1 Use of GARDASIL ® in Boys and Men Vaccines and Related Biological Products Advisory Committee Meeting September 9, 2009 Merck Research Laboratories

1

Use of GARDASIL® in Boys and Men

Vaccines and Related Biological ProductsAdvisory Committee Meeting

September 9, 2009

Merck Research Laboratories

2

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 boys

and men

3

GARDASIL® Quadrivalent HPV (Types 6, 11, 16, 18)

L1 Virus-Like Particle (VLP) Vaccine

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

Dose (µg)

Constituent

225

Merck’sAAHS

Adjuvant†

20

HPV 6

40

HPV 11

40

HPV 16

20

HPV 18

L1 VLP

† Amorphous aluminum hydroxyphosphate sulfate.

4

Clinical Program for GARDASIL®

Jan2003

Jan2004

Jan2005

Jan2009

Jan2006

Jan2008

Jan2007

Jan2010

GARDASIL approval

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



Yr 5 Immune MemoryEvaluation

Duration of Efficacy Registry StudyNordic Region

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

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

5


Jan2003

Jan2004

Jan2005

Jan2009

Jan2006

Jan2008

Jan2007

Jan2010








Adolescent Vaccine Effectiveness StudyProtocol 018 (N=936F, 839M) 9-15-year-olds, both genders

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

GARDASIL approval

6


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

Jan2003

Jan2004

Jan2005

Jan2009

Jan2006

Jan2008

Jan2007

Jan2010

Male sBLA Submission

Adolescent Vaccine Effectiveness StudyProtocol 018 (N=936F, 839M) 9-15-year-olds, both genders

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

GARDASIL approval








7

Current Indication

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

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 16and 18

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

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

8

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 of

spontaneous 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

9

There Are Unmet Medical Needs forBoys 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

10

GARDASIL® 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

11

Agenda






and men

12

Proposed Indication

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.

13

Basis for Proposed Indication

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

14

Consultants

David Cornblath, MD Johns Hopkins University

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

15

Agenda


– Proposed Indication




and men

16

Human Papillomavirus (HPV)

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

17

HPV Infection and Productive Life Cycle

Infection of basal cells of epithelium

Differentiation of infected cells

Expression of viral proteins and change of cell growth

Release of virions within desquamating cells

HPV virion

18

Burden of HPV-Related Diseases in Men

1 http://www.cdc.gov/vaccines/recs/acip/downloads/mtg-slides-feb09/10-2-hpv.pdf.2 American Cancer Society. Cancer facts & figures 2008

http://www.cancer.org/downloads/stt/CFF2008Table_pg4.pdf3 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.

Estimated Number of New Cases in Men – USA, 2008

Anogenital warts1

Cancers2-5

Oral cavity and oropharynx Anus/anal canal/anorectumPenis/external genital

Total cancers

Disease

250,000

25,31020201250

NewCases

~100

259040

% DetectableHPV

250,000

63001800

500

8600

New HPV-Related Cases

Annually

19

Anogenital Warts (Condyloma Acuminata)

Anogenital warts are common– ~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

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.

20

Incidence of Genital Warts Peaks inEarly Adulthood

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

0

50

100

150

200

250

300

0-9

10-1

4

15-1

9

20-2

4

25-2

9

30-3

9

40-4

9

50-5

9

60-6

9

70-7

980

+

Age (years)

Inci

denc

e pe

r10

0,00

0 In

divi

dual

s

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

21

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

1 Insinga RP, et al. CID. 2003;36:1397-1403.2 Based on literature review on treatment of warts.3 Winer RL, et al. J Infect Dis. 2005;191:731-738.

22

HPV Causes Penile Cancer

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.

23

HPV is Sexually Transmitted

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 Biomarkers Prev. 2008;17(4):805-808.2 Giuliano 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.

24

Summary of HPV Disease Burden in Men

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

25

Agenda






and men

26

Rationale ofClinical 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

27

Objectives of Clinical 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

28

Clinical Development Program in Boys and Men

Efficacy/Safety/Immunogenicity

Protocol 02016- to 26-year-old men

n=4055

29




n=4055

Safety/ImmunogenicityProtocol 016

10- to 15-year-old boysn=508 boys



30




n=4055

ImmunobridgingSafety/Immunogenicity

Protocol 01610- to 15-year-old boys

n=508 boys



31




n=4055

Safety Assessment





32

Agenda




• Efficacy• Immunobridging • Safety


and men

33

Objectives

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%

Protocol 020

34

Objectives

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 6 months apart

• DNA detection at any visit

Success criteria– Lower bound of confidence interval for vaccine efficacy

above 20%

Protocol 020

35

Objectives

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

Protocol 020

36

Study Design

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

37

Genital Biopsy Collection

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

38

Disease Endpoint Assessment

Prepare Consecutive

Sections

External Genital Biopsy

Fixation, Processing & Paraffin Embedding

12

54

3

67

12

98

13

1011

39


Prepare Consecutive

Sections



H&E Staining and Histology1 2 12 13

12

54

3

67

12

98

13

1011

Pathology Panel

40


Prepare Consecutive

Sections




Extraction of DNA for HPV Multiplex PCR

3 54

12

54

3

67

12

98

13

1011

Pathology Panel

41EGL = external genital lesion.


