- In the Prevention of Cervical Cancer and Other Human
Papillomavirus Related Diseases After an Additional Year of Follow
Up in Large Phase III Clinical Studies Which Included More Than
New England Journal of Medicine publishes the most comprehensive and robust clinical data for any Human Papillomavirus vaccine
LYON, France, 10th May2007 – New clinical study results
confirm the high and sustained efficacy of Gardasil® in the
prevention of cervical cancer and other Human Papillomavirus
related diseases that occur before cervical cancer and beyond the
cervix. After three years of follow up in the large phase III
clinical studies FUTURE I and II, which included more than
17,000 women, Gardasil® prevented 98% to 100% of pre-cancerous
and potentially pre-cancerous cervical lesions (CIN 1-3),
pre-cancerous and potentially pre-cancerous vulvar and vaginal
lesions (VaIN 1-3 and VIN 1-3), and genital warts caused by Human
Papillomavirus types 6, 11, 16 and 18. The results were published
today in the New England Journal of Medicine (NEJM). ,
The new three years results substantiate previous phase III results which demonstrated up to 100% efficacy against the same diseases after two years of follow up and on which the licensure of Gardasil® was essentially based. The results also add to other recently presented three years phase III data. The currently available phase III results for Gardasil® are the most comprehensive and robust clinical data presented for any Human Papillomavirus vaccine. Previously presented data from a phase II study had shown Gardasil® to be 100% efficacious against cervical lesions and genital warts after five years of follow up post-enrolment. ,a)
"The efficacy results on which the licensure of Gardasil® was based, were already excellent and very reliable. The new data clearly demonstrate that this high efficacy is likely to persist for a long time. The gap in development of disease between women in the placebo and those in the vaccine group continued to widen over the three years. This means that the precision of the data continued to increase; even more young women than initially thought could benefit from Gardasil®," comments Professor Margaret Stanley of the University of Cambridge, UK.
The virus types 6, 11, 16 and 18 directly targeted by Gardasil® cause the vast majority of genital Human Papillomavirus diseases. It is estimated that among Human Papillomavirus diseases in Europe, they cause 75% of cervical cancer, 95% of vulvar and vaginal cancers, , 70% of pre-cancerous (CIN2/3) , and 50% of potentially pre-cancerous cervical lesions (CIN1) , 80% of pre-cancerous vulvar (VIN2/3) and vaginal lesions (VaIN2/3)5,6, , , and 90% of genital warts. ,
In FUTURE I, after three years of follow up, Gardasil® prevented 100% of Human Papillomavirus types 6-, 11-, 16- and 18-related pre-cancerous and potentially pre-cancerous cervical lesions (CIN1-3); there was no case observed in the vaccine group compared to 65 cases in the placebo group. Gardasil® prevented also 100% of types 6-, 11-, 16- and 18-related pre-cancerous and potentially pre-cancerous vulvar and vaginal lesions (VIN1-3 and VaIN1-3) and genital warts; no case was observed in the vaccine group compared to 60 cases in the placebo group.b)
In FUTURE* II, after three years of follow up, Gardasil® prevented 98% of pre-cancerous cervical lesions (CIN†2/3) associated with Human Papillomavirus types 16 and 18; one case of CIN3 was observed in the vaccine group compared to 42 cases in the placebo group. b) In a combined analysis, including almost 17,000 women and recently presented at the 5th International Conference on Cervical Cancer (ICCC) in Venice, Gardasil® prevented 99% of pre-cancerous cervical lesions (CIN†2/3) associated with Human Papillomavirus types 16 and 18; 85 cases were obse rved in the placebo group compared to the one case of CIN3 observed in the vaccine group. ,c)
The one case of CIN3 in the vaccine group of FUTURE II involved a woman who had an infection with Human Papillomavirus type 52 at baseline and at five follow-up visits. Type16 was detected in only one of these visits suggesting that this case could have been type 52-related. To be conservative, this case was nevertheless included in the group that received the vaccine.
CIN2/3 is the obligate precursor of cervical cancer and the clinically most relevant endpoint for the US Food and Drug Administration (FDA) and the World Health Organization (WHO) to demonstrate efficacy in the prevention of cervical cancer.
In both studies, Gardasil® was generally well tolerated. The adverse events observed were similar to what has been previously reported.
Notes to editors
High efficacy has already led to vaccination of women in the
In light of the high efficacy shown by Gardasil® at licensure, the Data and Safety Monitoring Board of FUTURE I and II had recommended that women in the placebo group should be vaccinated with Gardasil®. The board recommended that the studies should be terminated as soon as feasible in order to provide the benefits of vaccination with Gardasil® to these women rapidly. In Europe, vaccination of women in the placebo groups of FUTURE I and II has already begun in the United Kingdom, Germany, Sweden, Norway, Denmark, Finland and Austria. In other countries, vaccination will start soon with the objective to complete vaccination before the end of the year 2007. In a similar way, vaccination of women in many other countries around the world, including the US, Australia and Canada, has begun or is anticipated to begin soon.
