Learning Objective  To know the results of the clinical trial, immune response and duration, and efficacy analysis for GARDASIL™. 1 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

Clinical Program for GARDASIL™: Selection of Trial End Points 1–3 Necessary criteria Possible End Points HPV* Infection CIN** 1 CIN 2/3 Required precursor for cervical cancer √—√ Prompts treatment——√ Reduction leads to cervical cancer reduction ——√ 1. Pagliusi SR, Aguado T. Vaccine. 2004;23:569– GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 3. Lowy DR, Frazer IH. Chapter 16: Prophylactic human papillomavirus vaccines. J Natl Cancer Inst Monogr. 2003:111–116. CIN 2/3 are World Health Organization (WHO) – recommended surrogate end points for HPV vaccine trials. 1 Surrogate end points are required because it is unethical to wait for the development of cervical cancer. 1,3 2 *HPV = human papillomavirus; **CIN = cervical intraepithelial neoplasia GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

Jan 2003 Jan 2004 Jan 2005 Jan 2009 Jan 2006 Jan 2008 Jan 2007 Jan 2010 Ph III–FUTURE I CIN/EGL* (N=5455) to 24-year-old women Ph II–P007 (N=1158) 2 Dose-ranging 16- to 23-year-old women Yr 5 Immune Memory Evaluation Ph III–P016, P018 (N=4836) Safety/immunogenicity 9- to 15-year-old boys and girls 5,6 Ph III–FUTURE II CIN 2/3 (N=12,167) to 26-year-old women Duration of Efficacy Registry Study Nordic Region Norwegian HPV Surveillance and Disease Burden/Population Effectiveness Study Ph II–P005 (N=2392) 1 Proof of Principle 16- to 23-year-old women Clinical Program for GARDASIL™ *EGL = external genital lesion GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Efficacy in women up to 45 years old Efficacy in 16- to 26-year-old men 1. Koutsky LA, Ault KA, Wheeler CM, et al. N Engl J Med. 2002;347:1645– Villa LL, Costa RLR, Petta CA, et al. Lancet Oncol. 2005;6:271– Garland SM, Hernandez-Avila M, Wheeler CM, et al. New Engl J Med. 2007;356:1928– The FUTURE II Study Group. New Engl J Med. 2007;356:1915– Block SL, Nolan T, Sattler C, et al. Pediatrics. 2006;118(5):2135 – Reisinger K, Block S, Lazcano-Ponce E, et al. Ped Infec Dis. 2007;26(3):201 –

GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Combined Phase II/Phase III Efficacy Studies of GARDASIL ™  20,541 women (16–26 years of age) from the Americas, Europe, and Asia were enrolled in one of four trials. 1  In one trial, subjects were randomized to either a monovalent HPV 16 L1 virus-like particle (VLP) vaccine or placebo. In three trials, subjects were randomized to either quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine or placebo. 1  Vaccine or placebo was administered at day 1 and months 2 and 6. 1  ThinPrep ® Pap smears and swabs for HPV DNA were taken at day 1, month 7, month 12 and in 6- to 12-month intervals thereafter until month 48. 2–3  All Pap tests and biopsies processed/read at a central laboratory. 3  Expert pathology panel read all slides for end-point determination. 3  20,541 women (16–26 years of age) from the Americas, Europe, and Asia were enrolled in one of four trials. 1  In one trial, subjects were randomized to either a monovalent HPV 16 L1 virus-like particle (VLP) vaccine or placebo. In three trials, subjects were randomized to either quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine or placebo. 1  Vaccine or placebo was administered at day 1 and months 2 and 6. 1  ThinPrep ® Pap smears and swabs for HPV DNA were taken at day 1, month 7, month 12 and in 6- to 12-month intervals thereafter until month 48. 2–3  All Pap tests and biopsies processed/read at a central laboratory. 3  Expert pathology panel read all slides for end-point determination GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA. 2. Koutsky LA, Ault KA, Wheeler CM, et al. N Engl J Med. 2002;347:1645– Garland SM, Hernandez-Avila M, Wheeler CM, et al. New Engl J Med. 2007;356:1928–1943.

Gardasil is Efficacious Against HPV 16 and 18-Related Disease *Analysis of CIN 2/3 and AIS end points included protocol 005. PPE Population; subjects were naïve to HPV types 6, 11, 16, and/or 18PPE Population; subjects were naïve to HPV types 6, 11, 16, and/or 18 Related Cases 100% Efficacy 99% Efficacy n=8,492 n=8,462 n=7,771 n=7, GARDASIL Worldwide Product Circular. Merck & Co., Inc., Whitehouse Station, NJ, USA.