Prepare Consecutive

Sections




Extraction of DNA for HPV Multiplex PCR

3 54

12

54

3

67

12

98

13

1011

No Case

Pathology PanelHPV 6/11/16/18PCR Positive

Case

HPV 6/11/16/18PCR Negative EGL

(Condyloma, PIN)No Case

Not EGL

42

Genital Swab Collection

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.

43

Efficacy Analysis Populations

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

44

Subject Accounting for Per-Protocol Efficacy Analysis

Screened4164

Protocol 020

45


Randomized4065

PlaceboGARDASIL®

2032

Screened4164

2033

Protocol 020

46


Randomized4065

PlaceboGARDASIL®

2032

Screened4164

Completed visits through Month 7

2025

1819

Received ≥1 dose

2033

2030

1814

Protocol 020

47


Randomized4065

PlaceboGARDASIL®

2032

Eligible for HPV 6/11/16/18

per-protocol analysis

Screened4164

Completed visits through Month 7

2025

1819

1397

Received ≥1 dose

2033

2030

1814

1408

Protocol 020

48

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

N = number of subjects randomized.† Subjects may be in more than one category.

Did not receive 3 doses

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

General protocol violators

Subjects†

165

169244248

83

GARDASIL®

(N=2032)

184

161221242

68

Placebo(N=2033)

Protocol 020

49

Baseline Characteristics of Randomized Subjects by Vaccination Group

N = number of subjects randomized.HM = Heterosexual men; MSM = men having sex with men; SD = Standard deviation.

HM

MSM

Age, yearsMean (SD)

Race/ethnicityAsianBlackHispanic AmericanWhiteOther

Characteristic

1731 (85%)

301 (15%)

20.6 (2.0)

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

GARDASIL®

(N=2032)

1732 (85%)

301 (15%)

20.5(2.0)

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

Placebo(N=2033)

Protocol 020

50

Agenda




• Efficacy• Immunobridging • Safety


and men

51

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.

Endpoint

GARDASIL®

Cases(n=1397)

PlaceboCases

(n=1408)%

Efficacy 95% CI p-Value

52


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.

EGL

Endpoint

3

GARDASIL®

Cases(n=1397)

31

PlaceboCases

(n=1408)

90

%Efficacy

69, 98

95% CI

<0.001

p-Value


53


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.

EGL

Condyloma acuminatum

PIN 1

PIN 2/3

Penile/perianal/perineal cancer

Endpoint

3

3

0

0

0

GARDASIL®

Cases(n=1397)

31

28

2

1

0

PlaceboCases

(n=1408)

90

89

100

100

NA

%Efficacy

69, 98

66, 98

<0, 100

<0, 100

NA

95% CI

<0.001

p-Value


54

Efficacy Against HPV 6/11-RelatedGenital Warts

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

Protocol 020

Per-Protocol Efficacy Population

89

%Efficacy

66, 98

95% CI

28

PlaceboCases

(n=1244)

3

GARDASIL®

Cases(n=1245)


Endpoint

55

Efficacy Against HPV 6/11-RelatedGenital Warts

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

Protocol 020

Per-Protocol Efficacy Population

Full Analysis Set

89

%Efficacy

66, 98

95% CI

28

PlaceboCases

(n=1244)

3

GARDASIL®

Cases(n=1245)


Endpoint

67

%Efficacy

47, 80

95% CI

71

PlaceboCases

(n=1937)

24

GARDASIL®

Cases(n=1943)


Endpoint

56

Time to Detection of HPV 6/11-RelatedGenital Warts

0 6 12 18 24 30Time Since Day 1 (in Months)

0

1

2

3C

umul

ativ

e P

erc

ent

Placebo

GARDASIL

o9v501p20KMppe Aug. 31, 2009

1245 1245 1223 1140 1058 9041244 1244 1219 1143 1052 883

GARDASILNumber of Subjects at Risk

Placebo


Error bars indicate 95% confidence intervals.

57

Time to Detection of HPV 6/11-RelatedGenital Warts

0 6 12 18 24 30Time Since Day 1 (in Months)

0

1

2

3

4

5C

umul

ativ

e P

erce

nt

Placebo

GARDASIL

o9v501p20KMfas Aug. 31, 2009

1943 1835 1715 1581 1424 11851937 1829 1700 1547 1392 1141

GARDASILNumber of Subjects at Risk

Placebo

Protocol 020, Full Analysis Set

Error bars indicate 95% confidence intervals.

