UPDATE ON NONAVALENT HPV VACCINE KA YU TSE

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1 UPDATE ON NONAVALENT HPV VACCINE KA YU TSE

2 Outline HPV and related diseases HPV vaccines review 9-valent HPV vaccines

3 HPV-RELATED DISEASES

4 What is HPV? Non-enveloped virus containing double-stranded circular DNA Infects keratinocytes of skin and mucous membranes >200 types High-risk (International Agency for Research on Cancer): 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59 Bouvard V et al. Lan Onc 09 Forman D et al. Vaccines 12

5 HPV causes Multiple Diseases in Men and Women Penile Cancer 1,000 3,700 Vulvar & Vaginal Cancer Anal Cancer 1,600 2,800 Anal Cancer H&N Cancer 11,600 2,300 H&N Cancer 23,000 Cervical Cancer Male 329, ,000 Female Genital warts Genital warts Annual new cancers and genital warts related to HPV 6, 11, 16 and/or 18 In Males and Females in Europe Anna Giuliano 20 Sep 2011 Satellite Symposium IPC 2011 (Berlin) 5

6 Diseases in different anatomical location Benign oral lesions Common HPV genotypes Verruca vulgaris (common wart) HPV 1, 2, 4, and 7 Oral squamous cell papilloma HPV 6 and 11 Condyloma acuminata HPV 6 and 11 Focal epithelial hyperplasia (Heck disease) HPV 13 and 32 Recurrent respiratory papillomatosis HPV 6 and 11 Potentially malignant oral disorders Oral lichen planus HPV 6, 11, and 16 Leukoplakia HPV 6, 11, and 16 Erythroplakia HPV 6, 11, and 16 Malignant oral disorders Oropharyngeal squamous cell carcinoma HPV 16 (90%) Oral cavity cancer HPV 16 (96%) Benign anogenital lesions Condyloma acuminata HPV 6 (89%), HPV 11 (11%) Atypical and low-grade squamous cell lesion of the cervix HPV 16 (9%), HPV 6/11 (5%), HPV 31 (4%), HPV 33 (2%), HPV 18 (2%) Premalignant anogenital lesions Cervical high-grade squamous cell lesion HPV 16 (45%), HPV 31 (9%), HPV 33 (7%), HPV 18 (7%), HPV 58 (7%), HPV 52 (5%), HPV 35 (4%) Malignant anogenital lesions Cervical caner (squamous cell, adenocarcinoma, adenosquamous and others) Vaginal cancer HPV 16 (54%), HPV 18 (8%) Vulvar cancer HPV 16 (32%), HPV 18 (4%) Anal cancer HPV 16 (75%), HPV 18 (3%) Penile cancer HPV 16 (60%), HPV 18 (13%), HPV 6/11 (8%) Benign skin lesions Common wart HPV 1 and 2 Flat warts HPV 3 and 10 Potentially malignant skin disorders Epidermodysplasia verruciformis HPV 5 and 8 HPV 16 (61%), HPV 18 (10%), HPV 45 (6%), HPV 31 (4%), HPV 33 (4%), HPV 52 (3%), HPV 35 (2%), HPV 58 (2%) Grce M et al. Clin Dermatol 14

7 CA cervix 99.7% HPV-related 70% due to HPV 16, 18

8 Time Months Years Normal HPV CIN 1 CIN 2 CIN 3 CA Cervix (LSILs) (HSILs) CIN cervical intraepithelial neoplasia 子宮頸癌前病變 LSIL low grade squamous intraepithelial lesion 低度鱗狀細胞上皮內病變 HSIL - high grade squamous intraepithelial lesion 高度鱗狀細胞上皮內病變

9 WHO classification (2014) For all HPV-related cervical, vaginal and vulval lesions: Condyloma and CIN I (VaIN I, VIN 1) = LGSIL CIN II/III (VaIN II/III, VIN II/III) = HGSIL

