Sunday 9th October, 2005
GARDASIL, an investigational vaccine from Merck & Co., Inc., prevented 100 percent of high-grade cervical pre-cancers and non-invasive cervical cancers (CIN 2/3 and AIS) associated with human papillomavirus (HPV) types 16 and 18 in a new phase III study.
The analysis compared GARDASIL (quadrivalent human papillomavirus types 6, 11, 16, 18, recombinant vaccine) to placebo in women who were not infected with HPV 16 and 18 at enrollment and who remained free of infection through the completion of the vaccination regimen. Women were followed for an average of two years after enrollment. Tomorrow these data will be presented for the first time at the Infectious Diseases Society of America (IDSA) annual meeting.
This trial is part of the ongoing phase III program for GARDASIL, which involves over 25,000 people in 33 countries worldwide. Merck remains on track to submit a Biologics License Application for GARDASIL to the Food and Drug Administration in the fourth quarter of 2005. More than 12,000 women from 13 countries participated in this trial.
This phase III study, titled FUTURE II, is a prospective, randomized, double-blind, placebo-controlled study with two vaccination groups. Women aged 16 to 26 years were randomized to receive a three-dose regimen of either GARDASIL or placebo at Day 1, Month 2, and Month 6. A total of 12,167 women were enrolled from 90 study centers in Brazil, Colombia, Denmark, Finland, Iceland, Mexico, Norway, Peru, Poland, Singapore, Sweden, the United Kingdom and the United States (including Puerto Rico) and were equally allocated between the two groups. A group of 6,082 females received GARDASIL and another group of 6,075 received placebo.
FUTURE II evaluated the incidence of HPV 16/18-related cervical pre-cancers known as CIN (cervical intraepithelial neoplasia) 2/3 and non-invasive cancers. CIN 2 is a moderate-grade lesion of the cervix. CIN 3 represents both high-grade lesions and CIS (carcinoma in situ), the immediate pre-cursor to invasive squamous cell cervical cancer. AIS is the early development of adenocarcinoma (or glandular cancer) of the cervix. CIN 3 and AIS are defined as Stage 0 cancer according to the International Federation of Gynecology and Obstetrics (FIGO) classification.
The primary analysis of this trial evaluated the incidence of CIN 2/3 and AIS in women who received three doses of GARDASIL, had no major protocol violations and remained free of HPV 16 and/or HPV 18 infection through month 7; this analysis started 30 days after completion of the vaccination regimen, and followed women for an average of 17 months after completion of the regimen. In this group, GARDASIL prevented 100 percent of cases of high-grade pre-cancer and non-invasive cancer (CIN 2/3 or AIS) associated with HPV types 16 and 18 (p < 0.001); no cases of CIN 2/3 or AIS were observed in the vaccine group (n=5,301) compared to 21 cases in the placebo group (n=5,258).
"These are the first pivotal data to show that vaccination with GARDASIL reduced HPV 16 and18-related cervical pre-cancer and non-invasive cervical cancer," said Laura Koutsky, Ph.D., principal investigator, HPV research group, University of Washington, Seattle.
A secondary analysis, also being presented, evaluated the incidence of CIN 2/3 and AIS in a broader group of women. This analysis started 30 days after administration of the first dose of GARDASIL or placebo, and included all of the women in the primary analysis group, as well as women who may have become infected with HPV 16 or HPV 18 during the vaccination period and women who may have violated the protocol in significant ways (for example, by missing certain protocol visits). On average, these women were followed for approximately two years. In this group, GARDASIL reduced the risk of developing high-grade pre-cancer and non-invasive cancer (CIN 2/CIN 3, or AIS) associated with HPV types 16 and 18 by 97 percent (n=5,736); one case was observed in the vaccine group compared to 36 in the placebo group (n=5,766).
There were no discontinuations due to serious vaccine-related adverse events. Adverse events were higher among those who received GARDASIL compared with placebo recipients. The most common vaccine-related adverse event reported was local discomfort at the injection site.
"Merck has been committed to vaccine research and development for over a century," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "We have hope that GARDASIL will continue the great Merck tradition of developing medicines and vaccines that make a real difference in people's lives."
GARDASIL was designed to target HPV types 16 and 18, which account for 70 percent of cervical cancers, and HPV types 6 and 11, which account for 90 percent of cases of genital warts. These four types also cause benign cervical changes that result in "abnormal" Pap tests.
GARDASIL is one of three late-stage vaccines in development at Merck. In April, Merck submitted Biologics License Applications to the FDA for ROTATEQ, a vaccine for rotavirus gastroenteritis, and ZOSTAVAX, a vaccine for shingles.
Approximately 20 million American men and women are infected with HPV
HPV has been identified as the cause of cervical cancer, pre-cancers, benign cervical lesions and genital warts. Cervical cancer, one of the leading cancers among women, results in approximately 290,000 deaths worldwide each year. In the United States an estimated 10,400 new cases of cervical cancer will be diagnosed in 2005, and there will be an estimated 3,700 deaths from cervical cancer. It is estimated that approximately 20 million men and women in the United States are infected with HPV. In most people, HPV goes away on its own. In some, however, certain high-risk or oncogenic types of HPV can lead to cervical cancer. The virus is also associated with abnormal Pap tests and genital warts. Each year, about one million women in the United States are told they have "an abnormal Pap" ? which may trigger additional testing, anxiety, and in some cases fears of cancer.
In 1995, Merck entered into a license agreement and collaboration with CSL Limited relating to technology used in GARDASIL. GARDASIL is also the subject of other third-party licensing agreements.
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