58

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

† 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.

Persistentinfection*

Endpoint

15

GARDASIL®

Cases(n=1390)

101

PlaceboCases

(n=1400)

86

%Efficacy

73, 93

95% CI†

<0.001

p-Value


59

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


† 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. ** DNA detection: Detection of vaccine type HPV DNA in samples from ≥1 visit.n = number of subjects in per-protocol population; CI = confidence interval.

Persistentinfection*

DNAdetection**

Endpoint

15

136

GARDASIL®

Cases(n=1390)

101

241

PlaceboCases

(n=1400)

86

45

%Efficacy

73, 93

32, 56

95% CI†

<0.001

<0.001

p-Value

60

Efficacy Against Persistent Infection* by HPV Type


* 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.

86

88

93

79

96

%Efficacy

73, 93

66, 97

57, 100

56, 91

76, 100

95% CI†

Placebo

101

33

15

41

25

Cases

1400

1238

1238

1264

1347

n

GARDASIL®

15

4

1

9

1

Cases

1390

1239

1239

1290

1327

n

HPV 6/11/16/18

HPV 6

HPV 11

HPV 16

HPV 18

HPV Type

61

GARDASIL® 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

62

Agenda






and men

63



n=4055

ImmunobridgingSafety/Immunogenicity

Protocol 01610- to 15-year-old boys

n=508 boys




64

Assessment of Immunogenicity

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

65

Immunobridging

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

66

Immunobridging Was DemonstratedRatio of Month 7 Anti-HPV GMTs

Boys 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.

0 0.5 1 1.5 2 2.5 3 3.5 4

GMT Ratio Boys:Men (95% CI)

HPV 6

HPV 11

HPV 16

HPV 18

Higher GMT in BoysHigher GMT in Men

67

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.

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

Seroconversion Rate Was High

HPV 6

HPV 11

HPV 16

HPV 18

Assay

9- to 15-Year-Old Boys

99.9

99.9

99.8

99.8

%

885

886

883

888

n

99.4, 100

99.4, 100

99.2, 100

99.2, 100

95% CI

16- to 26-Year-Old Men

98.9

99.2

98.8

97.4

%

1093

1093

1136

1175

n

98.1, 99.4

98.4, 99.6

97.9, 99.3

96.3, 98.2

95% CI

68

Summary of Immunobridging Results

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

69

Agenda






and men

70

Population for Safety Assessment



n=4055





AAHS placebo, n=2030

Saline placebo, n=275

GARDASIL®, n=2025

GARDASIL, n=508

GARDASIL, n=564

AAHS = amorphous aluminum hydroxyphosphate sulfate.

71

Assessment of Safety 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

72

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

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.

GARDASIL®

(N=3002)

221619271118527

900

64

n

74643718

0.300

0.20.1

%

14171177723338

100

43

n

64533315

0.000

0.20.1

%

Placebo(N=2219)

With one or more AEInjection-site AEs†

Systemic AEsVaccine-related systemic AEs

With SAEsVaccine-related SAEsDeaths

Discontinued due to AEDiscontinued due to a vaccine-related AE

Subjects

(Days 1-15 Following Any Vaccination)

73

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


N = number of subjects with follow-up; n = number of subjects in each category.AAHS = amorphous aluminum hydroxyphosphate sulfate; AE = adverse experience.

1924

18455004173126

60

n

64

62171411

2

%

GARDASIL®

(N=3002)

1046

99127518724

4

13

n

54

5114101

0.2

1

%

AAHSPlacebo

(N=1950)

128

1123922

38

2

n

48

4215813

1

%

Saline(N=269)

With injection site AE

PainErythemaSwellingPruritusBruising

Maximum intensity of severe

Subjects


74

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


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

1118

368246

128

n

37

128

4

%

GARDASIL®

(N=3002)

723

249145

67

n

33

117

3

%

Placebo(N=2219)

With systemic AE

HeadachePyrexia

Maximum intensity of severe

Subjects


75

Safety Profile for Entire Study PeriodAmong 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.

76

Summary of Safety Data inBoys 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

77

Agenda






and men

78

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 reports

in males

79

Post-licensure Long-Term Assessment of Safety 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

80

Post-licensure Safety Study in Boysand 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

81

Agenda





– Post-licensure Studies– Overall benefit-risk profile of GARDASIL use in boys

and men

82

Summary of Clinical Trial Results inBoys 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

83

Overall Benefit-Risk Profile of GARDASIL®

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

Documents

1 Use of GARDASIL ® in Boys and Men Vaccines and Related Biological Products Advisory Committee Meeting September 9, 2009 Merck Research Laboratories