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

2. 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. 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 infection or disease Dose (µg) Constituent 225 Merck’s AAHS Adjuvant † 20 HPV 6 40 HPV 11 40 HPV 16 20 HPV 18 L1 VLP † Amorphous aluminum hydroxyphosphate sulfate.

4. 4 Clinical Program for GARDASIL ® Jan 2003 Jan 2004 Jan 2005 Jan 2009 Jan 2006 Jan 2008 Jan 2007 Jan 2010 GARDASIL approval Protocol 013 (N=5455) 16-23-year-old women Protocol 005 (N=2409) 16-23-year-old women Protocol 007 (N=1158) 16-23-year-old women Yr 5 Immune Memory Evaluation Duration of Efficacy Registry Study Nordic Region Protocol 015 (N=12,167) 15-26-year-old women Protocol 019 (N=3819) 24-45-year-old adult women

5. 5 Clinical Program for GARDASIL ® Jan 2003 Jan 2004 Jan 2005 Jan 2009 Jan 2006 Jan 2008 Jan 2007 Jan 2010 Protocol 013 (N=5455) 16-23-year-old women Protocol 005 (N=2409) 16-23-year-old women Protocol 007 (N=1158) 16-23-year-old women Yr 5 Immune Memory Evaluation Duration of Efficacy Registry Study Nordic Region Protocol 015 (N=12,167) 15-26-year-old women Protocol 019 (N=3819) 24-45-year-old adult women Adolescent Vaccine Effectiveness Study Protocol 018 (N=936F, 839M) 9-15-year-olds, both genders Protocol 016 (N=506F, 508M) 10-15-year-olds, both genders GARDASIL approval

6. 6 Clinical Program for GARDASIL ® Protocol 020 (N=4055) 16-26-year-old males Jan 2003 Jan 2004 Jan 2005 Jan 2009 Jan 2006 Jan 2008 Jan 2007 Jan 2010 Male sBLA Submission Adolescent Vaccine Effectiveness Study Protocol 018 (N=936F, 839M) 9-15-year-olds, both genders Protocol 016 (N=506F, 508M) 10-15-year-olds, both genders GARDASIL approval Protocol 013 (N=5455) 16-23-year-old women Protocol 005 (N=2409) 16-23-year-old women Protocol 007 (N=1158) 16-23-year-old women Yr 5 Immune Memory Evaluation Duration of Efficacy Registry Study Nordic Region Protocol 015 (N=12,167) 15-26-year-old women Protocol 019 (N=3819) 24-45-year-old adult women

7. 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 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:

8. 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. 9 There Are Unmet Medical Needs for Boys 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 detect precancerous 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. 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. 11 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

12. 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. 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. 14 Consultants David Cornblath, MDJohns Hopkins University Mark Esser, PhDPPD Vaccines and Biologics Laboratory Anna Giuliano, PhDH. Lee Moffitt Cancer Center and Research Institute Joel Palefsky, MDUniversity of California, San Francisco Mark Stoler, MDUniversity of Virginia Lee-Jen Wei, PhDHarvard University

15. 15 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

16. 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. 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. 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.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. Estimated Number of New Cases in Men – USA, 2008 Anogenital warts 1 Cancers 2-5 Oral cavity and oropharynx Anus/anal canal/anorectum Penis/external genital Total cancers Disease 250,000 25,310 2020 1250 New Cases ~100 25 90 40 % Detectable HPV 250,000 6300 1800 500 8600 New HPV- Related Cases Annually

19. 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 diagnosis 1 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. 20 Incidence of Genital Warts Peaks in Early Adulthood Incidence of Genital Warts in Boys and Men by Age Group Private Health Insurance Data – USA, 2004 Incidence per 100,000 Individuals Source: Hoy T, et al. Curr Med Res Opin. 2009;25:2343-51.

