The product information of the four-type (6,11,16,18) human papillomavirus (HPV) vaccine Gardasil® has been updated to include cross-protective efficacy in preventing precancerous cervical lesions (CIN2/3 and AISiii) due to additional cancercausing HPV types related to HPV type 16.1

Statistically significant efficacy against disease was demonstrated against HPV 31 which is the second most common HPV type in Europe in causing precancerous cervical lesions, after type 16. It is also the fourth most common cervical cancer-causing HPV type in Europe, after HPV 16 and 18, and HPV 33.2

Gardasil® is the first and only HPV vaccine to have a cross-protective effect added to its product information under pharmacodynamic propertiesv and to have demonstrated this effect in clinical studies through preventing precancerous cervical lesions, the immediate precursor of cervical cancer.

"We investigated cross-protection through the prevention of precancerous cervical lesions - as we did with direct protection against vaccine-virus types and as recommended by the World Health Organisation (WHO) and the U.S. Food and Drug Administration (FDA) to demonstrate cervical cancer protection. The updated product information confirms our approach," says Dr.Patrick Poirot, Sanofi Pasteur MSD's vice-president for Medical and Scientific Affairs.

After up to four years of follow-up, efficacy for prevention of precancerous cervical lesions (CIN 2/3 or AIS)vi - in a combined endpoint that included the ten additional cancer-causing HPV types 31, 33, 35, 39, 45, 51, 52, 56, 58 and 59 - was 23%vii; efficacy for type 31 was 56% (95% CI [26.2,74.1]).

The new product information also includes the prevention of precancerous vaginal lesions (VaIN2/3ix) due to HPV types 16 and 18 which cause 90% of HPV-related vaginal cancer.3,4,x

"Precancerous vaginal lesions are difficult to detect. The treatment to avoid possible progression to cancer is challenging and often requires ablative therapy, partial vaginectomy and radiotherapy in case of invasive cancer. Recurrence is common," explains Elmar Joura, Professor of Gynae-Oncology at the University of Vienna. "In addition, women may suffer from anxiety, depression, sexual dysfunction and poor self-image."

Data5,6 from large phase II/III clinical studies confirmed sustained efficacy of 100%xi of Gardasil® against vaccine virus type-related precancerous vulvar (VIN2/3ix) and vaginal lesions.

Patrick Poirot adds: "As direct protection is the primary objective of HPV vaccination, our development focused on the demonstration of direct efficacy against precancerous cervical, vulvar and vaginal lesions and genital warts caused by the four HPV types directly targeted by the vaccine. And the impressive global endorsement of Gardasil®'s sustained high efficacy and unique profile proves us right. We are pleased to see that now, even the additional benefits that Gardasil®'s cross-protective effect could bring to women's health, are being recognised."

Global endorsement of Gardasil®'s efficacy and safety profile

Regulatory and health authorities across the world have endorsed Gardasil®'s high efficacy and good safety profile as demonstrated in clinical studies that were conducted during more than a decade including more than 25,000 women in 33 countries and as observed with extensive practical use during the past two years. Gardasil® has been approved in 104 and launched in 76 countries since June 2006. More than 30 million doses have been distributed worldwide by the end of June 2008.

The burden of cervical cancer and other HPV-related genital 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.7 Around 37,800 women are diagnosed with cervical cancer and about 17,000 women die from this disease each year.8 That equates to 47 women a day - or one every half-hour - dying from invasive cervical cancer.

It is estimated that the HPV types 6, 11, 16 and 18 contained in Gardasil® are together responsible for 75% of cervical cancers9, up to 70% of pre-cancerous (CIN 2/3) cervical lesions11,12, 50% of potentially precancerous lesions (CIN 1)13, a significant proportion of vulvar and vaginal cancers and their associated pre-cancerous lesions3,10,14,15, and 90% of genital warts in Europe17,18.1011,1213 9,14,15,1617,18

Indication of Gardasil®

Gardasil® is a vaccine for the prevention of premalignant genital lesions (cervical, vulvar and vaginal), cervical cancer and external genital warts (condyloma acuminata) causally related to Human Papillomavirus (HPV) types 6, 11, 16 and 18 (see section 5.1).

The indication is based on the demonstration of efficacy of Gardasil® in adult females 16 to 26 years of age and on the demonstration of immunogenicity of Gardasil® in 9- to 15-year old children and adolescents. Protective efficacy has not been evaluated in males (see section 5.1). The use of Gardasil® should be in accordance with official recommendations.

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.

i Gardasil® (Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed))
iii CIN = Cervical Intraepithelial Neoplasia grades 2 and 3; AIS = Adenocarcinoma in Situ
v Results have been included in the 5.1 section (pharmacodynamics properties) of the Summary of Product Characteristics (SPC).
vi Women not exposed to the respective individual type before and who had received at least one dose of Gardasil or placebo; case counting started at day 31 after the first dose. n (Gardasil) = 8427/8461, n (Placebo) = 8468/8508 depending on endpoint.
vii 95% CI [5.1,31.7]. Overall, efficacy was mainly driven by efficacy against HPV type 31 and less so by efficacy against other types. Studies were not powered to look at individual efficacy against HPV types not directly targeted by the vaccine
ix VaIN = Vaginal Intraepithelial Neoplasia grades 2 and 3; VIN = Vulvar Intraepithelial Neoplasia grades 2 and 3
x In the Therapeutic Indication (section 4.1 section) of the Summary of Product Characteristics (SPC).
xi 95% CI [82.6,100], in women (16-26) years not infected with types 6/11/16/18 and randomised to receive either Gardasil® (n =7,900) or placebo (n = 7,902) at day 1, and month 2 and 6 and were followed for up to 4 years after the start of vaccination.

References

1. Gardasil®, Summary of Product Characteristics (SPC), September 2008

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

3. 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.

4. Nascimento C et al. HPV prevalence and type distribution in carninomas and intraepithelial neoplasia lesions of the vulva and vagina, the first in a series of meta-analysis in anogenital sites other than cervix. Abstract presented at the 24th International Papillomavirus Conference and Clinical Workshop (IPCCW).Beijing, China, November 3-9, 2007.

5. 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 The Lancet 2007;369:1693- 1702

6. Lacey CJN, et al. Continued efficacy of quadrivalent HPV (types 6/11/16/18) L1 VLP Vaccine in preventing cervical or external genital disease: 4 years of follow up. Poster presentation at the 20th European Congress of Ostetrics and Gynaecology (EBCOG), 4-8 March, 2008, Lisbon, Portugal.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. Nascimento C et al. HPV prevalence and type distribution in carninomas and intraepithelial neoplasia lesions of the vulva and vagina, the first in a series of meta-analysis in anogenital sites other than cervix. Abstract presented at the 24th InternationalPapillomavirus Conference and Clinical Workshop (IPCCW).Beijing, China, November 3-9, 2007.

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

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

Sanofi Pasteur MSD is the only European company dedicated exclusively to vaccines

Sanofi Pasteur MSD