10 HPV infection (Global) Life time risk >50% A meta-analysis showed 11.7% prevalence of HPV infection in >1million women with normal cervical cytology Prevalence highest in women >25 years Second peak at 45 years in the Americas and Africa Bruni L et al. J Infect Dis 10

11 HPV infection (Hong Kong) Prevalence was 6.7% Peak at years Another smaller peak at years Risk factors: young age, >=4 sexual partners and smoking Chan PK et al. J Med Virol 09

12 CA cervix (Global) Incidence in

13 CA cervix (Global) 4th most common cancer in women in the world 528,000 new patients and 266,000 deaths in 2012

14 CA cervix

15 7 th commonest female cancer in Hong Kong Incidence Mortality Years New cases registered Rank in new female cancer Crude incidence rate* Age standardized rate* Median age at diagnosis Deaths registered Rank in female cancer deaths Crude mortality rate* Age standardized rate* Median age at death NA NA 159 NA NA NA NA 134 NA NA NA NA 144 NA NA > NA NA Hong Kong Cancer Registry 13

16 HPV VACCINES - REVIEW

17 WHAT IS HPV VACCINE?

18 L1 gene isolated Transferred to yeasts by plasmid vector L1 protein assembles to VLP Adsorbed onto adjuvant

19 Vaccines

20 AVAILABLE PROPHYLACTIC HPV VACCINES Bivalent HPV vaccine HPV 16, 18 Quadrivalent HPV vaccine HPV 6, 11, 16, 18 HK indication: >= 9 F HK indication: >=9 F & M Cervical cancer & precancerous Vulvar precancerous Vaginal precancersous 0, 1, 6 months (0, 6 months for 9 14 F) The above table is not a head-to-head comparison because of differences in composition and manufacturers Cervical cancer & precancerous Vulvar precancerous Vaginal precancerous Anal cancer and precancerous Genital warts 0, 2, 6 months (0, 6 months for 9 13 F & M)

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22 De Vincenzo et al. Int J Womens Health 14

23 Efficacy low grade lesions Protection of young women against incident low-grade lesions by the quadrivalent vaccine in FUTURE I and FUTURE II trials % Efficacy (95% CI) References Muñoz N et al. J Natl Cancer Inst 10 Dillner J et al. BMJ 10 ATP / PPE HPV 6/11/16/18 CIN (91.2 to 98.1) HPV 6/11/16/18 VIN1 HPV 6/11/16/18 VAIN1 100 (NA) 100 (NA) ITT / TVC -naïve HPV 6/11/16/18 CIN (93.4 to 99.5) 94.9 (90.8 to 97.1) HPV 6/11/16/18 VIN1 HPV 6/11/16/18 VAIN1 ITT / TVC* } 95.2 (70.0 to 99.9) 89.9 (57.0 to 97.6) 100 (NA) HPV 6/11/16/18 CIN (61.6 to 75.1) 68.8* (61.5 to 74.7) HPV 6/11/16/18 VIN (31.8 to 86.0) } 67.6 (32.3 to 85.9) HPV 6/11/16/18 VAIN (52.0 to 94.2)

24 Efficacy genital warts Protection of young women against HPV6/11-related genital warts by the quadrivalent vaccine in FUTURE I and FUTURE II trials % Efficacy (95% CI) References Muñoz N et al. J Natl Cancer Inst 10 Dillner J et al. BMJ 10 Follow-up periods 3.6 years 4 years ATP / PPE HPV 6/11 genital warts 98.9 (95.7 to 99.7) ITT / TVC -naïve HPV 6/11 genital warts 97.1 ( ) 96.3 (92.8 to 98.1) ITT / TVC* HPV 6/11 genital warts 79.3 ( ) 79.2* (72.7 to 84.2)

25 Efficacy - male 2014 US CDC recommendation

26 Cross protection Quadrivalent: FUTURE I / II Bivalent: PATRICIA, HPV 007 and 02323

27 Persistent infection ( 6 months) 4 yrs 6.4 yrs 9 yrs 4 yrs Cross protection efficacy decreased with increased FU Both vaccines do not prevent HPV 52 and 58 infections Malagón T et al. Lancet Infect Dis 12

