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Use of GARDASIL ® in Boys and Men . Vaccines and Related Biological Products Advisory Committee Meeting September 9, 2009. Merck Research Laboratories. Agenda. Patrick Brill-Edwards, MD Current status of GARDASIL ® Proposed indication Dalya Guris, MD, MPH

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Use of gardasil in boys and men l.jpg

Use of GARDASIL® in Boys and Men

Vaccines and Related Biological ProductsAdvisory Committee MeetingSeptember 9, 2009

Merck Research Laboratories


Agenda l.jpg
Agenda

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


Gardasil quadrivalent hpv types 6 11 16 18 l1 virus like particle vlp vaccine l.jpg

Merck’s adjuvant has been used for more than 20 years

VLPs manufactured in Saccharomyces cerevisiae (yeast)

The VLPs are not viruses, so cannot cause infectionor disease

Merck’sAAHSAdjuvant†

L1 VLP

Constituent

HPV 6

HPV 11

HPV 16

HPV 18

Dose (µg)

20

40

40

20

225

GARDASIL®Quadrivalent HPV (Types 6, 11, 16, 18)L1 Virus-Like Particle (VLP) Vaccine

† Amorphous aluminum hydroxyphosphate sulfate.


Clinical program for gardasil l.jpg

Protocol 005 (N=2409) 16-23-year-old women

Protocol 007 (N=1158) 16-23-year-old women

Yr 5 Immune MemoryEvaluation

Protocol 013 (N=5455) 16-23-year-old women

Protocol 015 (N=12,167) 15-26-year-old women

Duration of Efficacy Registry StudyNordic Region

Protocol 019 (N=3819)24-45-year-old adult women

Jan2003

Jan2004

Jan2005

Jan2006

Jan2007

Jan2008

Jan2009

Jan2010

Clinical Program for GARDASIL®

GARDASIL approval


Clinical program for gardasil5 l.jpg

Protocol 005 (N=2409) 16-23-year-old women

Protocol 007 (N=1158) 16-23-year-old women

Yr 5 Immune MemoryEvaluation

Protocol 013 (N=5455) 16-23-year-old women

Protocol 015 (N=12,167) 15-26-year-old women

Duration of Efficacy Registry StudyNordic Region

Protocol 019 (N=3819)24-45-year-old adult women

Protocol 016 (N=506F, 508M)10-15-year-olds, both genders

Protocol 018 (N=936F, 839M) 9-15-year-olds, both genders

Adolescent Vaccine Effectiveness Study

Jan2003

Jan2004

Jan2005

Jan2006

Jan2007

Jan2008

Jan2009

Jan2010

Clinical Program for GARDASIL®

GARDASIL approval


Clinical program for gardasil6 l.jpg

Protocol 005 (N=2409) 16-23-year-old women

Protocol 007 (N=1158) 16-23-year-old women

Yr 5 Immune MemoryEvaluation

Protocol 013 (N=5455) 16-23-year-old women

Protocol 015 (N=12,167) 15-26-year-old women

Duration of Efficacy Registry StudyNordic Region

Protocol 019 (N=3819)24-45-year-old adult women

Protocol 016 (N=506F, 508M)10-15-year-olds, both genders

Protocol 018 (N=936F, 839M) 9-15-year-olds, both genders

Adolescent Vaccine Effectiveness Study

Protocol 020 (N=4055)16-26-year-old males

GARDASIL approval

Male sBLA Submission

Jan2003

Jan2004

Jan2005

Jan2006

Jan2007

Jan2008

Jan2009

Jan2010

Clinical Program for GARDASIL®


Current indication l.jpg
Current Indication

GARDASIL® is a vaccine indicated in girls and women 9 through 26 years of age for the prevention of the following diseases caused by Human Papillomavirus (HPV) types included in the vaccine:

  • Cervical, vulvar, and vaginal cancer caused by HPV types 16 and 18

  • Genital warts (condyloma acuminata) caused by HPV types 6 and 11

And the following precancerous or dysplastic lesions caused by HPV types 6, 11, 16, and 18:

  • Cervical Intraepithelial Neoplasia (CIN) grade 2/3 and Cervical Adenocarcinoma in situ (AIS)

  • Cervical Intraepithelial Neoplasia (CIN) grade 1

  • Vulvar Intraepithelial Neoplasia (VIN) grade 2 and grade 3

  • Vaginal Intraepithelial Neoplasia (VaIN) grade 2 and grade 3


Comprehensive post licensure monitoring continues to confirm safety profile l.jpg
Comprehensive Post-licensure Monitoring Continues to Confirm Safety Profile

  • Merck has an ongoing risk assessment plan

    • Post-licensure safety study

    • Long-term safety and effectiveness studies

    • Pregnancy registry

    • Comprehensive post-licensure monitoring ofspontaneous reports

  • Public health authorities continue to confirm a favorable benefit-risk profile

    • As recently as August 20, 2009 FDA/CDC concluded “Gardasil continues to be safe and effective, and its benefits continue to outweigh its risks.”†

