# Presentation: 151948

## GARDASIL®Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Vaccine

- Vaccines and Related Biological ProductsAdvisory Committee MeetingMay 18, 2006

- Merck Research Laboratories

## GARDASIL® Agenda

- Patrick Brill-Edwards, MD
- Introduction and Overview (5 min)
- Eliav Barr, MD
- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Benefit/Risk Profile

## Proposed Indication

- GARDASIL® is a vaccine indicated for the prevention of cancer, precancerous or dysplastic lesions, genital warts, and infection caused by the HPV types targeted by the vaccine.

## There Is an Unmet Medical Need

- Cervical cancer is caused by the Human Papillomavirus (HPV)
- HPV infection is common
- Lifetime risk of HPV infection – >50%
- In US, lifetime risk for Cervical Intraepithelial Neoplasia (CIN) diagnosis – 25%
- >10% of adults will develop genital warts
- Cervical cancer is the 2nd most common cancer in women worldwide
- ~500,000 new cases and ~290,000 deaths annually
- Despite Pap testing, American women remain at risk for cervical cancer
- 10,370 new cases and 3,710 deaths in 2005

## GARDASIL® Meets the Unmet Need

- Currently no approved vaccine for prevention of cervical cancer
- Therefore VRBPAC in 2001 considered the endpoints for the basis of licensure
- Merck proposed:
- Not feasible to use cancer as endpoint
- Most infections/low grade precancer regress, therefore need to recommend endpoint that links to cancer
- Success of screening programs is due to detection of and definitive therapy for CIN 2/3
- VRBPAC recommendation: CIN 2/3 as basis for licensure

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

- VLPs manufactured in *Saccharomyces cerevisiae* (yeast)
- Given as 0.5-mL i.m. injection at 0, 2, 6 (months)
- Must be stored at 2 to 8C
- Vaccine cannot cause infection or disease

## Structural Model of HPV VLP

- BioengineeredL1 Proteins (5)

- L1 Pentamer

- Self-Assembled Virus-Like Particle

## GARDASIL® Phase III Results

- Comprehensive clinical program
- Randomized, placebo-controlled studies enrolling over 27,000 subjects in 33 countries
- GARDASIL® efficacy:
- Vaccines are most effective when given before exposure to infection
- GARDASIL® is efficacious; it is this high efficacy that is the basis for a Priority Review
- Is immunogenic
- Has an excellent safety profile

## Proposed Indications

- GARDASIL® is a vaccine indicated for the prevention of cancer, precancerous or dysplastic lesions, genital warts, and infection caused by the HPV types targeted by the vaccine.
- GARDASIL® is indicated for the prevention of the following caused by HPV 16 and 18:
- Cervical cancer
- Cervical Adenocarcinoma in situ (AIS)
- Cervical Intraepithelial Neoplasia (CIN) grade 2 and grade 3
- Vulvar and vaginal cancer
- Vulvar Intraepithelial Neoplasia (VIN) grade 2 and grade 3
- Vaginal Intraepithelial Neoplasia (VaIN) grade 2 and grade 3

## Proposed Indications (Cont.)

- GARDASIL® is indicated for the prevention of the following caused by HPV 6, 11, 16, and 18:
- Cervical Intraepithelial Neoplasia (CIN) grade 1
- Genital warts (condyloma acuminata)
- VIN grade 1 and VaIN grade 1
- HPV infection

## Overview

- Cervical cancer is caused by the Human Papillomavirus (HPV)
- GARDASIL® prevents disease caused by the most common HPV types
- GARDASIL® has the potential to meet an unmet medical need as the first vaccine to prevent cervical cancer

## GARDASIL® Consultants

- Laura Koutsky, PhD	University of WashingtonSeattle, WA
- Michael Cunningham, MD	University of WashingtonSeattle, WA
- Mark Stoler, MD	University of Virginia Charlottesville, VA
- Myron Levin, MD	University of Colorado                  Denver, CO
- Janet Wittes, PhD	Statistics Collaborative, Inc. Washington, DC

## GARDASIL® Agenda

- Patrick Brill-Edwards, MD
- Introduction and Overview
- Eliav Barr, MD
- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Benefit/Risk Profile

## GARDASIL® (Merck & Co., Inc.)

- Eliav Barr, MDMerck Research Laboratories

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Benefit/Risk Profile

## HPV Infection Causes Benign and Malignant Epithelial Dysplasia

- HPV is a potent carcinogen
- Cervix
- Vagina, vulva, anal canal
- Penis
- Tonsil, pharynx, larynx
- HPV causes benign tumors
- Low grade cervical, vulvar, vaginal dysplasia
- Genital warts
- Recurrent Respiratory Papillomatosis

## Lifetime Risk of HPV-Related Pathology

*CDC Fact Sheet*, May-2004.Ho et al. *NEJM* 1998.American Cancer Society: *Cancer Facts and Figures* 2005.CIN = Cervical Intraepithelial Neoplasia; AIS = Adenocarcinoma in situ.

