Results from a supportive analysis* of two large phase III studies, show that the four-type (6,11,16,18) cervical cancer vaccine Gardasil protected against pre-cancerous cervical lesions (CIN?? 2/3, AIS???) caused by ten other cancer-causing human papillomavirus types, in addition to the virus types directly targeted by the vaccine. The results were presented at the 47th annual ICAAC?§ conference in Chicago, US.1

These are the first publicly communicated results for a cervical cancer vaccine demonstrating the prevention of pre-cancerous cervical lesions due to human papillomavirus types not directly targeted by the vaccine.

"The prevention of pre-cancerous cervical lesions caused by additional virus types demonstrates that Gardasil® can provide cross-protective efficacy and could therefore provide additional protection from cervical cancer caused by these virus types not directly targeted by the vaccine," says Patrick Poirot, Vice-President for Medical and Scientific Affairs at Sanofi Pasteur MSD.

During a mean follow up of three years after the start of vaccination, Gardasil® prevented 38%** of pre-cancerous lesions (CIN2/3, AIS) caused by the ten human papillomavirus types 31/33/35/39/45/51/52/56/58/59. These ten additional virus types cause around 16% of cervical cancer in Europe2 and up to 22% of cervical cancer around the world.3

"There is a clear distinction between the prevention of disease caused by virus types directly targeted by the vaccine and the potential for some level of indirect protection through crossprotection. As expected, cross-protective efficacy is lower than direct efficacy because the additional virus types are different from those directly targeted. The true value of human papillomavirus vaccination remains in direct protection", comments Patrick Poirot.

Gardasil® has demonstrated up to 100% efficacy against pre-cancerous lesions, early cervical lesions, pre-cancerous vulvar lesions and genital warts due to the directly targeted human papillomavirus virus types 6, 11, 16 and 18.?? ?? ,4,5,6 A cross-protective efficacy of 38% against ten additional cancer-causing types is a significant extra benefit".

It is estimated that human papillomavirus-related types 6, 11, 16 and 18 cause 75% of cervical cancer in Europe,10 70% of pre-cancerous13,14 and 50% of potentially precancerous cervical lesions,15 a significant proportion of vulvar and vaginal cancers and their associated precancerous lesions11,12,16,17, and 90% of genital warts.18,19

* In a generally human papillomavirus-na??ve population; further study details see page 2.
??  Cervical Intraepithelial Neoplasia
??? Adenocarcinoma In Situ
?§ Interscience Conference on Antimicrobial Agents and Chemotherapy
** 95% CI [6,60]
?? ??  After complete vaccination with 3 doses, in women aged 15 to 26 years na??ve to the vaccine virus types until 7 months.
?§?§ European Union member states (except Romania and Bulgaria) plus Iceland, Norway & Switzerland

??? Gardasil® provides wider-ranging and earlier benefits than the prevention of cervical cancer alone. Wider benefit because it also helps prevent cervical lesions, vulvar lesions and genital warts; earlier benefit because these lesions, in particular early cervical lesions and genital warts, occur much faster than cervical cancer, often within a few months after exposure to the virus.

The burden of cervical cancer and other human papillomavirus diseases

Despite screening for early detection, cervical cancer remains the second most common cause of death from cancer (after breast cancer) among young women (15-44 years) in Europe?§?§.20 Around 33,500 women are diagnosed with, and 15,000 women die from cervical cancer each year.21

In addition, hundreds of thousands of women are diagnosed with other genital human papillomavirus diseases that start before the occurrence of cervical cancer and can touch other genital organs than the cervix. These diseases include precancerous and low grade cervical lesions13,15,22, vulvar and vaginal cancer11,12,23, precancerous vulvar and vaginal lesions16,17 ,24,25 and genital warts.26

Current EU indication of Gardasil

Gardasil®, human papillomavirus vaccine [types 6,11,16,18] (recombinant, adsorbed), can be given to children and adolescents 9 to15 years and adult females 16 to 26 years of age and is indicated for the prevention of cervical carcinoma (cervical cancer), high grade cervical dysplasia CIN2/3 (precancerous cervical lesions), high grade vulvar dysplastic lesions VIN 2/3 (precancerous vulvar lesions) and external genital warts (condyloma acuminata) caused by human papillomavirus types 6, 11, 16 and 18.

About Sanofi Pasteur MSD

Sanofi Pasteur MSD is a joint venture between sanofi pasteur, the vaccine division of sanofi-aventis, and Merck & Co., Inc. Combining innovation and expertise, Sanofi Pasteur MSD is the only company in Europe dedicated exclusively to vaccines. Sanofi Pasteur MSD is able to draw on the research expertise of sanofi pasteur and Merck & Co., Inc., together with their teams throughout the world, to focus on the development of new vaccines for Europe, which aim to extend protection to other diseases and perfect existing vaccines in order to improve the acceptability, efficacy and tolerability of vaccination.

