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Prophylactic Quadrivalent Human Papillomavirus (HPV) (Types 6, 11 ...

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  • Thus, the clinical program for the quadrivalent HPV vaccine has focused on evaluating vaccine efficacy against CIN 2/3 or worse. The clinical program has been conducted in 3 phases. Phase I studies in 300 subjects evaluated monovalent HPV vaccines. The Phase II studies expanded to 3500 subjects. The studies included a preliminary evaluation of vaccine efficacy, and a dose-ranging study of the quadrivalent vaccine. Finally, the Phase III studies are ongoing. They are evaluating the impact of the vaccine on rates of CIN 1, genital warts, and most importantly, CIN 2/3 or worse, related to vaccine HPV types.
  • We conducted a large placebo-controlled study of HPV 16 vaccine in 2392 U.S. college women. We designed the study to have an early look at efficacy. We reasoned that such a proof-of-concept would justify the investment in a full scale Phase III program. In addition, each woman was to be followed for 4 years, so that we could also look at long-range impact of the vaccine. The primary endpoint of the study was persistent HPV 16 infection, or HPV 16-related CIN. Persistent infection means detection of HPV 16 virus in swabs of the women’s cervix or vagina on at least 2 consecutive visits. HPV 16-related CIN means a diagnosis of low-grade or high-grade pre-cancer on a tissue specimen obtained from an area of abnormality on the cervix, AND detection of HPV 16 virus in the same lesion. Since we believed that the vaccine was most effective as a preventative agent, we performed our main efficacy evaluation in women who had not been infected with HPV 16 at the time of vaccination. We also enrolled women who were already infected with HPV 16 to see if the vaccine could help clear the infection – but that is a story for another day.
  • We had the first look at efficacy in 2001, when women had been in the study for an average of 2 years. These are the results. A total of 41 women developed a persistent HPV 16 infection, with or without evidence of a cervical pre-cancer (CIN). All 41 cases occurred in the placebo group. Thus, the vaccine had 100% efficacy. The results were highly significant. Of the 41 women with new HPV 16 infections, 9 women had already developed HPV 16-related CIN in the placebo group. Five of these were CIN 1 and four were CIN 2/3 – so you see, women were already developing high grade lesions. The results were published in New England Journal of Medicine – and the accompanying editorial was extremely positive. On the strength of these data, we embarked on the Phase III program. But we didn’t stop the study there. Rather, we wanted to get an early read on long-term efficacy and cancer prevention. Such data would strengthen Merck’s request for priority review of the vaccine at FDA and EU agencies, a status which would shorten our timelines by 6 months. So, the study continued for another 3 years.
  • We conducted a large placebo-controlled study of HPV 16 vaccine in 2392 U.S. college women. We designed the study to have an early look at efficacy. We reasoned that such a proof-of-concept would justify the investment in a full scale Phase III program. In addition, each woman was to be followed for 4 years, so that we could also look at long-range impact of the vaccine. The primary endpoint of the study was persistent HPV 16 infection, or HPV 16-related CIN. Persistent infection means detection of HPV 16 virus in swabs of the women’s cervix or vagina on at least 2 consecutive visits. HPV 16-related CIN means a diagnosis of low-grade or high-grade pre-cancer on a tissue specimen obtained from an area of abnormality on the cervix, AND detection of HPV 16 virus in the same lesion. Since we believed that the vaccine was most effective as a preventative agent, we performed our main efficacy evaluation in women who had not been infected with HPV 16 at the time of vaccination. We also enrolled women who were already infected with HPV 16 to see if the vaccine could help clear the infection – but that is a story for another day.
  • Diagram for Biopsy Thinsectioning.
  • Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination.
  • Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination.
  • Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination.
  • Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination.