† http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/VaccineSafety/ucm179549.htm


There are unmet medical needs for boys and men l.jpg
There Are Unmet Medical Needs for Safety ProfileBoys and Men

  • Adolescent and young adult men acquire HPV at a high rate

  • Genital warts due to HPV types 6 and 11 are one of the most common sexually transmitted diseases

    • Warts commonly recur despite different therapies

    • There is a significant psychosocial burden

  • HPV types 16 and 18 cause precancers, as well as penile and anal cancer in men

    • There is no standardized screening to detectprecancerous lesions in men

  • HPV types 6,11,16, and 18 cause persistent infection in men

  • Men play an important role in transmitting HPV to women


Gardasil helps address these needs l.jpg
GARDASIL Safety Profile® Helps Address These Needs

  • Currently in the U.S. there is no approved vaccine for the prevention of HPV diseases in boys and men

  • The clinical program in boys and men demonstrated that GARDASIL:

    • Is highly efficacious

    • Results in a robust immune response

    • Has a favorable safety profile

  • Efficacy was high across all populations studied, which supports the potential public health benefit of vaccinating boys and men


Agenda11 l.jpg
Agenda Safety Profile

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


Proposed indication l.jpg
Proposed Indication Safety Profile

GARDASIL® is indicated in boys and men 9 through 26 years of age for the prevention of genital warts (condyloma acuminata) caused by HPV types 6 and 11.


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Basis for Proposed Indication Safety Profile

  • The proposed indication is based upon disease endpoints,not infection

  • The majority of endpoints in the clinical development program were genital warts due to HPV types 6 and 11

  • Similar to women, high efficacy was observed in men against persistent infection caused by HPV types16 and 18

    • High efficacy against infection suggests a potential impact on HPV 16- and 18-related disease


Consultants l.jpg

David Cornblath, MD Johns Hopkins University Safety Profile

Mark Esser, PhD PPD Vaccines and Biologics Laboratory

Anna Giuliano, PhD H. Lee Moffitt Cancer Center and Research Institute

Joel Palefsky, MD University of California, San Francisco

Mark Stoler, MD University of Virginia

Lee-Jen Wei, PhD Harvard University

Consultants


Agenda15 l.jpg
Agenda Safety Profile

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed Indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


Human papillomavirus hpv l.jpg
Human Papillomavirus (HPV) Safety Profile

  • Non-enveloped double-stranded DNA virus

  • >100 types identified

  • ~30-40 types sexually transmitted

  • GARDASIL® contains antigens against HPV 6, 11, 16, and 18

    • HPV 6 and 11

      • Account for 90% of anogenital warts

      • Primary cause of recurrent respiratory papillomatosis

    • HPV 16 and 18

      • Account for 60%-95% of HPV-related anogenital and oropharyngeal cancers in men


Hpv infection and productive life cycle l.jpg
HPV Infection and Productive Life Cycle Safety Profile

HPV virion

Release of virions within desquamating cells

Expression of viral proteins and change of cell growth

Differentiation of infected cells

Infection of basal cells of epithelium


Burden of hpv related diseases in men l.jpg

New HPV- Safety ProfileRelated Cases

Annually

NewCases

% DetectableHPV

Disease

Anogenital warts1

Cancers2-5 Oral cavity and oropharynx Anus/anal canal/anorectum Penis/external genital

Total cancers

250,000

25,31020201250

~100

259040

250,000

63001800500

8600

Burden of HPV-Related Diseases in Men

Estimated Number of New Cases in Men – USA, 2008

1 http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-feb09/10-2-hpv.pdf.

2 American Cancer Society. Cancer facts & figures 2008http://www.cancer.org/downloads/stt/CFF2008Table_pg4.pdf

3 Kreimer AR, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:467-475.

4 Ryan DP, et al. N Engl J Med. 2000;342:792-800.

5 Parkin DM, Bray F. Vaccine. 2006;24S3:S3/11-25.


Anogenital warts condyloma acuminata l.jpg

Anogenital warts are common Safety Profile

~3.3 million of sexually active U.S. men aged 18-59 years with history of genital warts diagnosis1

Symptoms include:

Itching, burning, and tenderness

Anal or urethral bleeding or discharge

Anogenital warts associated with psychosocial burden, including anxiety and stigmatization

Anogenital Warts (Condyloma Acuminata)

Top image: Reprinted with permission from NZ DermNet (www.dermnetnz.org).

Bottom image: Used with permission from BioVision, Inc., Outremont, Quebec, Canada.

1 Dinh T-H, et al. Sex Transm Dis. 2008;35:357-360.


Incidence of genital warts peaks in early adulthood l.jpg

Incidence per Safety Profile100,000 Individuals

Incidence of Genital Warts Peaks inEarly Adulthood

Incidence of Genital Warts in Boys and Men by Age Group Private Health Insurance Data – USA, 2004

Source: Hoy T, et al. Curr Med Res Opin. 2009;25:2343-51.