## Cervical Cancer

- Every day, 800 women die from cervical cancer worldwide
- 500,000 new cases and 290,000 deaths annually
- Peak in 30s to 50s – peak productivity, family lives
- Two variants, both HPV related
- Squamous cell cancer (~80%)
- Preceded by Cervical Intraepithelial Neoplasia (CIN)
- Adenocarcinoma (~20%)
- Preceded by Adenocarcinoma in situ (AIS)

- World Health Organization. 2003:1-74.American Cancer Society: *Cancer Facts and Figures *2005.

## Cervical Cancer Screening

- In the US, Pap testing has reduced cervical cancer rates by 75%, but at high costs
- 50 Million Pap tests annually to yield...
- 3.5 Million Pap test abnormalities which result in...
- 1.4 Million cases of CIN 1, and
- 330,000 cases of CIN 2/3
- And the total cost is $4 to $6 Billion (per year)
- Despite availability of screening, over 10,000 American women develop cervical cancer annually

- World Health Organization. 2003:1-74.American Cancer Society: *Cancer Facts and Figures* 2005.
- National Cancer Institute Fact Sheet. *The Pap Test: Questions and Answers*.
- Schiffman M, et al. Findings to date from the ALTS. *Arch Pathol Lab Med.* 2003;127: 946-9.
- American Cancer Society: *Cancer Facts and Figures* 2006.

## Vulvar and Vaginal Cancer

- In the US, over 3,500 cases annually
- 40 to 50% of cases are caused by HPV
- Strong associations with cervical cancers and dysplasia
- Incidence of vulvar cancer in the US has increased in women below age 50 due to higher rates of HPV infection

- American Cancer Society. *Cancer Facts and Figures *2005.

## Annual Number of New Casesof HPV-Related Cancers in American Men

- American Cancer Society: *Cancer Facts and Figures *2006*.*
- Kreimer AR, et al. *Canc Epidemiol Biomarkers* *Prev*. 5002;14(2):467-75.
- Ryan DP, et al. *N Engl J Med.* 2000;342:792-800.
- Daling JR, et al. *Int J Cancer.* 2005;116:606-616.

## HPV Infection Causes Genital Warts

- >10% of men and women will be diagnosed with genital warts during their lives
- Clinical manifestations
- Painful, unsightly genital lesions
- Depression, disruption of primary relationship
- Treatment options
- Treated by ablation
- On average, 3 rounds of therapy required
- 30% recurrence

- Munk C, et al. *Sex Transm Dis.* 1997;24(10):567-72.
- Maw RD et al. *Int J STD AIDS.* 1998;9:571-8.
- Conaglen MH et al. *Int J STD* AIDS. 2001;12:651-8.
- Insinga RP et al. *Clin Infect Dis.* 2003;36:1397-403.
- von Krogh G et al. *Sex Transm Inf.* 2000;76:162-8.

## Recurrent Respiratory Papillomatosis (RRP)

- Clinical description
- Warty tumors of the larynx
- Hoarseness, airway obstruction
- Juvenile RRP – 2,300 cases annually (US)
- Typically diagnosed at age 3 to 4
- On average, 4 surgeries per year dueto airway obstruction
- Adult RRP – 3,600 cases annually (US)
- Typically diagnosed in 20’s or 30’s

- Derkay CS et al. *Otolaryngol Clin North Am.* 2000;33(5):1127-41.

- Ref: www.voiceproblems.org

- Ref: www.emedicine.com

## Immunologic Basis for GARDASIL®

- L1 HPV major capsid protein self-assembles into virus-like particles (VLPs)
- In animal models of papillomavirus infection using species-specific VLPs
- Vaccination results in protection from infection/disease
- Neutralizing antibodies induced
- Transfer of sera from vaccinated animals to unvaccinated animals results in transfer of protection

## GARDASIL® Covers the HPV Types Responsible for the Majority of Clinical HPV Disease in the US

- RRP = Recurrent Respiratory Papillomatosis.

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Objectives
- Study Populations
- Consistent study infrastructure
- Clinical Trial Results for GARDASIL®
- Overall Benefit/Risk Profile

## Primary Efficacy ObjectivesClinical Program for GARDASIL®

- Primary endpoints (application for licensure)
- 	Define the magnitude of prophylactic efficacy of GARDASIL® with respect to the incidence of HPV 6/11/16/18-related:
- Cervical cancer
- Vulvar, and vaginal cancers
- CIN, VIN, VaIN
- Genital warts
- Persistent infection
- Supplemental (subsequent filings)
- 	Assess the impact of GARDASIL® on the overall burden of clinical HPV disease

- CIN = Cervical Intraepithelial Neoplasia.AIS = Adenocarcinoma in situ.