  • Last week, we unblinded the study, after a total of 4 years of follow-up. The results are shown here, and they are as exciting as the primary results. The overall efficacy was 94%. For the same endpoint that were used in the first analysis, that is HPV 16 persistent infection or HPV 16-related CIN, the efficacy remained 100%. 26 women developed cervical abnormalities related to HPV 16. Of these 12 developed high-grade pre-cancer, the last stage of cervical abnormality prior to frank cancer. Furthermore, these results show the durability of the vaccine’s efficacy. Now I want to discuss the final line here. This end-of-study analysis differed from the first analysis because it included the last visits in the study. So although our endpoints were persistent infection and CIN related to HPV 16, they also included detection of HPV 16 on the last visit on record without a requirement for detection on 2 visits. Here, there were 19 cases in the placebo group and 7 cases in the vaccine group. Now these cases do not necessarily represent true infection –single time detection of HPV 16 in the cervicovaginal tract is a mixed bag of transient infection, deposition of HPV from an infected partner, or contamination from instruments used in GYN offices. However, since women with HPV 16 detection on the very last visit in the study were not followed for another visit, we couldn’t tell whether they had persistent infection or not. One thing we do know is that none of the 7 vaccine cases had evidence of CIN or pap test abnormalities, suggesting contamination.
  • CIN 2-3 is clinically relevant endpoint. Although long term follow-up is not possible (always treated), presumably will prevent HPV 16 related cancer.

Prophylactic Quadrivalent Human Papillomavirus (HPV) (Types 6, 11 ... Prophylactic Quadrivalent Human Papillomavirus (HPV) (Types 6, 11 ... Presentation Transcript

  • Human Papillomaviruses (HPV): The Background, Current Status and Future of Vaccines to Prevent HPV Infection, Abnormal Genital Lesions and Cervical Cancer
    • Cosette M. Wheeler, PhD
    • Departments of Molecular Genetics & Microbiology
    • And Obstetrics & Gynecology
    • University of New Mexico Health Sciences Center
    • Albuquerque, New Mexico
  • Learning Objectives
    • Identify risk factors for acquiring HPV infection
    • Discuss the causal relationship between HPv and cervical cancer and HPV and genital warts
    • Identify recent clinical findings on HPV vaccines in development
  • Papillomaviruses are small DNA viruses that coevolved with ALL animals HPV Life Cycle HPV Protein Expression Late genes L1&L2 Early Genes E6 & E7 Early Genes E4 & E5 Early Genes E1 & E2 Stratum Corneum Stratum Granulosum Stratum Spinosum Stratum Basale Basement Membrane
  •  
  • Natural history of CC: factors & co-factors
    • HPV genotypes
    • HPV variants
    • Multiple types
    • Viral load
    • Viral integration
    • Early AFSI
    • High NOSP
    • High-risk male partners
    • C. trachomatis
    • HSV-2
    • Sexual behavior
    • Hygiene
    • Condom use
    • Circumcision
    • Immunosuppresion
    • Cervical inflammation
    HPV INFECTION LSIL HSIL INVASIVE CANCER NORMAL
    • Immune surveillance & response
    • Genetic susceptibility
    • Viral factors
    • Smoking
    • Parity
    • OC use
    • HIV
    • Other STIs
  •  
  • Incidence of Cervical HPV Detection in Women From the Time of Onset of Their First Sexual Relationship Collins et al. Brit J Obstet Gynecol 2002;109: 96 to 98 Time since first intercourse (months) 0% 10% 20% 30% 40% 50% 60% 70% 0 6 12 18 24 30 36 42 48 Cervical HPV Detection
  • 10 20 30 40 50 Age in Years HPV 16 or 18 cervical infection CIN Sexual debut Invasive Cervix Cancer Menarche CIS Micro-invasive Cervix Cancer Natural History of HPV 16/18-Related Cervical Neoplasia: Estimated Median Age of Events ASC-US (atypical squamous cells of undetermined significance)
  • Lifetime Risk of HPV Related Disease
    • Genital HPV Infection is the Most Common Viral STI Worldwide
      • Lifetime risk of HPV infection for sexually active males and females ≥ 50% (80%)
    • Estimated lifetime risk of developing genital warts ~ 10% 1, 2
    • Women participating in routine screening
      • abnormal Pap smear:  35%
      • CIN ~ 25%
      • invasive cervical cancer: <1%
    • Women without routine screening
      • invasive cervical cancer: 3 to 4%
    1) 1 Franco, E. L., et al. in : New Developments in Cervical Screening and Prevention , Oxford, Blackwell Science, 1997: 14-22. 2) 2 Tortolero-Luna, G. Hematology and Oncology Clinics of North America , 13 (1), 1999: 245-257.