21. 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 episode 1 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 treatment 2 –Median duration of genital warts is 6 months 3 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. 22 HPV Causes Penile Cancer HPV detected in 42% to 80% 1 HPV types 16 and 18 - most frequently identified types in tumors 2,3 High-grade penile/perianal/perineal intraepithelial neoplasia (PIN 2/3) considered precancerous 4 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. 23 HPV is Sexually Transmitted HPV is one of the most common sexually transmitted diseases 1 Infection is often asymptomatic or subclinical, allowing transmission to occur without the knowledge of partners 2 Circumcision and condom use may reduce transmission, but do not eliminate risk of HPV infection 3-6 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. 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. 25 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

26. 26 Rationale of Clinical 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. 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. 28 Clinical Development Program in Boys and Men Efficacy/ Safety/Immunogenicity Protocol 020 16- to 26-year-old men n=4055

29. 29 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/Immunogenicity Protocol 018 9- to 15-year-old boys n=839 boys

30. 30 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

31. 31 Clinical Development Program in Boys and Men Efficacy/ Safety/Immunogenicity Protocol 020 16- to 26-year-old men n=4055 Safety Assessment 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

32. 32 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

33. 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. 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. 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. 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. 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. 38 Disease Endpoint Assessment Prepare Consecutive Sections External Genital Biopsy Fixation, Processing & Paraffin Embedding 1 2 5 4 3 6 7 12 9 8 13 10 11

39. 39 Disease Endpoint Assessment Prepare Consecutive Sections External Genital Biopsy Fixation, Processing & Paraffin Embedding H&E Staining and Histology 121213 1 2 5 4 3 6 7 12 9 8 13 10 11 Pathology Panel

40. 40 Disease Endpoint Assessment Prepare Consecutive Sections External Genital Biopsy Fixation, Processing & Paraffin Embedding H&E Staining and Histology 121213 Extraction of DNA for HPV Multiplex PCR 354 1 2 5 4 3 6 7 12 9 8 13 10 11 Pathology Panel

41. 41 EGL = external genital lesion. Disease Endpoint Assessment Prepare Consecutive Sections External Genital Biopsy Fixation, Processing & Paraffin Embedding H&E Staining and Histology 121213 Extraction of DNA for HPV Multiplex PCR 354 1 2 5 4 3 6 7 12 9 8 13 10 11 No Case Pathology Panel HPV 6/11/16/18 PCR Positive Case HPV 6/11/16/18 PCR Negative EGL (Condyloma, PIN) No Case Not EGL

42. 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. 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. 44 Subject Accounting for Per-Protocol Efficacy Analysis Screened 4164 Protocol 020

45. 45 Subject Accounting for Per-Protocol Efficacy Analysis Randomized 4065 Placebo GARDASIL ® 2032 Screened 4164 2033 Protocol 020

46. 46 Subject Accounting for Per-Protocol Efficacy Analysis Randomized 4065 Placebo GARDASIL ® 2032 Screened 4164 Completed visits through Month 7 2025 1819 Received ≥1 dose 2033 2030 1814 Protocol 020

47. 47 Subject Accounting for Per-Protocol Efficacy Analysis Randomized 4065 Placebo GARDASIL ® 2032 Eligible for HPV 6/11/16/18 per-protocol analysis Screened 4164 Completed visits through Month 7 2025 1819 1397 Received ≥1 dose 2033 2030 1814 1408 Protocol 020

48. 48 Main Reasons for Ineligibility for HPV 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 1 Month 7 Inadequate samples at Day 1–Month 7 General protocol violators Subjects † 165 169 244 248 83 GARDASIL ® (N=2032) 184 161 221 242 68 Placebo (N=2033) Protocol 020

49. 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, years Mean (SD) Race/ethnicity Asian Black Hispanic American White Other 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. 50 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

51. 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) Placebo Cases (n=1408) % Efficacy 95% CIp-Value

52. 52 Efficacy Against HPV 6/11/16/18-Related External Genital Lesions (EGL) 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 Placebo Cases (n=1408) 90 % Efficacy 69, 98 95% CI <0.001 p-Value Protocol 020, Per-Protocol Efficacy Population

53. 53 Efficacy Against HPV 6/11/16/18-Related External Genital Lesions (EGL) 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 3300033000 GARDASIL ® Cases (n=1397) 31 28 2 1 0 Placebo Cases (n=1408) 90 89 100 NA % Efficacy 69, 98 66, 98 <0, 100 NA 95% CI <0.001 p-Value Protocol 020, Per-Protocol Efficacy Population

54. 54 Efficacy Against HPV 6/11-Related Genital 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 Placebo Cases (n=1244) 3 GARDASIL ® Cases (n=1245) Condyloma acuminatum Endpoint

55. 55 Efficacy Against HPV 6/11-Related Genital 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 Placebo Cases (n=1244) 3 GARDASIL ® Cases (n=1245) Condyloma acuminatum Endpoint 6767 % Efficacy 47, 80 95% CI 71 Placebo Cases (n=1937) 24 GARDASIL ® Cases (n=1943) Condyloma acuminatum Endpoint

56. 56 Time to Detection of HPV 6/11-Related Genital Warts Protocol 020, Per-Protocol Efficacy Population Error bars indicate 95% confidence intervals.

