness
• Interaction of vaccination with cervical
  screening programs
• Long-term safety

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