High burden of disease in the setting of inadequate treatment options l.jpg
High Burden of Disease in the Setting of Inadequate Treatment Options

  • Approximately 750,000 health care visits annually by males

    • On average 3.1 health care visits per episode1

  • Myriad of treatments include topical agents, cryotherapy, and surgical methods

  • Current therapies are inadequate and have potential for severe pain and scarring

  • 10%-90% of warts recur after treatment2

    • Median duration of genital warts is 6 months3

1Insinga RP, et al. CID. 2003;36:1397-1403.

2 Based on literature review on treatment of warts.

3Winer RL, et al. J Infect Dis. 2005;191:731-738.


Hpv causes penile cancer l.jpg
HPV Causes Penile Cancer Treatment Options

  • HPV detected in 42% to 80%1

  • HPV types 16 and 18 - most frequently identified types in tumors2,3

  • High-grade penile/perianal/perineal intraepithelial neoplasia (PIN 2/3) considered precancerous4

  • No standardized screening in men for early detection of precancerous lesions and prevention of progression to cancer

1 Partridge JM, Koutsky LA. Lancet Infect Dis. 2006;6:21-31.

2 Cupp MR, et al. J Urol. 1995;154:1024-9.

3 Pascual A, et al. Histol Histopathol. 2007;22:177–183.

4 Cubilla, et al. Int J Surg Pathol. 2004;12:351-64.


Hpv is sexually transmitted l.jpg
HPV is Sexually Transmitted Treatment Options

  • HPV is one of the most common sexually transmitted diseases1

  • Infection is often asymptomatic or subclinical, allowing transmission to occur without the knowledge of partners2

  • Circumcision and condom use may reduce transmission, but do not eliminate risk of HPV infection3-6

  • Preventing HPV disease/infection through immunization may be important for protection of unvaccinated sexual partners

1 Giuliano AR, et al. Cancer Epidemiol BiomarkersPrev. 2008;17(4):805-808.

2Giuliano AR. Gynecol Oncol. 2007;107(suppl 1):S24-S26.

3 Winer RL, et al. N Engl J Med. 2006;354:2645-2654.

4 Castellsagué X, et al. N Engl J Med. 2002;346:1105-1112.

5 Hernandez BY, et al. Emerging Infect Dis. 2008;14:888-894.

6 Baldwin SB, et al. Sex Transmit Dis. 2004;31:601-607.


Summary of hpv disease burden in men l.jpg
Summary of HPV Disease Burden in Men Treatment Options

  • HPV is associated with substantial burden of disease in men

  • HPV 6 and 11 primary cause of genital warts, one of the most common sexually transmitted diseases

  • HPV 16 and 18 strongly associated with anogenital precancers and cancers

  • No standardized screening for HPV infection or early detection of disease in men

  • There is an unmet medical and public health need and prevention through immunization will address this need


Agenda25 l.jpg
Agenda Treatment Options

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


Rationale of clinical development program l.jpg
Rationale of Treatment OptionsClinical Development Program

  • GARDASIL® is a prophylactic vaccine

  • Vaccination prior to sexual debut and exposure to HPV would provide the most benefit

  • Preadolescent boys, similar to girls, are optimal age group for routine immunization

  • Efficacy studies among preadolescents are not feasible


Objectives of clinical development program l.jpg
Objectives of Treatment OptionsClinical Development Program

  • Clinical development program in boys/men used a similar approach to that used in girls/women

    • Demonstrate efficacy in young adult men

    • Immunobridge efficacy from adults to preadolescents and adolescents

    • Demonstrate safety in all age groups studied


Clinical development program in boys and men l.jpg
Clinical Development Program in Boys and Men Treatment Options

Efficacy/Safety/Immunogenicity

Protocol 020

16- to 26-year-old men

n=4055


Clinical development program in boys and men29 l.jpg

Efficacy/ Treatment OptionsSafety/Immunogenicity

Protocol 020

16- to 26-year-old men

n=4055

Safety/Immunogenicity

Protocol 016

10- to 15-year-old boys

n=508 boys

Safety/Immunogenicity

Protocol 018

9- to 15-year-old boys

n=839 boys

Clinical Development Program in Boys and Men


Clinical development program in boys and men30 l.jpg
Clinical Development Program in Boys and Men Treatment Options

Efficacy/Safety/Immunogenicity

Protocol 020

16- to 26-year-old men

n=4055

Immunobridging

Safety/Immunogenicity

Protocol 016

10- to 15-year-old boys

n=508 boys

Safety/Immunogenicity

Protocol 018

9- to 15-year-old boys

n=839 boys


Clinical development program in boys and men31 l.jpg
Clinical Development Program in Boys and Men Treatment Options