57. 57 Time to Detection of HPV 6/11-Related Genital Warts Protocol 020, Full Analysis Set Error bars indicate 95% confidence intervals.

58. 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. Persistent infection* Endpoint 15 GARDASIL ® Cases (n=1390) 101 Placebo Cases (n=1400) 86 % Efficacy 73, 93 95% CI † <0.001 p-Value Protocol 020, Per-Protocol Efficacy Population

59. 59 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. **DNA detection: Detection of vaccine type HPV DNA in samples from ≥1 visit. n = number of subjects in per-protocol population; CI = confidence interval. Persistent infection* DNA detection** Endpoint 15 136 GARDASIL ® Cases (n=1390) 101 241 Placebo Cases (n=1400) 86 45 % Efficacy 73, 93 32, 56 95% CI † <0.001 p-Value

60. 60 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. 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 1264 1347 n GARDASIL ® 15 4 1 9 1 Cases 1390 1239 1290 1327 n HPV 6/11/16/18 HPV 6 HPV 11 HPV 16 HPV 18 HPV Type

61. 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. 62 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

63. 63 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

64. 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. 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. 66 Immunobridging Was Demonstrated Ratio 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. 00.51 1.522.533.54 GMT Ratio Boys:Men (95% CI) HPV 6 HPV 11 HPV 16 HPV 18 Higher GMT in Boys Higher GMT in Men

67. 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 99.8 % 885 886 883 888 n 99.4, 100 99.2, 100 95% CI 16- to 26-Year-Old Men 98.9 99.2 98.8 97.4 % 1093 1136 1175 n 98.1, 99.4 98.4, 99.6 97.9, 99.3 96.3, 98.2 95% CI

68. 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. 69 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

70. 70 Population for Safety Assessment 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 AAHS placebo, n=2030 Saline placebo, n=275 GARDASIL ®, n=2025 GARDASIL, n=508 GARDASIL, n=564 AAHS = amorphous aluminum hydroxyphosphate sulfate.

71. 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. 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) 2216 1927 1118 527 9 0 0 6 4 n 74 64 37 18 0.3 0 0 0.2 0.1 % 1417 1177 723 338 1 0 0 4 3 n 64 53 33 15 0.0 0 0 0.2 0.1 % Placebo (N=2219) With one or more AE Injection-site AEs † Systemic AEs Vaccine-related systemic AEs With SAEs Vaccine-related SAEs Deaths Discontinued due to AE Discontinued due to a vaccine-related AE Subjects (Days 1-15 Following Any Vaccination)

73. 73 Injection Site AEs Reported by ≥1% of Boys and Men 9-26 Years of Age 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. 1924 1845 500 417 31 26 60 n 64 62 17 14 1 1 2 % GARDASIL ® (N=3002) 1046 991 275 187 24 4 13 n 54 51 14 10 1 0.2 1 % AAHS Placebo (N=1950) 128 112 39 22 3 8 2 n 48 42 15 8 1 3 1 % Saline (N=269) With injection site AE Pain Erythema Swelling Pruritus Bruising Maximum intensity of severe Subjects (Days 1-5 Following Any Vaccination)

74. 74 Systemic AEs Reported by ≥5% of Boys and Men 9-26 Years of Age Protocols 016, 018 and 020 N = number of subjects with follow-up; n = number of subjects in each category. AE = adverse experience. 1118 368 246 128 n 37 12 8 4 % GARDASIL ® (N=3002) 723 249 145 67 n 33 11 7 3 % Placebo (N=2219) With systemic AE Headache Pyrexia Maximum intensity of severe Subjects (Days 1-15 Following Any Vaccination)

75. 75 Safety Profile for Entire Study Period Among 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. 76 Summary of Safety Data in Boys and Men GARDASIL ® was well tolerated in boys and men 9-26 years of 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. 77 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

78. 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. 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. 80 Post-licensure Safety Study in Boys and 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. 81 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

82. 82 Summary of Clinical Trial Results in Boys 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 all populations studied

83. 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