28 Cross protection - WHO Bivalent vaccine induces strong neutralizing anti- body responses (>50% seropositivity) to HPV-31, 33, 45 and 52 Quadrivalent vaccine induces neutralizing antibody responses to HPV-31, 33 and 52 Bivalent vaccine appeared to have broader and higher magnitude of serum-neutralizing antibody responses against non-vaccine HPV types Clinical significance and longevity of this crossprotection are unclear WHO position paper : Human Papillomavirus Vaccine 14

29 NONAVALENT HPV VACCINES 1. OVERVIEW 2. EFFICACY AND IMMUNOGENICITY 3. SAFETY 4. COST-EFFECTIVENESS 5. PREVIOUS USE OF HPV VACCINES

30 NONAVALENT HPV VACCINES 1. OVERVIEW

31 Relative Contribution (%) of 9 HPV Types 9 HPV Types (6/11/16/18/31/33/45/52/58) in Cervical Cancer: Consistency Across World Regions Worldwide North America Latin America Europe Africa Asia Oceania (n=8,977) (n=160) (n=3,404) (n=2,058) (n=544) (n=2,641) (n=170) a Chart represents the relative contribution of the 9 HPV types in HPV-positive cervical cancer cases in an international study of 8,977 HPV-positive cases; the dashed-line highlights the worldwide relative contribution of ~90%. Serrano B et al. Infect Agent Cancer. 2012;7:38.

32 WORLDWIDE BURDEN OF HPV DISEASE HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 are 9 of the most common types in HPVrelated cancers and diseases in males and females 1 6 Estimated Type Contribution for Certain HPV-Related Cancer and Disease Cases 4 HPV types cause: (6, 11, 16, and 18) 9 HPV types cause a total of: (6, 11, 16, 18, 31, 33, 45, 52, and 58) Cervical cancer cases 70% 1 90% 1 Vulvar cancer cases a 75% 2 90% 2 Vaginal cancer cases a 65% 3 85% 3 Anal cancer cases a 85% 4 90% 95% 4 High-grade cervical precancers a,b 50% 5 80% 5 Low-grade cervical lesions a 25% 5 50% 5 Genital warts cases 90% 6 90% 6 a Not all cervical precancers and lesions, and vulvar, vaginal, and anal cancer cases are caused by HPV. Approximately 90% of high-grade cervical precancers, 7 75% of low-grade cervical lesions, 7 30% of vulvar cancer cases, 2 70% to 75% of vaginal cancer cases, 3 and 85% to 90% of anal cancer cases 4 are HPV related. b High-grade cervical precancers defined as cervical intraepithelial neoplasia (CIN) 2/3. 1. de Sanjosé S et al. Lancet Oncol. 2010;11: de Sanjosé S et al. Eur J Cancer. 2013;49: Alemany L et al. Eur J Cancer. 2014;50: Alemany L et al. Int J Cancer. 2015;136: Joura EA et al. Cancer Epidemiol Biomarkers Prev. 2014;23: Garland SM et al. J Infect Dis. 2009;199: Guan P et al. Int J Cancer. 2012;131:

33 HPV distribution in cervical cancer in Hong Kong HPV 16,18 = 68% HPV 31, 33, 45, 52, 58 = 23% HPV 16, 18, 31, 33, 45, 52, 58 = 91% (HPV 52, 58 = 16%) Chan PK et al. Int J Cancer 09

34 GARDASIL9 APPROVALS 2 US: 9-26 M&F North America Europe 3 United States 1 Canada 2 Canada: 9-45 F 9-26 M Macau EU: > 9 M&F Hong Kong HK & Macau: > 9 M&F ASIA PACIFIC & JAPAN Australia 4 Hong Kong Macau Australia: 9-45 F 9-15 M 1. FDA approves Gardasil 9 for prevention of certain cancers caused by five additional types of HPV [press release]. Silver Spring, MD: US Food and Drug Administration; December 10, Accessed January 27, CTV News.ca Staff. Health Canada approves new, more potent HPV vaccine. February 17, Accessed March 20,