Gardasil is Efficacious Against HPV 6/11/16/18-Related Lesions *Genital Warts, VIN 1, VaIN 1. PPE Population; subjects were naïve to HPV types 6, 11, 16, and/or 18PPE Population; subjects were naïve to HPV types 6, 11, 16, and/or 18 Related Cases 99% Efficacy 96% Efficacy n=7,863 n=7,900 n=7,899

GARDASIL ™ Phase III Adolescent Immunogenicity Substudy: Study Rationale and Objective  Rationale 1 – Prophylactic HPV vaccines are most effective when given before population enters risk period for acquisition of infection. 1 – Peak prevalence of HPV occurs among women during their teens and in their 20s. 2 – Young adolescents represent an ideal population for HPV vaccination. 1  Objective – – Determine whether HPV L1 VLP vaccine-induced anti- HPV neutralizing antibody responses in 10- to 15-year- old girls and boys are comparable to responses in 16- to 23-year-old females. 3 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. 1. Schiller JT, Davies P. Nature Rev. 2004;2:343– Schiffman M, Castle PE. N Engl J Med. 2005;353:2101– Block SL, Nolan T, Sattler C, et al. Pediatrics. 2006;118:2135–

Immune Response to GARDASIL™: Neutralizing Anti-HPV GMTs* at Month 7 Females 10–15 Years of Age Males 10–15 Years of Age Females 16–23 Years of Age GMTs in adolescents were statistically noninferior to those in young adult females (P<0.001)** **A P value <0.025 supports a conclusion that the specific type anti-HPV response in 10- to 15-year-old adolescents was noninferior to the response in 16- to 23-year-old females. Block SL, Nolan T, Sattler C, et al. Pediatrics. 2006;118:2135–2145. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. *GMTs = geometric mean titers 10

Per-protocol immunogenicity (PPI) population (ages 9–26)* Neutralizing anti-HPV 6 GMTs at month 7 *Inclusive of five study protocols (all GMTs measured using cLIA); **cLIA = competitive Luminex ® immunoassay Neutralizing Antibodies After Vaccination: Relation to Age at Enrollment 11

Immunologic Persistence With GARDASIL™ One Year Postdose 3* BoysGirlsn % seropositive n Anti-HPV Anti-HPV Anti-HPV Anti-HPV In both boys and girls, GMTs at month 18 were approximately 4- to 7-fold lower than the GMTs observed at month 7. *In the per-protocol population GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Reisinger KS, Block SL, Lazcano-Ponce E, et al. Pediatr Infect Dis J. 2007;26(3):201–209. Seropositive is defined as anti-HPV serum cLIA levels ≥20, 16, 20, 24 mMU/mL for HPV types 6, 11, 16, and 18, respectively. 12

GARDASIL™ (20/40/40/20 μg) Neutralizing Anti-HPV Immunogenicity In a double-blind, placebo-controlled, dose-ranging study of quadrivalent HPV (types 6, 11, 16, 18) L1 VLP vaccine HPV 6 *** HPV 11 *** Time Since Vaccination (Months) ,000 GMT with 95% CI mMU/mL (Log Scale) ** * HPV 18 *** HPV 16 Per-Protocol Subjects (GARDASIL) *Vaccination GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Adapted from Olsson S-E, Villa LL, Costa RLR, et al. Vaccine. 2007;25:4931–

GARDASIL™ Demonstrated Immune Memory Antibodies were built up during the 3-dose vaccination series. When tested by antigen challenge, vaccinated subjects demonstrated classic immune memory—the hallmark of long-term protection. 1 Minimum protective level of antibodies is defined through breakthrough cases. Through five years, there were no breakthrough cases for GARDASIL, while there were continuing infections for placebo Time (months) VVVA Anti-HPV 16 response (GMT levels with 95% CI) Immune memory response was proven by antigen challenge 1 GARDASIL n=78 placebo n=70 12 Time Antigen challenge A Antigen challenge at month 60 Vaccination series for GARDASIL V Vaccination at day 0, month 2, and month 6 Antibody levels stabilized through at least five years… and counting Data on file, MSD. 14 GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA.

HPV 6, 11, 16, or 18-related GARDASILPlacebo NCasesNCasesEfficacy 95% CI PersistentInfection2352* % (83, 100) Disease % (12, 100) CIN 1, 2, or 3 CIN 1, 2, or % (<0, 100) Vulvar/vaginal neoplasias or genital warts % (<0, 100) GARDASIL™: Durable Protection Through Five Years A total of 241 subjects were entered into the five-year extension phase of protocol 007. *One case of confirmed persistent infection: HPV 18 DNA detected at months 12 and 18 only (not a case in the five-year extension). *One case of HPV 16 DNA detected at the last visit (month 36); not a subject in the five-year extension phase. GARDASIL is a trademark of Merck & Co., Inc., Whitehouse Station, NJ, USA. Villa LL, Costa R, Petta R, et al. Br J Cancer. 2006;95:1459–1466. PPE population; subjects were naïve to HPV types 6, 11, 16, and/or 18 15

Registry-Based Follow-Up Vaccination Efficacy Reports 5 years7 years9 years 4 years6 years2 years Follow-Up Through Nordic Registries Provides a Sentinel Cohort 3.5 years FUTURE* II Study *FUTURE = Females United To Unilaterally Reduce Endo/Ectocervical Disease **Multiple countries Launch** 16

Nordic Cancer Registry Extension: Long-Term Efficacy of Vaccination  Nordic European countries have organized mass- screening programs. – Compulsory reporting of Paps, biopsies, CIN/cancer – Registries are sources for prospective studies  Through these registries, we can evaluate: – Duration of effectiveness – Interaction of vaccination with cervical screening programs – Long-term safety  Nordic European countries have organized mass- screening programs. – Compulsory reporting of Paps, biopsies, CIN/cancer – Registries are sources for prospective studies  Through these registries, we can evaluate: – Duration of effectiveness – Interaction of vaccination with cervical screening programs – Long-term safety 17