Gardasil Demonstrates High Efficacy Against Precancerous Cervical Lesions In Longest Follow-Up Of Large Phase III Clinical Studi

Gardasil Demonstrates High Efficacy Against Precancerous Cervical Lesions In Longest Follow-Up Of Large Phase III Clinical Studies

A combined analysis of four phase II/III studies which enrolled more than 20,000 women confirmed that the quadrivalent (6,11,16,18) cervical cancer vaccine Gardasil® has sustained 98% to 100% efficacy in the prevention of vaccine virus type-related precancerous cervical lesions in young women. These new data were presented at the 19th International Congress on Anti-Cancer Treatment (ICACT) in Paris, France1.

"These new results confirm Gardasil®'s impressive track record of sustained high efficacy. They include by far the longest follow-up for any cervical cancer vaccine in large phase III studies and strongly substantiate the evidence that the protection provided by Gardasil® is likely to be longlasting", comments lead study investigator Prof. Elmar Joura, from the University of Vienna, Austria.

In light of the high and sustained efficacy of Gardasil®, the independent Data and Safety Monitoring Board (DSMB) of the large phase III studies (FUTURE I & II) recommended last year that these studies be terminated as soon as feasible. Thus, the studies were ended after four years and the women in the placebo group have now been offered Gardasil®, to give them the opportunity to benefit from vaccination.

In the primary study population of young women (16-26 years) **, Gardasil® prevented 98%†† of HPV 16/18-related precancerous cervical lesions (CIN2/3‡‡ or AIS§§), according to the combined analysis.

Supplementary analyses in a sub-population of young women (16-26 years) *** revealed 100%††† efficacy against HPV 16/18-related CIN2/3 or AIS. This sub-population was chosen to approximate a population before sexual debut. Government funded HPV vaccination programmes have generally targeted young girls because it is thought that the maximum benefit and protection from HPV vaccination could be achieved from vaccination prior to the onset of sexual activity.

* Gardasil® (Human Papillomavirus Vaccine [Types 6, 11, 16, 18] (Recombinant, adsorbed))
** not exposed to the relevant human papillomavirus (HPV) types (6,11,16,18) targeted by Gardasil® before vaccination
†† 95% CI [94,100] The two cases observed in the vaccine group were cases of CIN3. There is evidence suggesting that they were caused by virus types not targeted by the vaccine but which were nevertheless counted as HPV-16 related CIN3 according to the strict and conservative case definitions and study standards. One of these cases was positive for HPV 52 at baseline and positive to HPV 52 in 5 histology specimens (both biopsy and LEEP). HPV 16 DNA was detected in one histology sample but at no other time points. The second case was positive for HPV 51 at baseline and positive to HPV 56 in 3 histology specimens (LEEP). HPV 16 DNA was detected in one histology sample (biopsy) but at no other time points.
‡‡ Cervical Intraepithelial Neoplasia grades 2 and 3
§§ Adenocarcinoma in Situ
*** not exposed to the four vaccine types and to ten additional HPV types before vaccination
††† 95% CI [93,100]

The new results are consistent with previous results from the five years follow-up of the pivotal phase II study in a smaller population. "This extends the robustness of the data from a few hundreds to many thousand women," adds Patrick Poirot, vice president for Medical and Scientific Affairs at Sanofi Pasteur MSD. "Phase III results are of greatest importance for regulatory and health authorities when they evaluate a vaccine".

In addition, the follow-up of the pivotal phase II study has ended after five years. The women in the placebo group have also been offered the opportunity to be protected with Gardasil®.

In addition to the robust follow-ups in phase II and III studies, Gardasil® has been demonstrated to induce immune memory. Demonstrating immune memory means demonstrating that the immune system has memorised the vaccine virus types and can be expected to provide protection when exposed again to these types, potentially even years later2. Experts consider the demonstration of immune memory a hallmark of long-term protection.

"With five years of follow up in phase II studies followed by the demonstration of immune memory plus the longest ethically acceptable follow up in our large phase III studies we have provided the three key elements to make mothers, young women, physicians and health authorities confident about long-term protection with Gardasil®", concludes Patrick Poirot.

About the studies

The FUTURE I and II studies are phase III, prospective, double-blind, placebo-controlled randomized studies conducted in 16 countries. Over 17,000 women participated in the trials. They were aged 16 to 26 and received three doses of either Gardasil® or placebo at day 1, month 2, and month 6.

FUTURE I evaluated the incidence of pre-cancerous and early cervical lesions (CIN 1-3), pre-cancerous and early vulvar and vaginal lesions (VIN1-3 and VaIN1-3) and external genital warts caused by the HPV 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 HPV types 16 and 18.

For the phase II/III combined analysis, 16,957 women (16-26 years) were enrolled and randomised to receive either Gardasil® (n = 8,493) or placebo (n = 8464) at day 1, month 2 and month 6 and were followed for up to 4 years after the start of vaccination. Pap tests were taken at regular 6- or 12-month intervals and evaluated using the Bethesda System-2001. Comprehensive anogenital examinations were scheduled at day 1, and every 6 to 12 months thereafter. Colposcopy referral was algorithm-based. Biopsies were HPV-typed. Histology slides were read by a blinded pathology panel. Analyses were per protocol (received 3 doses, had no major protocol violations, were seronegative at day 1 and DNA negative day 1 to month 7 to the relevant HPV vaccine type).There were two cases of CIN3 observed in the vaccine group (n = 8,493) and 112 cases observed in the placebo group (n = 8,464). Supplementary analyses were done in subjects who were negative to the four HPV vaccine types and ten additional types at day 1 (generally HPV naïve). There was no case observed in the vaccine group compared to 52 cases observed in the placebo group

Notes

Since its first approval in 2006, Gardasil® has been approved in 93 countries worldwide and launched in 76 of them and has met with rapid adoption (more than 20 million doses distributed worldwide).

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‡‡‡.3 Around 33,500 women are diagnosed with, and 15,000 women die from cervical cancer each year.4

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 affect other genital organs than the cervix. These diseases include pre-cancerous and early cervical lesions5,6,7, vulvar and vaginal cancer8,9,10, pre-cancerous vulvar and vaginal lesions11,12,13,14 and genital warts.15
It is estimated that human papillomavirus types 6, 11, 16 and 18 together cause 75% of cervical cancer16 (types 16/18), 70% of pre-cancerous (CIN2/3)5,17 and 50% of potentially pre-cancerous cervical lesions(CIN1)6, a significant proportion of vulvar and vaginal cancers and their associated pre-cancerous lesions8,9,23,24, and 90% of genital warts in Europe.19,20

Virus types 6/11 cause 10% of early cervical lesions in Europe in addition to the 25% of early cervical lesions caused by types 16 and 18.19,21,22 Virus types 6 /11 also cause 90% of genital warts15,18, 22,23,24

Current UK 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.

‡‡‡ European Union member states (except Romania and Bulgaria) plus Iceland, Norway & Switzerland

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