35 HKPC page 1 HKPC

36 Summary of Completed Clinical Trials Study Population Objective Pivotal Efficacy Study Protocol Women, years Dose-ranging, efficacy, immunogenicity, safety Immunobridging Studies in Adolescents Protocol Girls and boys, 9 15 years; women years Adult-to-adolescent immunobridging Protocol Girls, 9 15 years 4vHPV vaccine-to-9vhpv vaccine immunobridging Immunobridging Studies in Young Adult Men Protocol Men and women, years Male immunogenicity, female-male immunobridging 1. Joura EA et al. N Engl J Med. 2015;372: Van Damme P et al. Pediatrics. 2015;136:e28 e Vesikari T et al. Pediatr Infect Dis J Jun 18 [Epub ahead of print]. doi: /INF Castellsagué X et al. Vaccine Jul 2 [Epub ahead of print]. doi: /j.vaccine

37 Summary of Completed Clinical Trials (continued) Study Population Objective Study in Prior Recipients of 4vHPV Vaccine Protocol Girls and women, years Safety and immunogenicity in prior 4vHPV recipients Concomitant Use Studies a Protocol Girls and boys, years Concomitant use: Menactra b, Adacel c Protocol Girls and boys, years Concomitant use: Repevax d a Menactra, Adacel, and Repevax are registered trademarks of Sanofi Pasteur Inc; b Meningococcal (groups A, C, Y, and W-135) polysaccharide diphtheria toxoid conjugate vaccine 4 ; c Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine adsorbed 5 ; d Diphtheria, tetanus, pertussis (acellular, component), 37and poliomyelitis (inactivated) vaccine (adsorbed, reduced antigen(s) content) Luxembourg A et al. Presented at: 29th International Papillomavirus Conference; August 20 25, 2014; Seattle, WA. 2. Schilling A et al. Pediatrics Aug 3 [Epub ahead of print]. doi: /peds Kosalaraksa P et al. Pediatr Infect Dis J. 2015;34: Menactra [prescribing information]. Swiftwater, PA: Sanofi Pasteur; Adacel [prescribing information]. Swiftwater, PA: Sanofi Pasteur; Repevax [package leaflet] Lyon, France: Sanofi Pasteur; 2012.

38 Some ongoing studies» Long Term Follow-Up (14 years immunogenicity and effectiveness, HPV type replacement)» Adult Women Efficacy Study (27-45 y.o.)» 2-dose Regimen Study (9-14 y.o: 0, 6 months, 0,12 months)» Safety Registry Study (post marketing surveillance, active & passive)

39 NONAVALENT HPV VACCINES 2. EFFICACY AND IMMUNOGENICITY

40 KEY OBJECTIVES OF 9VHPV VACCINE CLINICAL PROGRAM Topic Women (HPV 6/11/16/18) 1 Women (HPV 31/33/45/52/58) 1 Adolescents 2 Men 3 Objective Provide similar level of protection as 4vHPV vaccine against infection / disease due to HPV 6/11/16/18 Provide an increased level of protection as compared with 4vHPV vaccine against disease due to HPV 31/33/45/52/58 Noninferior immunogenicity in adolescents vs young women (immunobridging) Noninferior immunogenicity in young men vs young women (immunobridging) Safety 1-3 Acceptable safety/tolerability profile 1. Joura EA et al. N Engl J Med. 2015;372: Van Damme P et al. Pediatrics. 2015;136:e28 e Castellsagué X et al. Vaccine Jul 2 [Epub ahead of print]. doi: /j.vaccine

41 Efficacy and Immunogencitiy Joura EA et al. NEJM 15

42 PIVOTAL EFFICACY STUDY (PROTOCOL 001) ~14,000 young women (16 26 years) Phase 2b; randomized 1:1 to receive 4vHPV vaccine or 9vHPV vaccine at 0, 2, and 6 months. Followed up to 54 months (end of study) with intensive screening. a Included fixed-event design: primary efficacy analysis performed when at least 30 primary efficacy endpoints b were observed Females years Females years 9vHPV 9vHPV 9vHPV 4vHPV 4vHPV 4vHPV Safety Assessment (all subjects) Follow-up for efficacy Month a Pap test and gynecologic swab (HPV detection) every 6 months during follow-up period (subjects with abnormal Pap tests were to be triaged to colposcopy; b Confirmed cases=subjects in the per-protocol population identified as having a high-grade lesion (as adjudicated by a pathology panel) with detection of at least 1 HPV type 31, 33, 45, 52, or 58 as determined by PCR test results. PCR=polymerase chain reaction.