- VIN = Vulvar Intraepithelial Neoplasia.VaIN = Vaginal Intraepithelial Neoplasia.

## Natural History of HPV Infection Guides Definition of Cervical Cancer Surrogates

**0 to 1 Year**

**0 to 3 Years**

**Up to 20 Years**

**Initial****HPV Infection**

**Continuing****Infection**

**CIN 2/3 or AIS**

**Cervical Cancer**

**CIN 1**

**Cleared HPV Infection**

**Definitive Efficacy**

## CIN 2/3 and AIS ― Established Surrogate Markers for Cervical Cancer

- CIN 2/3 and AIS ― Established Surrogate Markers for Cervical Cancer

**0 to 1 Year**

**0 to 3 Years**

**Up to 20 Years**

**Initial****HPV Infection**

**CIN 1**

**Cleared HPV Infection**

**Definitive Efficacy**

**Cervical Cancer**

**CIN 2/3 or AIS**

**Continuing****Infection**

## Vulvar and Vaginal Intraepithelial Neoplasia Grade 2/3 (VIN 2/3, VaIN 2/3)

- Natural history of HPV-related vulvar and vaginal cancer closely mimics that of cervical cancer
- Cancer arises from VIN 2/3 or VaIN 2/3 lesions
- In a series of untreated VIN 2/3, 16% progressed to invasive cancer at a mean interval of 3.9 years
- In a series of treated VaIN 2/3, 2% progressed to invasive cancer at a median follow-up of 2 years

- VIN = Vulvar Intraepithelial Neoplasia.VaIN = Vaginal Intraepithelial Neoplasia.

## Primary Immunogenicity andSafety Objectives

- Immunogenicity:
- Bridge efficacy findings in 16- to 26-year-olds to 9- to 15-year-olds
- Define the duration of immune responses to GARDASIL®
- Concomitant administration with Hepatitis B vaccine
- Safety:
- Describe the safety profile of GARDASIL® in all populations for which the vaccine will be indicated
- Describe pregnancy outcomes in subjects who received GARDASIL®

## Studies Conducted in Age Rangesat Risk for HPV Disease

- Insinga RP. *Clin Inf Dis.* 2003;36:1397-1403.

- Incidence of New Genital Warts by Age in US

## Studies Conducted in Age Rangesat Risk for HPV Disease

- Incidence of New Genital Warts by Age in US

**Main Efficacy**

- Age (years)

- Rate of New Genital Warts per 1000 Person-Years

- Insinga RP. *Clin Inf Dis.* 2003;36:1397-1403.

## Studies Conducted in Age Rangesat Risk for HPV Disease

**Adolescent****Bridging**

**Main Efficacy**

- Incidence of New Genital Warts by Age in US

- Insinga RP. *Clin Inf Dis.* 2003;36:1397-1403.

## Consistent Study Infrastructure

- It was anticipated that the efficacy trials would span several years, and that they would be combined to provide higher precision for efficacy
- Consistent study infrastructure:
- Standardized collection of specimens
- Central pathology laboratory for cytology, histology
- Central HPV detection laboratory
- Validated pathology panel (endpoint diagnosis)
- Data and Safety Monitoring Board

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Study Population
- Efficacy and Immunogenicity
- Prophylactic Efficacy (the impact of administration of GARDASIL® to HPV-naïve subjects on the incidence of HPV 6/11/16/18-related disease)
- Population Impact (the impact of administration of GARDASIL® on the overall incidence of HPV disease, regardless of the causal HPV type)
- Bridging Efficacy Findings from Women to Adolescents
- Duration of Efficacy
- Safety
- Overall Benefit/Risk Profile

## Clinical Program in >27,000 SubjectsDiversity to Allow Generalization to Real World

- Ethnicity/region/economic status
- 27,004 subjects
- 33 countries on 5 continents
- Age/gender
- 16- to 26-year-old adolescent and young adult women
- 9- to 15-year-old girls
- 9- to 15-year-old boys
- HPV disease
- Enrollment regardless of baseline HPV status
- Endpoints spanning range of severity
- Cervical, vaginal, vulvar disease
- Patterns of management of Pap test findings

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Study Population
- Efficacy and Immunogenicity
- Prophylactic Efficacy
- Population Impact
- Bridging Efficacy Findings from Women to Adolescents
- Duration of Efficacy
- Safety
- Overall Benefit/Risk Profile

## Phase II/III Efficacy Program

- EGL = External Genital Lesion.