Efficacy/Safety/Immunogenicity

Protocol 020

16- to 26-year-old men

n=4055

Safety/Immunogenicity

Protocol 016

10- to 15-year-old boys

n=508 boys

Safety

Assessment

Safety/Immunogenicity

Protocol 018

9- to 15-year-old boys

n=839 boys


Agenda32 l.jpg
Agenda Treatment Options

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


Objectives l.jpg
Objectives Treatment Options

Protocol 020

  • Primary efficacy objective

    • Assess efficacy against combined incidence of HPV 6/11/16/18-related external genital lesions (EGL)

      • External genital warts

      • Penile/perianal/perineal intraepithelial neoplasia (PIN)

      • Penile, perianal, or perineal cancer

  • Analysis to be conducted when at least 32 cases of vaccine-type related EGL observed

  • Success criterion

    • Lower bound of confidence interval for vaccine efficacy above 20%


Objectives34 l.jpg
Objectives Treatment Options

Protocol 020

  • Secondary efficacy objectives

    • Assess efficacy against combined incidence of HPV 6/11/16/18-related

      • Persistent infection

        • Detection of same vaccine type HPV DNA in ≥2 consecutive anogenital samples collected 6months apart

      • DNA detection at any visit

  • Success criteria

    • Lower bound of confidence interval for vaccine efficacy above 20%


Objectives35 l.jpg
Objectives Treatment Options

Protocol 020

  • Exploratory efficacy objective

    • Among men having sex with men (MSM) assess efficacy against combined incidence of HPV 6/11/16/18-related

      • Anal intraepithelial neoplasia (AIN) or anal cancer

  • Analysis to be conducted when at least 17 cases of vaccine-type related AIN/anal cancer observed

  • Number of cases required not achieved at time of primary endpoint analysis


Study design l.jpg
Study Design Treatment Options

  • Multinational, randomized (1:1), double-blind, placebo-controlled

    • Monitored by external Data Safety Monitoring Board

  • Vaccine/placebo administered at Day 1, Months 2 and 6

  • Subjects enrolled

    • Heterosexual men (HM) 16-23 years of age

    • Men having sex with men (MSM) 16-26 years of age

  • Key exclusion criteria

    • History of genital warts

    • Genital lesions clinically HPV-related or unknown etiology

    • No history of sexual activity

    • >5 lifetime sexual partners

  • Subjects were followed for up to 36 months

    • Median follow up: 34 months after Dose 1


Genital biopsy collection l.jpg
Genital Biopsy Collection Treatment Options

  • External genital lesions biopsied

    • Definitely, probably or possibly HPV-related, or

    • Unknown etiology by clinical evaluation

  • Recurrent lesions not biopsied

    • Occurring within 2 months in the same anatomic location and with same morphology

  • Biopsies

    • Adjudicated by blinded, external Pathology Panel

    • PCR tested for HPV detection


Disease endpoint assessment l.jpg

External Treatment Options

Genital

Biopsy

13

Fixation, Processing &

Paraffin Embedding

12

Prepare

Consecutive

Sections

11

10

9

8

7

6

5

4

3

2

1

Disease Endpoint Assessment


Disease endpoint assessment39 l.jpg

External Treatment Options

Genital

Biopsy

13

Fixation, Processing &

Paraffin Embedding

12

Prepare

Consecutive

Sections

11

10

9

8

7

6

5

4

3

2

1

H&E Staining and Histology

1

2

12

13

Pathology Panel

Disease Endpoint Assessment


Disease endpoint assessment40 l.jpg

External Treatment Options

Genital

Biopsy

13

Fixation, Processing &

Paraffin Embedding

12

Prepare

Consecutive

Sections

11

10

9

8

7

6

5

4

3

2

1

Extraction of DNA for

HPV Multiplex PCR

H&E Staining and Histology

3

4

5

1

2

12

13

Pathology Panel

Disease Endpoint Assessment


Disease endpoint assessment41 l.jpg

External Treatment Options

Genital

Biopsy

13

Fixation, Processing &

Paraffin Embedding

12

Prepare

Consecutive

Sections

11

10

9

8

7

6

5

4

3

2

1

Extraction of DNA for

HPV Multiplex PCR

H&E Staining and Histology

3

4

5

1

2

12

13

HPV 6/11/16/18

PCR Positive

Pathology Panel

HPV 6/11/16/18

PCR Negative

Not EGL

EGL(Condyloma, PIN)

Case

No Case

No Case

Disease Endpoint Assessment

EGL = external genital lesion.


Genital swab collection l.jpg
Genital Swab Collection Treatment Options

  • Genital swabs collected at Day 1, Months 7, 12 and every 6 months thereafter

  • From all subjects 3 separate swabs from penis, scrotum, perineum/perianal areas

  • Additionally, anal canal swabbed in MSM

  • Skin of external genitalia filed and swabbed separately with sterile wetted DACRON™ swab

  • Analysis of genital swabs

    • Swabs tested separately by PCR for HPV DNA

    • Subject considered HPV-positive at a visit if ≥1 swab found positive by PCR

MSM = men having sex with men.