43 PRIMARY OBJECTIVES TO SUPPORT EFFICACY OF 9VHPV VACCINE COMPARED WITH 4VHPV VACCINE 1 4vHPV Vaccine Demonstrate noninferior immunogenicity (immunobridging as surrogate for efficacy) Demonstrate efficacy vHPV Vaccine 1. Luxembourg A et al. Contemp Clin Trials. 2015;42:18 25.

44 Joura EA et al. NEJM 15

45 Joura EA et al. NEJM 15

46 Joura EA et al. NEJM 15

47 Number of Cases PIVOTAL EFFICACY STUDY (PROTOCOL 001): EFFICACY RESULTS 1 PER-PROTOCOL EFFICACY POPULATION Combined Incidence of HPV 31, 33, 45, 52, or 58 Related Cervical, Vulvar, and Vaginal Disease VE: 97.4% (95% CI: 85.0, 99.9) VE: 97.1% (95% CI: 83.5, 99.9) 4vHPV vaccine (n=7,105) vHPV vaccine (n=7,099) Cervical/Vulvar/Vaginal Disease a CIN 2/3 or AIS VE: 100% (95% CI: 39.4, 100) 7 CIN 3 a Includes CIN 2/3, AIS, cervical cancer, VIN 2/3, VaIN 2/3, vulvar cancer, and vaginal cancer. AIS=adenocarcinoma in situ; CI=confidence interval; CIN=cervical intraepithelial neoplasia; VaIN=vaginal intraepithelial neoplasia; VIN=vulvar intraepithelial neoplasia; VE=vaccine efficacy. 1. GARDASIL 9 [summary of product characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2015.

48 Number of Cases PIVOTAL EFFICACY STUDY (PROTOCOL 001): EFFICACY RESULTS 1 PER-PROTOCOL EFFICACY POPULATION» 9vHPV vaccine was efficacious in the prevention of persistent infection related to HPV types 31, 33, 45, 52, and 58. Incidence of HPV 31, 33, 45, 52, or 58 Related Persistent Infection 1, VE: 96.0% (95% CI: 94.6, 97.1) 946 VE: 96.7% (95% CI: 95.1, 97.9) 657 4vHPV vaccine (n=7,105) 9vHPV vaccine (n=7,099) Month Persistent Infection a Month Persistent Infection a a Detection of the same HPV type in samples collected from 2 or more consecutive visits (for >6-month persistent infection) or from 3 or more consecutive visits (for >12-month persistent infection), with an interval of 6 months (±1 month) between visits. VE=vaccine efficacy. 1. GARDASIL 9 [summary of product characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2015.

49 Number of Cases PIVOTAL EFFICACY STUDY (PROTOCOL 001): EFFICACY RESULTS 1 PER-PROTOCOL EFFICACY POPULATION» 9vHPV vaccine resulted in a reduction in the incidence of HPV 31, 33, 45, 52, and 58 related Pap test abnormalities and cervical procedures. Rates of HPV 31, 33, 45, 52, or 58 Related Pap Test Abnormalities and Cervical Procedures VE: 90.2% (95% CI: 75.0, 96.8) 506 VE: 92.9% (95% CI: 90.2, 95.1) 4vHPV vaccine (n=7,105) 9vHPV vaccine (n=7,099) n=6,014 n=6,013 n=5,882 n=5,883 Cervical Procedures a Pap Abnormalities b a Definitive therapy, loop electrosurgical excision procedure (LEEP) or conization. b Graded ASCUS HR-HPV+ or worse. ASCUS=atypical squamous cells of undetermined significance; CI=confidence interval; HR-HPV=high-risk human papillomavirus; VE=vaccine efficacy. 1. GARDASIL 9 [summary of product characteristics]. Lyon, France: Sanofi Pasteur MSD SNC; 2015.