## Phase II/III Efficacy Population

- Percent of Total
- Mean Age (Years)
- Non-Virgin
- Chlamydia (+)
- ASC-US or Worse
- HPV 6,11,16, or 18 (+)†
- Naïve to All 4 Types†

- Day 1 Parameter

- 100%
- 20
- 94%
- 4%
- 12%
- 27%
- 73%

- TotalN=20,887

- 4%
- 21
- 96%
- 3%
- 7%
- 16%
- 84%

- AsiaPacificN=748

- 44%
- 20
- 92%
- 3%
- 11%
- 25%
- 75%

- EuropeN=9181

- 27%
- 21
- 99%
- 7%
- 12%
- 32%
- 68%

- LatinAmericaN=5666

- 25%
- 20
- 93%
- 3%
- 14%
- 25%
- 75%

- NorthAmericaN=5292

- † Evaluated for Protocols 007, 013 and 015 only.ASC-US = Atypical Squamous Cells of Undetermined Significance.

## Principal Efficacy Endpoints

- HPV 16/18-related CIN 2/3 and AIS
- Surrogate for cervical cancer
- HPV 16/18-related VIN 2/3 and VaIN 2/3
- Surrogate for vulvar and vaginal cancer
- HPV 6/11/16/18-related CIN (any grade) and AIS
- HPV 6/11/16/18-related External Genital Lesions (EGLs)

## Defining Disease Endpoints

## Prophylactic Efficacy Populations

- GARDASIL® is intended to be a prophylactic vaccine
- Efficacy trials allowed enrollment of subjects regardless of baseline HPV status
- Subjects already infected with a vaccine HPV type were not eligible for prophylactic efficacy evaluations for that type

## Role of Baseline HPV Status in Endpoint Counting for Prophylactic Efficacy

## Prophylactic Efficacy Population

- Per-Protocol Efficacy (PPE)
- Primary analysis population
- Approximates adolescents or adults who receive a full course of GARDASIL® prior to exposure to vaccine types
- HPV-Naïve Modified Intention-to-Treat (HN-MITT)
- Supportive analyses
- Approximates adolescents or adults who receive ≥1 dose of GARDASIL® prior to exposure to vaccine types

## Prophylactic Efficacy Populations 

- +

- =

- HPV-naïve at Day 1
- Remain free of HPV infection during the course of vaccination
- Had follow-up visits
- No protocol violation
- Received all 3 doses
- Endpoint counting starting after Month 7

**Per-Protocol Efficacy (PPE)****(~87% of Enrolled Subjects)**

- Infected during the course of vaccination
- Protocol violator
- Received <3 doses
- Had no follow-up visits post Month 7
- Endpoints between Month 1 and Month 7

**Additional Subjects****(~8% of Overall Population)**

- Naïve to relevant HPV types at Day 1
- Had follow-up visits
- Case counting starting at Month 1

**HPV-Naïve MITT (HN-MITT)****†****(~95% of Enrolled Subjects)**

- † In Clinical Study Reports, termed MITT-2.

## Timing of Analyses

- Primary efficacy analyses were case driven
- Analyses triggered when a requisite number of endpoint cases were observed in the PPE population of the relevant studies
- After the primary analyses, studies continued
- Efficacy over longer duration of follow-up
- Population impact analyses

- PPE = Per-Protocol Efficacy.

## HPV 16- and 18-Related Cervical Cancer, Vulvar Cancer, and Vaginal Cancer

## HPV 16/18-Related Cervical Cancer Prevention

- Primary endpoint - HPV 16/18-related CIN 2/3 and AIS
- Immediate/obligate precursor to cervical cancer caused by high risk HPV types in GARDASIL®
- Endpoint recommended by VRBPAC
- Primary studies
- Protocol 015 CIN 2/3 efficacy study (N=12,157)
- Combined Efficacy Population to increase precision
- Protocol 005, 007, 013, 015 (N=20,887)

- VRBPAC = Vaccines and Related Biologic Products Advisory Committee.

## HPV 16/18-Related Cervical Cancer Prevention

- Primary Analysis Population
- Per-Protocol Efficacy (PPE) Population
- Statistical criteria for success
- P015: Lower bound of CI>0%
- [005, 007, 013, 015]: Lower Bound of CI>25%
- Supplemental analyses in HPV-Naïve MITT population
- HPV 16/18-related CIN 2/3 and AIS
- HPV 16/18-related CIN 3 and AIS

- CI = Confidence Interval. MITT = Modified Intention-to-Treat.

- Statistical Considerations

## HPV 16/18-Related Cervical Cancer Protocol 015

**Subjects are counted once per applicable row.**
- CI = Confidence interval (for PPE composite endpoint, 97.96% CI – multiplicity adjusted for interim analysis; for remaining rows, 95% CI).
- HN-MITT = HPV-naïve Modified Intention-to-Treat.