Protection against additional virus types through cross
In large phase III clinical stu dies, including more than 17,000 womenb),c), Gardasil® provided benefits against pre-cancerous (CIN2/3) and potentially pre-cancerous cervical lesions (CIN1) caused by additional virus types not directly targeted by the vaccine. The additional virus types cause more than 10% of cervical cancer and substantial proportions of pre-cancerous and potentially pre-cancerous cervical lesions. The data have recently been submitted to the European Medicines Agency (EMEA) and the US Food and Drug Administration in order to update the marketing authorisation for Gardasil®.
The burden of cervical cancer and other Human Papillomavirus
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 . Around 33,500 women are diagnosed with, and 15,000 women die from cervical cancer each year (the equivalent of 40 women per day or nearly 2 per hour).
In addition, hundreds of thousands of women are diagnosed with other Human Papillomavirus diseases that start before cervical cancer and go beyond the cervix. These diseases include pre-cancerous and potentially pre-cancerous cervical lesions7,9, , vulvar and vaginal cancer5,6, , pre-cancerous vulvar and vaginal lesions10,11, , and genital warts.
Cervical cancer is caused by Human Papillomavirus. , The virus is very common, with 70% of sexually active people estimated to become exposed at some point in life. , , Genital infections with Human Papillomavirus are very common with the majority of infections occurring in adolescence or early adulthood. ,
EU indication of Gardasil®
According to the licence in the EU, 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 (cervic al 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.
Worldwide availability of Gardasil®
Gardasil® has been developed by Merck & Co., Inc. and Sanofi Pasteur MSD. In Europe, the vaccine is marketed by Sanofi Pasteur MSD.
Gardasil® has been approved in 70 countries (many under accelerated review timelines), including the EU, the US, Canada and Australia and has met with very broad acceptance. Additional applications are currently under review with regulatory agencies in many more countries around the world.
The EU licensed Gardasil® within just 9 months compared to a usual review time of 13-15 months. After gaining the license in September 2006 Sanofi Pasteur MSD has made Gardasil® available in 18 European countries.
Merck is actively working to accelerate the availability of Gardasil® in the developing world. Clinical trials for the development of Gardasil® have already included participants from 33 countries on 5 continents in a variety of settings. Clinical studies in developing world countries are being initiated to assess the efficacy of Gardasil® in other environments. Merck will donate free vaccine to the non-profit organisation PATH to support demonstration studies to accelerate the availability of Human Papillomavirus vaccines in the most impoverished countries. Merck is also working with India's Council of Medical Research to study Gardasil® in India. Merck will make our new vaccines, including Gardasil®, available to developing world countries at dramatically lower prices.
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.
Dr. Arne Näveke
Executive Director, Communication Europe
Sanofi Pasteur MSD
Tel +33 4 37 28 40 40
Fax +33 4 37 28 44 04
Clinical study details
a) 551 16-23 year-old women were enrolled and vaccinated in a randomised, placebo-controlled trial. Subjects received vaccine or placebo at Day 1, Months 2, and 6. At regular intervals through 3 years, subjects underwent serum anti-HPV testing. A subset (241 subjects) underwent 2 additional years of follow up. Subjects who originally received vaccine were given another dose at Month 60, while placebo subjects initiated a 3-dose vaccine regimen. Anti-HPV responses were measured 1 and 4 weeks post-dose 4 (subjects who originally received vaccine) or post-dose 1 (subjects who originally received placebo).
b) FUTURE I and II are phase III, prospective, double-blind, placebo-controlled randomised studies conducted in 16 countries. The women who participated in the trials were aged 16 to 26 and received three doses of either Gardasil® or placebo at day 1, month 2, and month 6. The primary analyses of these trials evaluated the efficacy of Gardasil® compared to placebo in women who were negative to the relevant Human Papillomavirus types (6, 11, 16 and/or 18) when they started the study, remained free of infection with the relevant Human Papillomavirus types through month 7, received all three doses of Gardasil® within one year and had no protocol violations.
FUTURE I evaluated th e incidence of pre-cancerous and potentially pre-cancerous cervical lesions (CIN 1-3), pre-cancerous and potentially pre-cancerous vulvar and vaginal lesions (VIN1-3 and VaIN1-3) and external genital warts caused by the Human Papillomavirus types 6, 11, 16 and 18. FUTURE II evaluated the prevention of pre-cancerous cervical lesions (CIN 2/3) and non-invasive cancers (AIS) caused by Human Papillomavirus types 16 and 18.
c) 20,541 women (16-26 years) from the Americas, Europe and Asia were enrolled in one of four trials. In one trial, subjects were randomised to either a monovalent Human Papillomavirus 16 vaccine or placebo. In 3 trials, subjects were randomised to either Gardasil® (types 6/11/16/18) or placebo. For all trials, vaccination occurred at day 1, and months 2 and 6. The primary endpoint was the combined incidence of Human Papillomavirus types 16/18-related CIN 2/3, AIS, or cervical cancer. In the Human Papillomavirus 16 vaccine study, only Human Papillomavirus 16-related cases were considered. Analyses were done in a per protocol (PP) population (subjects received 3 doses, had no major protocol violations, were Human Papillomavirus 16/18 seronegative at day 1 and Human Papillomavirus 16/18 DNA negative Day 1 through month 7). Endpoint counts began at Month 7.