  •  
  • Prevalence of HPV DNA in over 1,000 cervical cancer biopsies from 22 countries : 99.7% J. Pathol. 189: 12-19, 1999 HPV is a necessary cause of invasive cervical cancer worldwide
  • Colombia The Philippines Brazil Spain Morocco Mali Thailand Paraguay USA Bolivia Chile Argentina Panama Canada Germany Poland Guinea Benin Tanzania Uganda Indonesia Cuba Algeria IARC International prevalence survey of HPV types in cervical cancer
  • Prevalence of HPV types in cervical cancer
    • Any HPV 99.7 %
    • HPV 16 57.4 %
    • HPV 18 16.6 % 81 %
    • HPV 45 6.8 % 89 %
    • HPV 31 4.3 % 96%
    • HPV 33 3.7 %
    • HPV 52 2.5 %
    • HPV 58 2.3 %
    • HPV 35 2.2 %
  • Geographical distribution of HPV types in cervical cancer HPV type 16 18 45 31 33 OTH
  •  
    • A vaccine that prevents HPV16- and 18-related intraepithelial lesions and neoplasms will be a major advance in anogenital cancer control
  • HPV Viral-Like Particle (VLP) Vaccines Schematic of HPV VLP Electron micrograph of VLP HPV Neutralizing Epitopes Are Conformational and Reside in Pentameric (5 x L1) Capsomere Subunits Connected by Invading C-termini Modis Y et al (2002) Atomic Model of the Papillomavirus Capsid. EMBO;21:4754-4762
  • HPV Vaccine Programs Conducted in 3 Phases
    • Phase I in 300 subjects
      • Immunogenicity and tolerability of a range of doses of monovalent HPV L1 VLP vaccines
    • Phase II in 3,500 subjects
      • Immunogenicity/tolerability of a range of HPV L1 VLP vaccine dose formulations
      • Preliminary proof of efficacy
      • Koutsky LA, Ault KA, Wheeler CM, Jansen KU, Barr E, Alvarez FB, Chiacchierini LM. Results from a phase II human papillomavirus virus-like particle vaccine efficacy trial. New England Journal of Medicine. 2002; 347:1646-1651.
      • Diane M Harper, Eduardo L Franco, Cosette Wheeler, Daron G Ferris, David Jenkins et al. Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomized controlled trial. Lancet. 2004;364:1757-65.
      • Villa LL, Costa RLR, Petta CA, Andrade RP, Ault KA, Giuliano AR, Wheeler CM, Koutsky LA et al. A Double-blind, Placebo-controlled Efficacy Trial of a Prophylactic Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) L1 Virus-Like Particle (VLP) Vaccine in Young Women. Lancet Oncology. 2005;6:271-278.
  • HPV Vaccine Programs Conducted in 3 Phases (cont.)