## HPV 16/18-Related Cervical Cancer  [Protocols 005, 007, 013, 015]

**Subjects are counted once per applicable row.**
- CI = Confidence interval.
- HN-MITT = HPV-naïve Modified Intention-to-Treat.

## HPV 16/18-Related Cervical Cancer [Protocols 005, 007, 013, 015]

- HPV-Naïve MITT Population

**Subjects are counted once per applicable row.**

## HPV 16/18-Related Vulvar and Vaginal Cancer Prevention

- Immediate precursors for vulvar and vaginal cancer caused by high risk HPV types in GARDASIL®
- VIN 2/3 and VaIN 2/3 are uncommon
- Analyze integrated efficacy trial data set for GARDASIL® (P007, P013, P015)
- P005 (HPV 16 vaccine) did not include detailed genital evaluation, so was not included

- VIN = Vulvar Intraepithelial Neoplasia.
- VaIN = Vaginal Intraepithelial Neoplasia.

## HPV 16/18-Related Vulvar and Vaginal Cancer PreventionStatistical Considerations

- HPV-naïve MITT: Largest prophylactic efficacy population
- Statistical criteria for success
- Prespecified exploratory evaluation

- HPV 16/18-Related Vulvar and Vaginal Cancer PreventionStatistical Considerations

## HPV 16/18-Related Vulvar and Vaginal Cancer in [P007, P013, P015]

- HPV-Naïve MITT Population

## Summary – Cancer Prevention

- Prophylactic administration of GARDASIL® was highly efficacious in preventing
- HPV 16/18-related Cervical Cancer (via CIN 2/3 and AIS)
- HPV 16/18-related Vulvar Cancer (via VIN 2/3)
- HPV 16/18-related Vaginal Cancer (via VaIN 2/3)
- Universal administration of GARDASIL® has the potential to impact 350,000 cases of cervical cancer annually worldwide

## HPV 6-, 11-, 16-, and 18-RelatedCIN (Any Grade) and AIS

## HPV 6/11/16/18-Related CIN or AISPrimary Endpoint

- Primary endpoint - HPV 6/11/16/18-related CIN (any grade), AIS
- HPV 6/11/16/18 cause ~700,000 CIN cases every year in the US
- Primary evaluation in Protocol 013
- Study designed for detection of CIN of any grade
- Supplemental analyses in combined dataset of efficacy trials that evaluated GARDASIL®

## HPV 6/11/16/18-Related CIN (Any Grade) or AIS PreventionStatistical Considerations

- Primary analysis population
- Per-protocol efficacy (PPE) population
- Statistical criteria for success
- P013: Lower bound of CI>20%
- Supplemental analyses in HPV-Naïve MITT population
- Protocol 013
- Combined efficacy studies of GARDASIL® [007, 013, 015]

## HPV 6/11/16/18-Related CINor AIS in Protocol 013

**Subjects are counted once per applicable row.**
- CI = Confidence interval (for PPE composite endpoint, 97.5% CI multiplicity adjusted for 2 primary endpoints; for remaining rows, 95% CI).

## HPV 6/11/16/18-Related CINor AIS in [P007, P013, P015]

**Cases in subjects who received GARDASIL****®**** were CIN 1 detected early****in the follow-up period – not due to waning immunity**

**Subjects are counted once per applicable row.**

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

## HPV 6/11/16/18-Related EGLsPrimary Endpoint

- Primary endpoint - HPV 6/11/16/18-related genital warts, VIN (any grade), VaIN (any grade)
- Overall burden of vulvar and vaginal disease caused by new HPV 6/11/16/18 infections
- Primary evaluation in Protocol 013
- Study designed to focus on EGL detection
- Supplemental analyses in combined efficacy studies for GARDASIL® (Protocol 007, 013, 015)
- Protocol 005 did not systematically evaluate genital lesions

- EGL = External Genital Lesions.
- VIN = Vulvar Intraepithelial Neoplasia.
- VaIN = Vaginal Intraepithelial Neoplasia.

## HPV 6/11/16/18-Related EGL PreventionStatistical Considerations

- Primary analysis population
- Per-protocol efficacy (PPE) population
- Statistical criterion for success
- P013: Lower bound of CI>20%
- Supplemental analyses in HPV-naïve MITT population
- Protocol 013
- Combined efficacy studies of GARDASIL® [007, 013, 015]

## HPV 6/11/16/18-Related EGL Protocol 013

**Subjects are counted once per applicable row.**
- CI = Confidence interval (for composite endpoint, 97.5% CI multiplicity adjusted for 2 primary endpoints; for remaining rows, 95% CI).

