Use of GARDASIL ® in Boys and Men

Use of GARDASIL® in Boys and Men Vaccines and Related Biological ProductsAdvisory Committee MeetingSeptember 9, 2009 Merck Research Laboratories

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

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.

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

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

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 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 • 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 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

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

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.

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

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 Consultants

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

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

HPV Infection and Productive Life Cycle 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

New HPV-Related 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 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 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 per100,000 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 • 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 • 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 • 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 • 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

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

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

Clinical Development Program in Boys and Men Efficacy/Safety/Immunogenicity Protocol 020 16- to 26-year-old men n=4055

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/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 Men 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 Men 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

Objectives 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%

Objectives 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%

Objectives 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 • 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 • 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

External 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

External 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

External 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

External 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 • 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 • 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 Protocol 020 Screened4164

Screened4164 Placebo GARDASIL® Randomized4065 2032 2033 Subject Accounting for Per-Protocol Efficacy Analysis Protocol 020

Screened4164 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

Screened4164 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

GARDASIL® (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.

GARDASIL® (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.

Use of GARDASIL ® in Boys and Men