    • Phase III in >20,000 subjects
      • Efficacy of HPV L1 VLP vaccine vs. vaccine type-related
        • CIN 1
        • Genital warts
        • CIN 2/3+
  • HPV L1 VLP Phase III Vaccines
    • Quadrivalent HPV Types 6, 11, 16, 18 L1 VLP vaccine (Gardasil®, Merck Research Laboratories, West Point, PA.) – Phase II and III Reported
    • Di-valent HPV Types 16 and 18 (Cervarix™, GlaxoSmithKline) – Phase II Reported
  • GSK Vaccine Efficacy: Persistent Infection (all samples) Harper DM et al, The Lancet, 2004
  • Summary of HPV-001 Efficacy Data: HPV 16 and/or 18 Cervical Protection Vaccine Efficacy 91% 93% 100% Incident Infection Persistent Infection Cytology Harper et al, The Lancet, 2004 *Analysis of incident/persistent infection and cytology performed in ATP cohort (cervical samples). Analysis of CIN performed in ITT cohort (DNA detected in tissue) 100% CIN
    • GSK efficacy study
      • Global: North America, Latin America, Asia Pacific, Europe
      • N = 18,000 (15-25 year old women)
    • National Cancer Institute (NCI) efficacy study
      • Population-based trial in Guanacaste, Costa Rica
      • Clinical trial management – Allan Hildesheim (NCI PI), Rolando Herrero (Costa Rican PI)
      • N ~12,000 (18-25 year old women)
    • Both trials assessing CIN 2+ endpoints
    GSK Phase III Efficacy Studies
    • Definitive evaluation of the impact of prophylactic HPV vaccination on cervical intraepithelial neoplasia grade 2 and 3 (CIN2/3), squamous cell carcinoma in situ (CIS), adenocarcinoma in situ (AIS) and cervical cancer has been recently reported for Merck quadrivalent HPV 6, 11, 16, and 18 VLP vaccine
  • Merck Quadrivalent HPV (Types 6, 11, 16, 18) L1 VLP Vaccine Dose-Ranging and Phase II Efficacy Study
    • Double-blind, placebo-controlled study
      • In 1106 women aged 16 to 23 (U.S., Brazil, E.U.)
      • Followed for 3 years, 6 month intervals
      • 3 formulations of HPV vaccine or Placebo given at enrollment, Month 2, and Month 6
    * GARDASIL ® formulation 200 80 40 80 80 High 160 40 40 40 40 Med 120 20 40 40 20 *Low 0 0 0 0 0 Pbo Total VLP (  g) HPV 18 VLP (  g) HPV 16 VLP (  g) HPV 11 VLP (  g) HPV 6 VLP (  g) Group
  • Quadrivalent HPV Vaccine Study: Results of Dose-Ranging Phase 10 100 1000 HPV 11 HPV 16 HPV 18 HPV 6 Geometric Mean Titer (mMU/mL) Placebo 40/40/40/40  g 80/80/40/80  g 20/40/40/20  g Levels after Natural Infection
  • Quadrivalent HPV Vaccine Study: Anti-HPV 18 Immunogenicity Over 3.0 Years Serum cLIA GMT, mMU/mL 0 2 3 6 7 12 18 24 30 36 Time (Months) 10 100 1000 10000 Per-Protocol Subjects (Phase III formulation) Baseline Seropositive & PCR Negative Subjects (Placebo Group)
  • Quadrivalent HPV Vaccine Study: Anti-HPV 16 Immunogenicity Over 3.0 Years Serum cLIA GMT, mMU/mL 0 2 3 6 7 12 18 24 30 36 Time (Months) 10 100 1000 10000 Per-Protocol Subjects (Phase III formulation) Baseline Seropositive & PCR Negative Subjects (Placebo Group)
  • Quadrivalent HPV Vaccine Study: Efficacy Evaluation by HPV Type
    • Vaccine cases:
      • HPV 16: 3 cases single positive at the last visit on record
      • HPV 18: 1 case persistent HPV 18 infection
    Per-Protocol Efficacy Cohort Villa et al, Lancet Oncology 2005; 6: 271-78. Vaccine Cases 4 0 0 3 1 Vaccine Efficacy 90% 100% 100% 86% 89% 71-97% 95% Confidence Interval P- Value <10 –3 36 13 3 21 9 Placebo Cases Endpoint HPV 6/11/16/18 Infxn, CIN, or GW HPV 6-related HPV 11-related HPV 16-related HPV 18-related
  • Antibody levels among non-cases vs. single case of persistent HPV 18 infection (vaccine recipients) 0 2 3 6 7 12 18 24 30 36 Time (Months) 10 100 1000 10000 Serum cLIA GMT, mMU/mL Non-Cases for HPV 18 combined Subject A Detection of HPV 18 DNA No evidence that HPV vaccine titers are any different in cases compared to non-cases – No minimum protective antibody level known ____ … ..