## HPV 6/11/16/18-Related EGL[P007, P013, P015]

- HPV 6/11/16/18-Related EGL[P007, P013, P015]

## Other Prophylactic Efficacy Findings

- In subjects who are already infected with one vaccine HPV type, high efficacy in preventing CIN or EGL caused by the remaining 3 vaccine HPV types
- Efficacy uniformly high across
- Ethnic groups
- Sexual behavior patterns
- Co-infection with other common pathogens
- Variations in dosing regimen did not impact efficacy
- Only dosing requirement for inclusion in PPE population was receipt of 3 doses of vaccine/placebo within a 1 year period

## Conclusions – Prophylactic Efficacy

- HPV 16/18-related cervical cancer (via CIN 2/3 and AIS)
- HPV 16/18-related vulvar and vaginal cancer (via VIN 2/3 and VaIN 2/3)
- HPV 6/11/16/18-related CIN (any grade) and AIS
- HPV 6/11/16/18-related EGL

- Prophylactic administration of GARDASIL® to 16- to 26-Year-old women is highly effective in preventing:

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Study Population
- Efficacy and Immunogenicity
- Prophylactic Efficacy
- Population Impact
- Bridging Efficacy Findings from Women to Adolescents
- Duration of Efficacy
- Safety
- Overall Benefit/Risk Profile

## Prophylactic Population Impact Approximating HPV-Naïve Adolescents

- Research question:
- If GARDASIL® is given prior to sexual debut, what is the magnitude of reduction in the overall risk for cervical cancer?
- Overall risk for cervical cancer due to:
- Vaccine HPV types (~70%)
- Non-vaccine HPV types (~30%)
- Requirement to answer this question:
- Efficacy study starting in young adolescents – not feasible
- Modeling the impact in a population of young women that is naïve to HPV types causing ~95% of cervical cancer
- HPV 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59
- Definitive evaluation at end of the Phase III studies (2007)

## Prophylactic Population Impact Preliminary Analysis

- Current (preliminary) evaluation
- Negative to 4 vaccine HPV types
- Unknown status for 10 other HPV types
- Instead: Negative Pap test
- Negative Pap test
- Excludes ~65% of CIN 2/3 and AIS present at Day 1 caused by non-vaccine HPV types
- Unable to exclude subjects infected with non-vaccine HPV types at Day 1 who later develop CIN 2/3 or AIS
- Result – efficacy analysis includes CIN 2/3 or AIS cases in subjects who are HPV-infected at Day 1
- Impacts efficacy findings, especially early in the study

## Prophylactic Population ImpactPartially HPV-Naïve Population

- Efficacy (Truly HPV-Naïve Population)
- (Efficacy for HPV 16/18-related CIN 2/3 and AIS) x (Proportion of overall CIN 2/3 and AIS caused by HPV 16/18)
- Expected Efficacy = 99% x 0.55 = 54.5%
- Efficacy (Partially HPV-Naïve Population) should be lower

- (Protocols 007, 013 and 015)

## Time to Detection of CIN 2/3 or AIS(Regardless of Causal HPV Type) 

- Partially HPV-Naïve Population [P007, P013, P015]

**CIN 2/3 in Subjects Presumably HPV-Infected at Day 1**

**CIN 2/3 in Subjects Presumably HPV-****Naïve at Day 1**

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Study Population
- Efficacy and Immunogenicity
- Prophylactic Efficacy
- Population Impact
- Bridging Efficacy Findings from Women to Adolescents
- Duration of Efficacy
- Safety
- Overall Benefit/Risk Profile

## Bridging Efficacy Results in Adultsto Adolescents

- Studies in sexually-naïve young adolescents are not feasible
- FDA and Merck agreed that efficacy findings in 16- to 26-year-olds can be applied to adolescents using immunogenicity bridging
- Demonstrate that immune responses to GARDASIL® in9- to 15-year-olds are non-inferior to those in 16- to 26-year-olds

## Fold-Difference in Month 7 Anti-HPV GMTs Between Adolescents vs. Adults 

- Protocol 016 Adolescent/Adult Bridging Study

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Overall Study Population
- Efficacy and Immunogenicity
- Prophylactic Efficacy
- Population Impact
- Bridging Efficacy Findings from Women to Adolescents
- Duration of Efficacy
- Safety
- Overall Benefit/Risk Profile

## Immune Correlates of Efficacy

- High prophylactic efficacy
- No documented breakthroughs due to waning immunity
- Precludes defining a minimal protective anti-HPV level

## Persistence of Anti-HPV 16 Immunogenicity HPV 16 Vaccine Efficacy Study (Protocol 005)

## Sentinel Cohort to EvaluateDuration of Efficacy

- The Nordic Region requires reporting of Pap test and biopsy results by national ID number to centralized registries
- In 5498 CIN 2/3 study subjects enrolled in the region, these registries will be used to define long-term duration of efficacy