Efficacy analysis populations l.jpg
Efficacy Analysis Populations Treatment Options

  • Primary efficacy analysis

    • Per-protocol efficacy (PPE) population

      • Received 3 doses of vaccine/placebo

      • To the relevant HPV type

        • Seronegative at Day 1

        • PCR negative at Day 1 and Month 7

      • Endpoints were counted starting after Month 7

  • Supportive intention-to-treat analysis

    • Full analysis set (FAS)

      • Received ≥1 dose vaccine/placebo

      • Endpoints were counted starting after Day 1

      • Efficacy in FAS expected to be lower than in PPE


Subject accounting for per protocol efficacy analysis l.jpg
Subject Accounting for Per-Protocol Efficacy Analysis Treatment Options

Protocol 020

Screened4164


Subject accounting for per protocol efficacy analysis45 l.jpg

Screened Treatment Options4164

Placebo

GARDASIL®

Randomized4065

2032

2033

Subject Accounting for Per-Protocol Efficacy Analysis

Protocol 020


Subject accounting for per protocol efficacy analysis46 l.jpg

Screened Treatment Options4164

Placebo

GARDASIL®

Randomized4065

2032

2033

2025

2030

Received ≥1 dose

1819

1814

Completed visits through Month 7

Subject Accounting for Per-Protocol Efficacy Analysis

Protocol 020


Subject accounting for per protocol efficacy analysis47 l.jpg

Screened Treatment Options4164

Placebo

GARDASIL®

Randomized4065

2032

2033

2025

2030

Received ≥1 dose

1819

1814

Completed visits through Month 7

Eligible for

HPV 6/11/16/18per-protocol analysis

1397

1408

Subject Accounting for Per-Protocol Efficacy Analysis

Protocol 020


Main reasons for ineligibility for hpv 6 11 16 18 per protocol efficacy analysis l.jpg

GARDASIL Treatment Options®

(N=2032)

Placebo

(N=2033)

Subjects†

Did not receive 3 doses

With missing PCR result Day 1 Month 7 Inadequate samples at Day 1–Month 7

General protocol violators

165

169244248

83

184

161221242

68

Main Reasons for Ineligibility forHPV 6/11/16/18 Per-Protocol Efficacy Analysis

Protocol 020

N = number of subjects randomized.

† Subjects may be in more than one category.


Baseline characteristics of randomized subjects by vaccination group l.jpg

GARDASIL Treatment Options®

(N=2032)

Placebo

(N=2033)

Characteristic

HM

MSM

Age, years Mean (SD)

Race/ethnicity Asian Black Hispanic American White Other

1731 (85%)

301 (15%)

20.6 (2.0)

201 (10%) 405 (20%) 412 (20%) 719 (35%) 295 (15%)

1732 (85%)

301 (15%)

20.5 (2.0)

205 (10%) 400 (20%) 423 (21%) 712 (35%) 293 (14%)

Baseline Characteristics of Randomized Subjects by Vaccination Group

Protocol 020

N = number of subjects randomized.

HM = Heterosexual men; MSM = men having sex with men; SD = Standard deviation.


Agenda50 l.jpg
Agenda Treatment Options

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


Efficacy against hpv 6 11 16 18 related external genital lesions egl l.jpg

GARDASIL Treatment Options®

Cases(n=1397)

Placebo

Cases(n=1408)

%Efficacy

Endpoint

95% CI

p-Value

Efficacy Against HPV 6/11/16/18-Related External Genital Lesions (EGL)

Protocol 020, Per-Protocol Efficacy Population

n = number of subjects in per-protocol population; CI = confidence interval.

EGLs include external genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer.


Efficacy against hpv 6 11 16 18 related external genital lesions egl52 l.jpg

GARDASIL Treatment Options®

Cases(n=1397)

Placebo

Cases(n=1408)

%Efficacy

Endpoint

95% CI

p-Value

EGL

3

31

90

69, 98

<0.001

Efficacy Against HPV 6/11/16/18-Related External Genital Lesions (EGL)

Protocol 020, Per-Protocol Efficacy Population

n = number of subjects in per-protocol population; CI = confidence interval.

EGLs include external genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer.


Efficacy against hpv 6 11 16 18 related external genital lesions egl53 l.jpg

GARDASIL Treatment Options®

Cases(n=1397)

Placebo

Cases(n=1408)

%Efficacy

Endpoint

95% CI

p-Value

EGL

Condyloma acuminatum

PIN 1

PIN 2/3

Penile/perianal/ perineal cancer

3

3

0

0

0

31

28

2

1

0

90

89

100

100

NA

69, 98

66, 98

<0, 100

<0, 100

NA

<0.001

Efficacy Against HPV 6/11/16/18-Related External Genital Lesions (EGL)

Protocol 020, Per-Protocol Efficacy Population

n = number of subjects in per-protocol population; CI = confidence interval.