50 Joura EA et al. NEJM 15

51 Contribution of high risk HPV types covered by the bi- and quadrivalent vaccines and the nonavalent vaccine to cervical cancer and precancerous cervical lesions. The overall contribution of HPV to CIN 1 = 73%, CIN 2 = 86%, CIN 3 = 93%, cervical cancer = 100% Hartwig S et al. Papillomavirus Res 15

52 Geometric Mean Titer (mmu/ml) PIVOTAL EFFICACY STUDY (PROTOCOL 001): IMMUNOGENICITY RESULTS 1 PER-PROTOCOL IMMUNOGENICITY POPULATION Noninferiority criterion a was met for HPV types 6, 11, 16, and 18 for 9vHPV vaccine compared with 4vHPV vaccine in women 16 to 26 years of age. 10,000 GMTs at Month 7 in Women 16 to 26 Years of Age 4vHPV vaccine (n=6,795) 9vHPV vaccine (n=6,792) 1, Anti-HPV 6 Anti-HPV 11 Anti-HPV 16 Anti-HPV 18 a Noninferiority criterion: lower bound of 95% CI of GMT ratio >0.67. CI=confidence interval; GMT=geometric mean titer. Joura EA et al. NEJM 15

53 Efficacy and Immunogencitiy Main beneficial effects in those Uninfected on D1 Related to HPV 31, 33, 45, 52, and 58 Non-inferior to 4-valent in HPV 6, 11, 16, 18 related lesions

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55 NONAVALENT HPV VACCINES 3. SAFETY

56 Percentage of Subjects SAFETY OF 9VHPV VACCINE: RESULTS (ALL STUDIES) Pooled safety of 7 clinical studies (Protocol 001, 002, 003, 005, 006, 007, and 009) girls of 9 to 26 years receinv at lesast 1 dose of 9vHPV vaccine Most injection-site reactions were mild to moderate in intensity. Injection-Site AEs and Vaccine-Related Systemic AEs Reported at a Frequency of 1% Injection Site AEs 1 5 Days Postvaccination (Any Dose) Vaccine-Related Systemic AEs 1 15 Days Postvaccination (Any Dose) Pain Swelling Erythema Pruritus Bruising Headache Pyrexia Nausea Dizziness Fatigue Adverse Events 56

57 Protocol Side effects Events 9vHPV Vaccine qhpv Vaccine (N = 7071) (N = 7078) Participants with one or more adverse events 6640 (93.9) 6419 (90.7) Injection-site event 6414 (90.7) 6012 (84.9) Pain 6356 (89.9) 5910 (83.5) Swelling 2830 (40.0) 2035 (28.8) Erythema 2407 (34.0) 1810 (25.6) Pruritus 388 (5.5) 282 (4.0) Systemic event 3948 (55.8) 3883 (54.9) Vaccine-related event 2086 (29.5) 1929 (27.3) Serious event 233 (3.3) 183 (2.6) Vaccine-related event 2 (0) 2 (0) Discontinuation due to adverse event 8 (0.1) 4 (0.1) Vaccine-related event 5 (0.1) 5 (0.1) Joura EA et al. NEJM 15

58 NONAVALENT HPV VACCINES 4. COST-EFFECTIVENESS

59 IMPACT AND COST-EFFECTIVENESS ANALYSES OF 9VHPV VACCINE IN THE UNITED STATES: METHODS 1 3 different models have been applied to predict the impact and costeffectiveness of 9vHPV vaccination in the United States: HPV-ADVISE model (based on published Canadian model recalibrated to fit US data) 2 Merck model (based on published 4vHPV vaccine model) 3 Simplified model (based on published 4vHPV vaccine model) Chesson HW. Presented at: Advisory Committee on Immunization Practices meeting; February 26, Drolet M et al. Int J Cancer. 2014;134: Elbasha EH, Dasbach EJ. Vaccine. 2010;28: Chesson HW et al. Vaccine. 2011;29:

60 Percent Change in Incidence ESTIMATED EFFECTIVENESS OF 9VHPV VS 4VHPV VACCINE IN THE UNITED STATES: RESULTS FROM HPV-ADVISE 1 GIRLS & BOYS, BASE CASE, NO CROSS-PROTECTION FOR 4VHPV A CIN 2/3 Cervical Cancer 0% -10% -20% -30% -40% 61% 65% -50% -60% -70% 19% 14% -80% -90% -100% Years Since Start of Vaccination a Base case: vaccine-type efficacy=95%, duration=lifelong. Predictions: Mean estimate generated by the 50 best fitting parameter sets. CIN=cervical intraepithelial neoplasia. 1. Chesson HW. Presented at: Advisory Committee on Immunization Practices meeting; February 26, vHPV Vaccine Girls & Boys (no cross-protection) 9vHPV Vaccine Girls & Boys

61 COST-EFFECTIVENESS ANALYSES OF 9VHPV VACCINE: SUMMARY OF RESULTS BY METHOD 1,2 9VHPV (M&F) VS 4VHPV (M&F) Compared with 4vHPV vaccine, primary vaccination with 9vHPV vaccine for males and females is likely to be cost-saving. These results are consistent across and within various models. Cost per QALY < $0 in most scenarios (< $25,000 in all sensitivity analyses) Model Incremental Cost Per QALY Gained a No 4vHPV Cross-Protection With 4vHPV Cross-Protection HPV-ADVISE < $0 (cost-saving) < $0 (cost-saving) MERCK < $0 (cost-saving) Not reported SIMPLIFIED < $0 (cost-saving) $8,100 a HPV-ADVISE results are in 2010 US dollars. Merck model and simplified model are in 2013 US dollars. M=male; F=female; QALY=quality-adjusted life year. 1. Chesson HW. Presented at: Advisory Committee on Immunization Practices meeting; February 26, Petrosky E, et al. Centers for Disease Control and Prevention (CDC). MMWR. 2015;64(11):

62 NONAVALENT HPV VACCINES 5. PREVIOUS USE OF HPV VACCINES

63 PRIOR RECIPIENTS OF 4VHPV (PROTOCOL 006): STUDY DESIGN Safety/tolerability endpoints: injection site and systemic AEs from day 1 to 15 following any vaccination, and SAEs from day 1 through month 7 (1 month after the last vaccination), and death and vaccine-related SAEs throughout the study Immunogenicity endpoint: anti-hpv 6, 11, 16, 18, 31, 33, 45, 52, 58 GMTs at day 1, month 2, and month 7 Immunogenicity Assessment Prior 4vHPV vaccination (All 3 doses administered within 1 year) Girls and women years (n=618) Girls and women years (n=306) 9vHPV Placebo 9vHPV Placebo 9vHPV Placebo 12 months (Time interval between 4vHPV dose 3 and 9vHPV dose 1) Month Safety Assessment AE=adverse event; GMT=geometric mean titer; SAE=serious adverse event Garland SM, et al. Vaccine. 2015

64 Geometric Mean Titers (mmu/ml) PRIOR RECIPIENTS OF 4VHPV (PROTOCOL 006): IMMUNOGENICITY RESULTS BY TIMEPOINT GMTs at Day 1, Month 2, and Month 7 Postvaccination With 9vHPV Vaccine in Prior 4vHPV Vaccine Recipients a (N=615) 100,000 10,000 1,000 Immune memory response Immunogenic Day 1 Month 2 Month HPV Type a For HPV types 33, 45, 52 and 58 day 1 GMTs shown above are the maximum value(s) that correspond to those reported as less than by Garland et al. (e.g. <3 graphed as 3) and may make baseline GMTs appear higher than the actual values due to the nature of a log scale Garland SM, et al. Vaccine. 2015