**Registry-Based Follow-Up**

- 2003

- 2004

- 2005

- 2006

- 2007

- 2008

- 2013

- 2010

- 2011

- 2012

- 2009

**Protocol 015**

**Vaccination**

- Efficacy Reports

- 3 yr

- 5 yr

- 7 yr

- 9 yr

- 2 yr

- 4 yr

- 6 yr

**Launch in US****(Assuming Approval)**

## Efficacy Summary

- Prophylactic administration of GARDASIL® is highly effective in preventing cervical and genital disease caused by HPV 6, 11, 16, and 18
- GARDASIL® reduces overall burden of HPV disease
- Protective efficacy demonstrated for at least 3.5 years Postdose 3 (HPV 16) and at least 2.5 years postdose 3(HPV 6, 11, 18)
- Robust immunogenicity bridging from adults to 16- to 26-year-olds to 9- to 15-year-olds
- Sentinel cohort has been set up to evaluate long-term efficacy well in advance of the general population

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Program Design
- Efficacy and Immunogenicity
- Safety
- General Safety (9- to 26-Year-Olds)
- Pregnancy Outcomes
- Overall Benefit/Risk Profile

## Adverse Experience Reporting

- Non-serious AEs collected Day 1 through Day 15 Post-vaccination on Vaccination Report Card (VRC) in all studies
- Serious AEs collected Day 1 through Day 15 Postvaccination _and_ at any time during the study if the event was:
- Death of a study subject
- Was determined by the investigator to be possibly, probably, or definitely vaccine related
- Was determined by the investigator to be possibly, probably, or definitely related to a study procedure
- Mandatory worksheet completed to ensure no Serious AEs went unreported
- Also collected new medical history at every visit
- Data and Safety Monitoring Board supervision of Phase III studies

## Safety Populations

**All Subjects in All Studies (N=27,004)**

**Monovalent HPV Vaccines or Placebo (N=3464)**

**Quadrivalent HPV Vaccine With Higher VLP or Alum Doses than GARDASIL****®**** (N=552)**

**Quadrivalent HPV Vaccine With Lower VLP Doses than ****GARDASIL****®**** (N=1524)**

**Serious Adverse Experiences**
**Pregnancy Outcomes**
**New Medical History**

_**Safety Population**_** ****GARDASIL****®**** or Placebo (N=21,464)**

_**Detailed Safety Population**_** ****(N=10,224)**

**Vaccination Report Card (VRC) (Nonserious AEs)**

**Protocol 015 Selected Sites **** (N=11,240)**

**Spontaneous Reporting (Nonserious AEs)**

## Summary of SAEs, Deaths, DiscontinuationsSafety Population Days 1 to 15 Following Any Vaccination

-  One subjects who received GARDASIL® reported a serious VR AE beyond Day 15 after vaccination.
-  Seven subjects who received GARDASIL® and 6 subjects in the placebo group died beyond Day 15
-   after vaccination.

## Serious Adverse Experiences Judged to Vaccine-Related in the Safety PopulationDay 1 to 15 Following Any Vaccination

## Overall Adverse Experience (AE) SummaryDetailed Safety Population Days 1 to 15 Following Any Vaccination

## Maximum TemperaturesDetailed Safety Population Days 1 to 5 Following Any Vaccination

- All temperatures were oral or oral equivalent

## Clinical Adverse Experience (AE) SummaryDays 1 to 15 Following Any Vaccination Visit

- Subjects Given GARDASIL®(Detailed Safety Population) by Gender + Age

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Program Design
- Efficacy and Immunogenicity
- Safety
- General Safety (9- to 26-Year-Olds)
- Pregnancy Outcomes
- Overall Benefit/Risk Profile

## Pregnancy Outcomes Reportingin Phase III Studies

- All pregnancies followed for outcome
- Medical history during pregnancy
- Outcomes (mother and child) in neonatal period
- Follow-up in infants until end of study
- Cause of spontaneous abortion
- Reason for elective termination

- 1 Scott JR et al. *Early Pregnancy Loss*. 8th Ed. Philadelphia: 1999:143-53.; Wilcox AJ et al. Time of Implantation of the Conceptus and Loss of Pregnancy. *N Engl J Med.* 1999;340(23):1796-9; Wang X et al. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. *Fertil Steril.* 2003;79(3):577-84.
- 2  Quick Reference: Birth Defects (http://www.marchofdimes.com/printableArticles/14332_1206.asp).