EGLs include external genital warts, penile/perianal/perineal intraepithelial neoplasia (PIN), penile, perianal, or perineal cancer.


Efficacy against hpv 6 11 related genital warts l.jpg

Placebo Treatment Options

Cases

(n=1244)

GARDASIL®

Cases

(n=1245)

%Efficacy

Endpoint

95% CI

Condyloma acuminatum

3

89

28

66, 98

Efficacy Against HPV 6/11-RelatedGenital Warts

Protocol 020

Per-Protocol Efficacy Population

n = number of subjects in the relevant population; CI = confidence interval.


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Placebo Treatment Options

Cases

(n=1937)

Placebo

Cases

(n=1244)

GARDASIL®

Cases

(n=1943)

GARDASIL®

Cases

(n=1245)

%Efficacy

%Efficacy

Endpoint

Endpoint

95% CI

95% CI

Condyloma acuminatum

3

89

28

66, 98

24

67

71

47, 80

Condyloma acuminatum

Efficacy Against HPV 6/11-RelatedGenital Warts

Protocol 020

Per-Protocol Efficacy Population

Full Analysis Set

n = number of subjects in the relevant population; CI = confidence interval.


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Time to Detection of HPV 6/11-Related Treatment OptionsGenital Warts

Protocol 020, Per-Protocol Efficacy Population

Error bars indicate 95% confidence intervals.


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Time to Detection of HPV 6/11-Related Treatment OptionsGenital Warts

Protocol 020, Full Analysis Set

Error bars indicate 95% confidence intervals.


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GARDASIL Treatment Options®

Cases(n=1390)

Placebo

Cases(n=1400)

%Efficacy

Endpoint

95% CI†

p-Value

Persistentinfection*

15

101

86

73, 93

<0.001

Efficacy Against HPV 6/11/16/18-Related Persistent Infection and DNA Detection

Protocol 020, Per-Protocol Efficacy Population

† For persistent infection 97.5% CI, for DNA detection 95% CI.

* Persistent infection: Detection of same vaccine type HPV DNA in ≥2 consecutive anogenital samples collected ≥6 months apart.

n = number of subjects in per-protocol population; CI = confidence interval.


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GARDASIL Treatment Options®

Cases(n=1390)

Placebo

Cases(n=1400)

%Efficacy

95% CI†

p-Value

Endpoint

73, 93

32, 56

<0.001

<0.001

15

136

101

241

Persistentinfection*

DNAdetection**

86

45

Efficacy Against HPV 6/11/16/18-Related Persistent Infection and DNA Detection

Protocol 020, Per-Protocol Efficacy Population

† For persistent infection 97.5% CI, for DNA detection 95% CI.

* Persistent infection: Detection of same vaccine type HPV DNA in ≥2 consecutive anogenital samplescollected 6 months apart.

** DNA detection: Detection of vaccine type HPV DNA in samples from ≥1 visit.

n = number of subjects in per-protocol population; CI = confidence interval.


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GARDASIL Treatment Options®

Placebo

%Efficacy

95% CI†

HPV Type

Cases

n

n

Cases

HPV 6/11/16/18

HPV 6

HPV 11

HPV 16

HPV 18

86

88

93

79

96

73, 93

66, 97

57, 100

56, 91

76, 100

1390

1239

1239

1290

1327

15

4

1

9

1

1400

1238

1238

1264

1347

101

33

15

41

25

Efficacy Against Persistent Infection* by HPV Type

Protocol 020, Per-Protocol Efficacy Population

* Persistent infection: Detection of same vaccine type HPV DNA in ≥2 consecutive anogenital samples collected 6 months apart.

† For HPV 6/11/16/18-related persistent infection 97.5% CI.

n = number of subjects in type-specific per-protocol population; CI = confidence interval.


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GARDASIL Treatment Options® is Efficacious in 16- to 26-Year-Old Men Against Primary and Secondary Endpoints

  • HPV 6/11/16/18-related external genital lesions

  • HPV 6/11-related genital warts

  • HPV 6/11/16/18-related persistent infection

    • Efficacy is similarly high in preventing persistent infection related to each HPV type

  • HPV 6/11/16/18 DNA detection


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Agenda Treatment Options

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


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Clinical Development Program in Boys and Men Treatment Options

Efficacy/Safety/Immunogenicity

Protocol 020

16- to 26-year-old men

n=4055

Immunobridging

Safety/Immunogenicity

Protocol 016

10- to 15-year-old boys

n=508 boys

Safety/Immunogenicity

Protocol 018

9- to 15-year-old boys

n=839 boys


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Assessment of Immunogenicity Treatment Options

  • Standardized across studies

    • Sera collected at Day 1 (prior to Dose 1) and Month 7 (1 month after Dose 3)