Clinical study details

Vaccine or placebo was administered at day 1, month 2 and month 6. Subjects were 15 to 26 years aged girls and women. Subjects underwent cervico-vaginal sampling and Pap testing at day 1 of the studies and at 6-12 month intervals for up to month 48. Specimens were human papillomavirus typed with histologic diagnoses via pathology panel. Analyses were conducted in a generally human papillomavirus na??ve population that approximates the primary target for human papillomavirus vaccination cohort. A total of 9,291 subjects, representing 53% of patients of enrolled subjects in FUTURE I/II studies (n=17,622) were generally human papillomavirus na??ve and therefore included in the analyses for diseases. Subjects received =1 dose, were naive to human papillomavirus types 6/11/16/18 and PCR(-) to 10 non-vaccine types (31/33/35/39/45/51/52/56/58/59) and had a normal Pap test at day 1 of the study. Case counting started at day 31.

References

1. Brown D., HPV Type 6/11/16/18 Vaccine: First Analysis Of Cross-Protection Against Persistent Infection, Cervical Intraepithelial Neoplasia (CIN), And Adenocarcinoma In Situ (AIS) Caused By Oncogenic HPV Types In Addition To 16/18; poster presentation G- 1720b, Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 17-19th September, 2007, Chicago.

2. Smith J, Lindsay L, Hoots B et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: A meta-analysis update, Int J Cancer 2007; 121:621-632.

3. Mu?±oz N, Bosch FX, de Sanjos?© S et al., Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med 2003; 348:518-527.

4. The FUTURE II study group. Effect of prophylactic human papillomavirus L1 virus-like-particle vaccine on risk of cervical intraepithelial neoplasia grade 2, grade 3, and adenocarcinoma in situ: a combined analysis of four randomised clinical trials. Lancet 2007;369: 18611868.

5. Garland SM et al. Quadrivalent Vaccine against Human Papillomavirus to Prevent Anogenital Diseases. NEnglJMed 2007:356;19;1928-1943.

6. Joura EA et al. Efficacy of a quadrivalent prophylactic human papillomavirus (types 6, 11, 16, and 18) L1 virus-like-particle vaccine against high-grade vulval and vaginal lesions: a combined analysis of three clinical trials, Lancet 2007;369;1693-1703.

10 . Clifford GM, Smith JS, Plummer M et al. Human Papillomavirus types in invasive cervical cancer worldwide: A meta-analysis. Br J Cancer 2003;88:63-73.

11. Daling JR, Madeleine MM, Schwartz SM et al. A population-based study of squamous cell vaginal cancer: HPV and cofactors. Gynecol Oncol 2002;84:263-270.

12. Madeleine MM, Daling JR, Carter JJ et al. Cofactors with Human Papillomavirus in a population-based study of vulvar cancer. J Natl Cancer Inst 1997;89:1516-1523.

13. Clifford GM, Smith JS, Aguado T et al. Comparison of HPV type distribution in high-grade cervical lesions and cervical cancer: A meta analysis. Br J Cancer 2003;89101-105.

14. Sotlar K, Diemer D, Dethleffs A et al. Detection and typing of Human Papillomavirus by E6 nested multiplex PCR. J Clin Microbiol 2004;42:3176-3184.

15. Clifford GM, Rana RK, Franceschi S et al. Human Papillomavirus genotype distribution in low-grade cervical lesions: Comparison by geographic region and with cervical cancer. Cancer Epidemiol Biomarkers Prev 2005;14:1157-1164.

16. van Beurden M, ten Kate FJW, Smits HL et al. Multifocal intraepithelial neoplasia grade III and multicentric lower genital tract neoplasia is associated with transcriptionally active Human Papillomavirus. Cancer 1995;75:2879-2884.

17. Hording U, Junge J, Poulson H et al. Vulvar intraepithelial neoplasia III: A viral disease of undetermined progressive potential. Gynecol Oncol 1995;56:276-279.

18. Wieland U, Pfister H. papillomaviruses in human pathology: Epidemiology, pathogenesis and oncologic role.In:Gross,Barasso EDS.Human Papillomavirus Infection:A clinical atlas.Ullstein Mosby1997;p1-18.

19. Von Krogh G. Management of anogenital warts (condylomata acuminata). Eur J Dermatol 2001;11:598-603.

20. Ferlay J, Bray F, Pisani P et al, editors. Globocan 2000: Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No.5. version 1.0. IARC Press, Lyon 2001.

21. Ferlay J, Bray F, Pisani P et al, editors. Globocan 2002: Cancer incidence, mortality and prevalence worldwide. IARC Cancer Base No.5. version 2.0. IARC Press, Lyon 2004.

22. Insinga RP, Glass AG and Rush BB. Diagnoses and outcomes in cervical cancer screening: A population-based study. Am J Obstet Gynecol 2004;191:105-113.

23. Parkin DM, Whelan SL, Ferlay J et al. Cancer incidence in five continents (GIS). Volume VIII. p606-611.

24. Dodge JA, Eltabbakh GH, Mount SL et al. Clinical features and risk of recurrence among patients with vaginal intraepithelial neoplasia. Gynecol Oncol 2001;83:363-369.

25. Jones RW. Vulval intraepithelial neoplasia: Current perspectives. Eur J Gynaecol Oncol 2001;22:393-402.

26. UK Health Protection Agency. CDR Weekly 2003;3(44)

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