## Pregnancy Outcomes in the Phase III ProgramDatabase as of 11-Nov-2005

## Pregnancy Outcomes in the Phase III Program Database as of 11-Nov-2005

- Fetuses/Infants With Known OutcomesEOP Within 30 Days of a Vaccination   Spontaneous Loss   Elective Termination   Live Birth
- Fetuses/Infants With Known OutcomesEOP Beyond 30 Days of a Vaccination   Spontaneous Loss   Elective Termination   Live Birth

- GARDASIL®

-  112   21   21   70
- 879† 236   93 549

- n

- (18.8)(18.8)(62.5)
- (26.8)(10.6)(62.5)

- (%)

- Placebo

- 115262366
- 898237117544

- n

- (22.6)(20.0)(57.4)
- (26.4)(13.0)(60.6)

- (%)

- † Type of fetal loss not reported for one fetus.

## Pregnancy Outcomes in the Phase III Program Database as of 11-Nov-2005

## Congenital Anomalies in 5 Pregnancies With EOP Within 30 Days of a Vaccination

## Pharmacovigilance Program (Proposed)

- Postlicensure study of 35,000 subjects to evaluate general safety and pregnancy outcomes
- A pregnancy registry to further monitor for pregnancy outcomes in women who receive GARDASIL®
- An evaluation of the long-term safety of GARDASIL® as part of the Nordic Cancer Registry program
- A population-based evaluation of the safety (and effectiveness) of GARDASIL® in Nordic countries planning to implement a mandatory HPV vaccine registry

## Safety Conclusions

- GARDASIL® is generally well tolerated in 9- to 26-year-olds
- GARDASIL® is associated with:
- An increase in injection-site AEs, compared with placebo
- Higher incidence of low-grade fevers, compared with placebo
- Individuals 9 to 26 years of age who receive GARDASIL® rarely discontinue vaccination due to an AE
- GARDASIL® is generally well tolerated in 9- to 26-year-old subjects who are positive to ≥1 vaccine HPV type
- Overall pregnancy outcomes are comparable between women who receive GARDASIL® or placebo
- Large pharmacovigilance monitoring program will be launched at licensure

## Presentation Outline

- Clinical Significance of HPV Disease
- Design of the Clinical Trials Program for GARDASIL®
- Clinical Trial Results for GARDASIL®
- Program Design
- Efficacy and Immunogenicity
- Safety
- Overall
- Special Populations (Children, Baseline HPV infected)
- Pregnancy Outcomes
- Overall Benefit/Risk Profile

## Burden of HPV Infection/Disease in American Men and Women Is High

- ~35,000 cancers annually
- HPV 16 and 18 cause ~25,000 of these cases
- ~1.4 Million CIN lesions annually
- HPV 16 and 18 cause ~530,000 of these cases
- HPV 6 and 11 cause ~175,000 of these cases
- ~1 Million cases of genital warts annually
- HPV 6 and 11 cause ~900,000 of these cases
- ~6,000 cases of RRP annually
- HPV 6 and 11 cause ~5400 of these cases

## GARDASIL® Definitively Shown to Prevent Clinical HPV Disease Due to HPV 6/11/16/18

- Integrated Phase II/Phase III Data Set

## Population Impact and Durationof Follow-Up Being Evaluated

- Population Impact
- Reductions in the overall burden of CIN, CIN 2/3 + AIS, EGL already observed
- Complete analysis to be provided in Spring 2007
- Long-term Duration of Efficacy
- Efficacy through up 3.5 years Postdose 3 shown
- No breakthroughs due to waning immunity
- Sentinel cohorts with follow-up >3 years ahead of general population will evaluate longer-term duration of efficacy
- Similar sentinel cohort set up in adolescents

## GARDASIL® Has a Favorable Safety Profile

- GARDASIL® is generally well tolerated in 9- to 26-year-old subjects
- Individuals 9 to 26 years of age who receive GARDASIL® rarely discontinue vaccination due to an AE
- Overall pregnancy outcomes are comparable between women who receive GARDASIL® or placebo
- Further pharmacovigilance monitoring is planned

## Positive Benefit/Risk Ratio for Vaccination of 9- to 15-Year-Old Boys

- In boys, GARDASIL® was immunogenic and well-tolerated
- Trial to confirm efficacy of GARDASIL® in 16- to 26-year-old men is ongoing and will continue post-licensure
- Strong public health rationale for vaccinating boys:
- Vaccine coverage in girls will be incomplete
- Males transmit HPV to females
- Previous experience with female-only vaccination showed that this approach failed to control female-only morbidity
- Gender-neutral vaccination will result in more rapid and complete reduction in the burden of HPV disease in women
- Propose labeling to allow flexibility in decision about optimal vaccination policy by public health authorities
- Indication to prevent diseases against which efficacy was shown
- Inclusion of all data in girls, women, boys

## Benefit/Risk Profile for GARDASIL®Is Favorable

- Cervical, vulvar, vaginal cancer prevention
- Reduction in the burden of cervical precancers and external genital lesions
- Excellent safety profile
- Large positive public health impact