    • Neutralizing antibody levels measured using multiplex competitive Luminex Immunoassay (cLIA)

  • Per-protocol immunogenicity (PPI) population

    • Received 3 doses of vaccine/placebo

    • To the relevant HPV type

      • Seronegative at Day 1

      • PCR negative at Day 1 and Month 7


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Immunobridging Treatment Options

  • Comparison of antibody response at Month 7 in the PPI populations of adolescent boys (Protocols 016 and 018 combined) versus men (Protocol 020)

  • Non-inferiority criteria:

    • Geometric mean titers (GMTs) - statistically <2-fold decrease, and

    • Seroconversion rates - statistically <5 percentage points decrease in the adolescents

PPI = per protocol immunogenicity


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HPV 6 Treatment Options

HPV 11

HPV 16

HPV 18

1.5

2

2.5

3

3.5

4

0

0.5

1

Higher GMT in Boys

Higher GMT in Men

GMT Ratio Boys:Men (95% CI)

Immunobridging Was Demonstrated

Ratio of Month 7 Anti-HPV GMTsBoys 9-15 Years to Men 16-26 Years of Age

Protocols 016, 018 and 020, Per-Protocol Immunogenicity Population

9- to 15-year-old male subjects from Protocols 016 and 018 and 16- to 26-year-old men from Protocol 020.

GMTs = Geometric mean titers. CI = Confidence interval.


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9- to 15-Year-Old Boys Treatment Options

16- to 26-Year-Old Men

Assay

95% CI

95% CI

%

%

n

n

98.9

99.2

98.8

97.4

HPV 6

HPV 11

HPV 16

HPV 18

1093

1093

1136

1175

99.4, 100

99.4, 100

99.2, 100

99.2, 100

98.1, 99.4

98.4, 99.6

97.9, 99.3

96.3, 98.2

99.9

99.9

99.8

99.8

885

886

883

888

Seroconversion Rate Was High

Summary of Anti-HPV Seroconversion† Among Boys and Men 9-26 Years of Age

Protocols 016, 018, 020, Per-Protocol Immunogenicity Population

† Seroconversion = at Month 7 HPV 6 cLIA ≥20 mMU/mL, HPV 11 cLIA ≥16 mMU/mL, HPV 16 cLIA ≥20 mMU/mL, HPV 18 cLIA ≥24 mMU/mL.

n = number of subjects in relevant per protocol immunogenicity population.

cLIA = competitive Luminex immunoassay; mMU = milli Merck units.

9- to 15-year-old male subjects from Protocols 016 and 018 and 16- to 26-year-old men from Protocol 020.


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Summary of Immunobridging Results Treatment Options

  • Immunobridging was successfully demonstrated

  • GARDASIL® efficacy is inferred in boys 9-15 years of age, through demonstrating non-inferiority of immune response compared to men 16-26 years of age


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Agenda Treatment Options

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


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Efficacy/ Treatment OptionsSafety/Immunogenicity

Protocol 020

16- to 26-year-old men

n=4055

Safety/Immunogenicity

Protocol 016

10- to 15-year-old boys

n=508 boys

Safety/Immunogenicity

Protocol 018

9- to 15-year-old boys

n=839 boys

Population for Safety Assessment

GARDASIL®, n=2025

AAHS placebo, n=2030

GARDASIL, n=508

GARDASIL, n=564

Saline placebo, n=275

AAHS = amorphous aluminum hydroxyphosphate sulfate.


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Assessment of Safety Treatment Options

  • All subjects who received ≥1 dose were assessed for safety

  • Non-serious adverse experiences (AEs) collected on vaccination report card Day 1 to Day 15 after each dose

  • Serious adverse experiences (SAEs) collected Day 1 to Day 15 after each dose

    • SAEs also collected during entire study if the event resulted in death, was vaccine- or procedure-related

  • Vaccine association for all AEs and SAEs determined by the investigator

    • A vaccine-related AE was one determined by the investigator to be definitely, probably or possibly related

  • Data on new onset medical conditions collected for the duration of the study


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GARDASIL Treatment Options®(N=3002)

Placebo(N=2219)

Subjects

n

%

n

%

With one or more AEInjection-site AEs†Systemic AEs Vaccine-related systemic AEs

With SAEsVaccine-related SAEsDeaths

Discontinued due to AEDiscontinued due to a vaccine-related AE

221619271118527

900

64

74643718

0.300

0.20.1

14171177723338

100

43

64533315

0.000

0.20.1

Summary of AEs Reported Among Boys and Men 9-26 Years of Age

(Days 1-15 Following Any Vaccination)

Protocols 016, 018 and 020

† All injection site adverse experiences considered vaccine-related.

N = number of subjects with follow up; n = number of subjects in each category.

AE = adverse experience; SAE = serious adverse experience.