  • Phase III Trial of Prophylactic Quadrivalent HPV 6, 11, 16, 18 L1 Virus-Like Particle (VLP) Vaccine - Merck: Prevention of Cervical Intraepithelial Neoplasia (CIN) and External Genital Lesions (EGL) – FUTURE I Prevention of Cervical Intraepithelial Neoplasia (CIN) 2/3 including Adeno- and Squamous-cell Carcinoma in situ (CIS) -FUTURE II General Trial Population Impact
  • FUTURE II Clinical Protocol
    • Randomized, double-blind, placebo-controlled study in 12,167 women aged 16 to 26 enrolled in 13 countries
    • 1:1 randomization to Gardasil™ or placebo
    • ThinPrep™ Pap tests, swabs for HPV DNA taken at Day 1 and Months 7, 12, 24, 36, 48, and sera tested at Day 1 in all subjects
    • Mandatory colposcopy and definitive therapy algorithm based on standard of care
    • All Pap tests and biopsies processed and read at a central laboratory
    • Expert Pathology panel read all slides for endpoint determination
  • FUTURE I and II Trial Primary Disease Endpoints: HPV 6/11-Rleated Extragenital Lesions HPV 16/18-Related CIN 2, CIN 3 (includes CIS), AIS, or Cervical Cancer Prepare Consecutive Sections Cervical Biopsy Fixation, Processing & Paraffin Embedding H&E Staining and Histology 1 2 12 13 No Case Wart/CIN - FUTURE I + CIN 2/3, AIS, Cancer – FUTURE II HPV 6/11/16/18 PCR Positive Case Vaccine Type PCR Negative Extraction of DNA for HPV Multiplex PCR 3 7 5 1 2 5 4 3 6 7 12 9 8 13 11 10
  • Statistical Plan
    • Primary Efficacy Evaluation in Per-Protocol (PP) Population
      • received 3 vaccinations within 1 year
      • no major protocol violations
      • HPV 16/18 sero(-) at Day 1 and HPV 16/18 DNA(-) Day 1 to Month 7
      • Cases counted starting after Month 7
    • Supportive analysis in Modified intention to treat (MITT) population
      • received ≥1 vaccination
      • HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1
      • Cases were counted starting 30 days after Day 1
    • Timing of efficacy analyses
      • Interim analyses when  19 endpoint cases seen in PP population
      • PP population efficacy tested at  =0.0204
      • For the HPV 16/18-related CIN 2, CIN 3 (includes CIS), AIS, or cervical cancer endpoint in the PP population, 97.96% CI reported. All other CIs are 95%.
  • Subject Characteristics FUTURE II 3614 (59.5%) 3613 (59.4%) Using hormonal contraception 2 2 Median Lifetime # of sex partners 16.6 16.6 Mean Age 1 st intercourse among non-virgins (~93.4%) 3941 (65%) 3936 (64%) Europe 89 (2%) 92 (2%) Asia-Pacific 1594 (26%) 1599 (26%) Latin America 456 (7%) 460 (8%) North America Region 15 to 26 15 to 26 Age range (yrs) 19.9 20.0 Mean age (yrs) Placebo (N = 6080) Vaccine (N = 6087)
  • Subject Accounting FUTURE II X 25/36 25/35 No post-Month 7 follow-up (16/18) X 548 443 at or before Month 7 X X 405 397 at Day 1 Sero (+) and/or DNA (+) to HPV 18 X 1,162 1,012 at or before Month 7 X X 964 954 at Day 1 Sero (+) and/or DNA (+) to HPV 16 X 315 275 General protocol violations Reason for exclusion 5,766 5,736 Included in MITT 5,258 5,301 Included in PP 6,075 6,082 Received ≥ 1 Injection MITT PP (N = 6,080) (N = 6,087) Population to which category applies Placebo Vaccine
  • Clinical Serious Adverse Experience (AE) Summary (Days 1 to 15 Following Any Vaccination Visit) *Deaths: one drug overdose and one traffic accident (<0.1) 1 (<0.1) 0 discontinuation due to a serious vaccine-related AE (<0.1) 1 (<0.1) 2 discontinuation due to a serious AE (0) 0 (<0.1) 2 discontinuation due to death* (<0.1) 2 (<0.1) 3 serious vaccine-related AE (0.3) 16 (0.3) 17 serious AE Number (%) of subjects with: 6031 6019 Subjects with follow-up (%) n (%) n Placebo (N=6076) Vaccine (N=6075)
  • Efficacy Results in PP Efficacy – FUTURE II Average 17 Months After Completion of the Vaccination Regimen
      • PP = received 3 vaccinations within 1 year; no major protocol violations; HPV 16/18 sero(-)