65 PRIOR RECIPIENTS OF 4VHPV (PROTOCOL 006): SEROPOSITIVITY RESULTS Summary of Anti-HPV clia Seropositivity Rates at Month 7 n Prior 4vHPV Vaccine Recipients 9vHPV Vaccine (N=615) Seropositivity (%) n Placebo (N=306) Seropositivity (%) Assay Anti-HPV Anti-HPV Anti-HPV Anti-HPV Anti-HPV Anti-HPV Anti-HPV Anti-HPV Anti-HPV clia=competitive Luminex immunoassay Garland SM, et al. Vaccine. 2015

66 PRIOR RECIPIENTS OF 4VHPV (PROTOCOL 006): SAFETY RESULTS (OVERVIEW) GIRLS AND WOMEN 12 TO 26 YEARS OF AGE Adverse Event 9vHPV Vaccine (N=608) Placebo (N=305) % (n) % (n) Injection-site 91.1 (554) 43.9 (134) Systemic event 59.7 (363) 55.7 (170) Vaccine-related a systemic event 30.6 (186) 25.9 (79) Serious event 0.5 (3) 1.0 (3) Vaccine-related a serious event 0.2 (1) 0.3 (1) Discontinued due to a vaccine-related a AE 0.5 (3) 0.0 (0) a Determined by the investigator to be possibly, probably, or definitely related to the vaccine. AE=adverse event. Garland SM, et al. Vaccine. 2015

67 If already completed 2/4-valent HPV vaccine. The European Medicines Agency summary of product characteristics Individuals who received a first dose with a given HPV vaccine should complete the vaccination course with that same vaccine. EMA. Cervarix European public assessment report. EMA; 08 EMA. Gardasil European public assessment report. EMA; 08. EMA. Gardasil 9. European public assessment report. EMA; 15 The US Advisory Committee on Immunization Practices (ACIP) Any available HPV vaccine product may be used to continue or complete the series for females for protection against HPV 16 and 18 Petrosky E et al. MMWR Morb Mortal Wkly Rep 15 National Center for Immunization and Respiratory Diseases C 15

68 If already completed 2/4-valent HPV vaccine. Parameters need to be considered: age at the start of vaccination (9-14 years Vs >15 years) the number of doses already received the time interval between doses Van Damme P et al. Vaccine 2016

69 Girls 9-14 years old Van Damme P et al. Vaccine 2016

70 If already completed 2/4-valent HPV vaccine. In girls >15 years of age whose initial series was given before 15 years Revaccination should be considered 3 doses 9vHPV vaccine in M0, 2 and 6 months Van Damme P et al. Vaccine 2016

71 AVAILABLE PROPHYLACTIC HPV VACCINES 2v HPV vaccine HPV 16, 18 HK indication: >= 9 F Cervical cancer & precancerous Vulvar precancerous Vaginal precancersous 0, 1, 6 months (0, 6 months for 9 14 F) 4v HPV vaccine HPV 6, 11, 16, 18 HK indication: >=9 F & M Cervical cancer & precancerous Vulvar precancerous Vaginal precancerous Anal cancer and precancerous Genital warts 0, 2, 6 months (0, 6 months for 9 13 F & M) 9v HPV vaccine HPV 6, 11, 16, 18, 31, 33, 45, 52, 58 HK indication: >=9 F & M Cervical cancer & precancerous Vulvar precancerous Vaginal precancerous Anal cancer and precancerous Genital warts 0, 2, 6 months (2-dose only approved in EU for 9-14 F & M; not in HK)

72 Conclusion Efficacious in girls years in the prevention of cervical, vulvar, and vaginal disease and persistent infection related to HPV types 31, 33, 45, 52, and 58. Noninferior immune responses compared with 4vHPV vaccine Effectiveness of 9vHPV vaccine against HPV types 6, 11, 16, and 18 related diseases can be inferred in 16- to 26-year-old girls Tolerable side effects Favourable cost-effectiveness profile