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AAHS Treatment Options

Placebo(N=1950)

GARDASIL®(N=3002)

Saline(N=269)

Subjects

n

%

n

%

n

%

192418455004173126

60

6462171411

2

1046991275187244

13

5451141010.2

1

128112392238

2

484215813

1

With injection site AEPainErythemaSwellingPruritusBruising

Maximum intensity of severe

Injection Site AEs Reported by ≥1% of Boys and Men 9-26 Years of Age

(Days 1-5 Following Any Vaccination)

Protocols 016, 018 and 020

N = number of subjects with follow-up; n = number of subjects in each category.

AAHS = amorphous aluminum hydroxyphosphate sulfate; AE = adverse experience.


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GARDASIL Treatment Options®(N=3002)

Placebo(N=2219)

Subjects

n

%

n

%

1118368246128

371284

723249145

67

33117

3

Systemic AEs Reported by ≥5% of Boys and Men 9-26 Years of Age

(Days 1-15 Following Any Vaccination)

Protocols 016, 018 and 020

With systemic AEHeadachePyrexia

Maximum intensity of severe

N = number of subjects with follow-up; n = number of subjects in each category.

AE = adverse experience.


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Safety Profile for Entire Study Period Treatment OptionsAmong Boys and Men 9-26 Years of Age

  • No SAEs were considered vaccine related

  • 4 deaths in vaccine and 10 deaths in placebo groups

    • None were considered vaccine related

  • New onset medical conditions

    • 46% in vaccine versus 42% in placebo group

    • Most common

      • Upper respiratory tract infection: 5% in vaccine versus 4% in placebo group

  • Proportion of subjects reporting conditions potentially consistent with autoimmune phenomena

    • 1.3% in vaccine versus 1.3% in placebo group

SAE = serious adverse experience.


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Summary of Safety Data in Treatment OptionsBoys and Men

  • GARDASIL® was well tolerated in boys and men 9-26 yearsof age

  • No serious adverse experiences considered vaccine related

  • Discontinuations due to adverse experiences were infrequent

  • More than 95% of adverse experiences reported were of mild to moderate intensity

  • GARDASIL safety profile in boys and men is consistent with that observed in girls and women


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Agenda Treatment Options

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure studies

    • Overall benefit-risk profile of GARDASIL use in boysand men


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Post-licensure Long-Term Assessment of Safety and Effectiveness in Boys and Men

  • Objective: To assess safety and effectiveness of GARDASIL® in boys and men after licensure

  • A comprehensive risk assessment plan was implemented by Merck for GARDASIL

  • Plan proposed to include boys/men

    • Long-term extension of Protocol 018

    • Long-term extension of Protocol 020

    • Post-licensure safety study

    • Ongoing assessment of spontaneous safety reportsin males


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Post-licensure Long-Term Assessment of Effectiveness in Boys and MenSafety and Effectiveness in Boys and Men

  • Objective: To assess long-term safety, effectiveness, and immunogenicity of GARDASIL® in 9- to 26-year-old boys/men

  • 9- to 15-year-old boys

    • Protocol 018 - started in 2003, extension implemented

  • 16- to 26-year-old men

    • Protocol 020 - started in 2004, extension proposed

  • Follow up of subjects regularly

  • 10-year follow up from Day 1


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Post-licensure Safety Study in Boys Effectiveness in Boys and Menand Men

  • Objective: To evaluate safety of GARDASIL® among 9- to 26-year-old boys/men

  • Methods:

    • Health maintenance organization database

    • 27,000 boys and men receiving at least one dose of GARDASIL

    • Safety assessment after any dose

      • All medical events resulting in emergency room visit or hospitalization


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Agenda Effectiveness in Boys and Men

  • Patrick Brill-Edwards, MD

    • Current status of GARDASIL®

    • Proposed indication

  • Dalya Guris, MD, MPH

    • Clinical significance of HPV disease in boys and men

    • Rationale and design of the clinical trials program

    • Clinical trial methods and results

      • Efficacy

      • Immunobridging

      • Safety

    • Post-licensure Studies

    • Overall benefit-risk profile of GARDASILuse in boysand men


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Summary of Clinical Trial Results in Effectiveness in Boys and MenBoys and Men

  • GARDASIL® is efficacious in men 16-26 years of age in preventing

    • HPV 6/11/16/18-related external genital lesions

    • HPV 6/11-related genital warts

    • HPV 6/11/16/18 persistent infection and DNA detection

  • Efficacy of GARDASIL inferred in 9- to 15-year-old boys through immunobridging

  • GARDASIL has a favorable safety profile in allpopulations studied


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Overall Benefit-Risk Profile of GARDASIL Effectiveness in Boys and Men®Use in Boys and Men

  • HPV is associated with substantial burden of disease in men

  • GARDASIL is highly efficacious against genital warts, the most common HPV-related disease

  • GARDASIL is generally well tolerated in boys and men

  • GARDASIL has a favorable benefit-risk profile in boys and men 9-26 years of age


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