      • at Day 1 and HPV 16/18 DNA(-) Day 1 to Month 7; Cases counted starting after Month 7
    CIN 3 includes squamous-cell carcinoma in situ (CIS); AIS = adenocarcinoma in situ (AIS) 1 AIS   15 CIN 3   5 CIN 2 By lesion type (worst diagnosis)- All in the Placebo group   (42– 100) 100 8 4,968 0 5,051 HPV 18-related   (75– 100) 100 16 4,405 0 4,552 HPV 16-related < 0.001 (76– 100) 100 21 5,258 0 5,301 HPV 16/18-related               CIN 2/3 or AIS Cases n Cases n   Endpoint   p-Value   CI   Efficacy (%) Placebo (N=6,075) Vaccine (N=6,082)  
  • Efficacy Results in MITT Population FUTURE II Average 24 Months After the First Vaccination
      • MITT = received ≥1 vaccination; HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1
      • Cases were counted starting 30 days after first vaccination
    Single case of HPV 16-related CIN 2 (Month 24) in vaccine group. HPV 16 DNA detected at Month 7. 4 AIS   23 CIN 3   10 CIN 2 By lesion type (worst diagnosis)   (60– 100) 100 11 5508 0 5,477 HPV 18-related   (78– 100) 96 28 4,957 1 4,944 HPV 16-related < 0.001 (83– 100) 97 36 5,766 1 5,736 HPV 16/18-related               CIN 2/3 or AIS Cases n Cases n   Endpoint   p-Value   CI   Efficacy (%) Placebo (N=6,075) Vaccine (N=6,082)  
  • Efficacy Results in MITT Population FUTURE I Average 26 Months After Completion of the Vaccination Regimen
      • MITT = received ≥1 vaccination; HPV 16/18 sero(-) and HPV 16/18 DNA(-) at Day 1
      • Cases were counted starting 30 days after first vaccination
    • CIN 3 includes squamous-cell carcinoma in situ (CIS); AIS = adenocarcinoma in situ (AIS)
    15%,100%
      • 100
    6 0 HPV 11-related CIN 43%,100% 92 12 1 HPV 6-related CIN P<0.001 87%,100% 97 57 2 HPV6/11/16/18-CIN 49%,100% 92 13 1 HPV 18-related CIN 88%,100% 100 32 0 HPV 16-related CIN Cases Cases   Endpoint   p-Value   CI   Efficacy (%) Placebo (N=2,258) Vaccine (N=2,240)  
  • Efficacy Results in MITT Population FUTURE I Average 26 Months After Completion of the Vaccination Regimen 53%,100% 93 14 1 HPV 11-related EGL 77%,99% 94 34 2 HPV 6-related EGL P<0.001 84%,99% 95 59 3 HPV 6/11/16/18-EGL 30%, 100% 100 7 0 HPV 18-related EGL 70%,100% 100 10 0 HPV 16-related EGL Cases Cases   Endpoint   p-Value   CI   Efficacy (%) Placebo (N=2,258) Vaccine (N=2,240)  
  • General Clinical Trial Population Impact of Gardasil Average 24 Months After the First Vaccination
      • General Population = received ≥1 vaccination; HPV 16/18 sero(+/-) and HPV16/18 DNA(+/-) at Day 1 - Cases were counted starting 30 days after first vaccination – Gardasil ® Trial Population had no more than 4 lifetime sex partners AND an average of only 2
      (35–56) (58-77) 46 69 317 184 8846 8962 170 58 8814 8954 HPV 6,11,16,18-related CIN, CIN 2/3, AIS HPV 6,11,16,18-related genital warts   (30– 88) 69 26 8962 8 8954 VIN 2/3 and VaIN 2/3 (23– 52) 39 201 9896 122 9831 CIN 2/3 or AIS               HPV 16/18 Cases n Cases n   Endpoint     95% CI Reduction (%) Placebo Vaccine  
  • Summary
    • A 3-dose regimen of Gardasil ® was 100% effective in preventing HPV 16/18-related CIN 2/3 and AIS in women who were HPV 16/18-naïve at enrollment and HPV 16/18 DNA(-) through the vaccination regimen
    • Efficacy remained high (97%) in MITT population (received ≥ 1 vaccination; includes protocol violators but which excluded women previously exposed to HPV vaccine types)
    • General trial population impact of Gardasil ® was significantly reduced compared to PP or MITT when women who had already been exposed to HPV vaccine types in the past (sero+) or who were currently infected with vaccine types (HPV DNA PCR+) were included
    • There is no clear evidence that Gardasil® or any other HPV vaccine provides benefit to women who are currently infected or have been infected in the past with HPV vaccine types
    • Administration of Gardasil ® was generally safe and well-tolerated
  • Other Important Take Home Messages I
    • It is critical that vaccinated and un-vaccinated women continue being screened under current early detection guidelines
      • Current first generation HPV vaccines do not protect against over 12 HPV types that cause ~30% of invasive cervical cancer
      • Duration of HPV vaccine immunity is unknown and how and when booster immunizations will be recommended is unknown
    • Public health and policy efforts are needed to ensure access and encourage high HPV vaccine coverage for all racial, ethnic, and socioeconomic groups, and particularly for girls/women of color, immigrants, those living in rural areas, low-income and uninsured women, and others who have limited access to health care services
  • Other Important Take Home Messages II
    • Clinical trials for Gardasil were not conducted in a general population of women (limited inclusion for lifetime sex # of partners and abnormal Pap history) although universal vaccination of women aged 13-26 was recommended
    • It is likely that the reduction in disease in a random general population will be less than that observed in the general Gardasil trial populations – US population average number of sex partners is ~ ≥ 4 for women ages 21-26
    • HPV 16/18
    • CIN 2/3 or AIS 39% (23– 52)
    • VIN 2/3 and VaIN 2/3 69% (30– 88)
    • HPV 6,11,16,18-related CIN, CIN 2/3, AIS 46% (35–56)
    • HPV 6,11,16,18-related genital warts 69% (58-77)
  • Other Important Take Home Messages III
    • In many cases women may be paying for HPV vaccines themselves - The potential benefit diminishes with increasing number of lifetime sexual partners
    • Vaccination of women over age 26 and of males is not currently recommended
    • HPV testing is not recommended prior to vaccination – current tests are not type-specific and even if and when type-specific HPV tests become available, single tests do not accurately measure current infections and CANNOT assess past exposure
  • Some Remaining Questions
    • Given competing health care demands and limited resources, is it rational to vaccinate the general population of women ages 19-26 many who have already been exposed (currently infected ) or whom are presumed immune and who should be attending screening programs ?
    • Will HPV vaccination give a false sense of protection and result in modification of screening behaviors or practices that will undermine the anticipated benefits of HPV vaccines?
    • There are no data to provide evidence for changes in screening of vaccinated women - however will financial constraints or alternate interests drive lengthening of Pap smear screening intervals to allow HPV vaccine expenditures ?
    • As changes in practices continue, will providers implement somewhat costly active screening reminders and pursue missed screens in support of the changing environment and potential problems as we move forward ?
  • Other Key Issues
    • If HPV vaccines are shown effective in men, will they be recommended given cost benefit and benefit to overall disease outcomes appear to be minimal based on modeling if penetration in women is high
    • Will women at greatest risk for this disease be provided to access to HPV vaccines – developing world, impoverished
  • Required Go-Forward Surveillance and Research
    • Ongoing research and surveillance should be conducted in diverse populations, including research on
      • duration of protective immunity,
      • population- and lesion-based changes in type-specific prevalence for the full spectrum of carcinogenic and non-carcinogenic genital HPV types,
      • changes in Pap test performance characteristics,
      • changes in screening practices and behaviors,
      • comprehensive surveillance for reproductive toxicities,
      • increasing vaccine coverage and acceptability, and impact on safe sexual behavior.