Merck plans to submit a Biologics License Application for Gardasil to the Food and Drug Administration in the fourth quarter of 2005.

Abnormal Pap Tests

Each year, about one million women in the United States are told they have "an abnormal Pap" -- a result that often triggers additional testing, anxiety and fear of cancer.

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.

HPV has been identified as the cause of cervical cancer, pre-cancers, benign cervical lesions and genital warts.

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.

Incidence of Pre-Cancers and Cancers

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 allocated equally between the two groups: 6,082 received Gardasil and 6,075 received placebo.

Future II evaluated the incidence of HPV 16/18-related cervical pre-cancers and non-invasive cancers.

The pre-cancers include two levels of CIN (cervical intraepithelial neoplasia). 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 (adenocarcinoma in situ) is the early development of glandular cancer of the cervix. CIN 3 and AIS are defined as Stage 0 cancer according to the International Federation of Gynecology and Obstetrics.

100 Percent Success

The trial's primary analysis started 30 days after completion of the vaccination regimen and followed participants an average of 17 months. Its purpose was to evaluate 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.

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. No cases of CIN 2/3 or AIS were observed in the vaccine group compared to 21 cases in the placebo group.

"These are the first pivotal data to show that vaccination with Gardasil reduced HPV 16 and 18-related cervical pre-cancer and non-invasive cervical cancer," notes Laura Koutsky, PhD, principal investigator of the HPV research group at the University of Washington, Seattle.

97 Percent Success

A secondary analysis also started 30 days after administration of the first dose of Gardasil or placebo, and followed participants for an average of two years. In addition to all of the women in the primary analysis group, it included women who became infected with HPV 16 or HPV 18 during the vaccination period, as well as women who violated the protocol in significant ways -- for example, by missing certain protocol visits.

In this group, Gardasil reduced the risk of developing high-grade pre-cancer and non-invasive cancer (CIN 2/3 or AIS) associated with HPV types 16 and 18 by 97 percent. One case was observed in the vaccine group compared to 36 in the placebo group.

Adverse events were higher among those who received Gardasil compared with placebo recipients, with local discomfort at the injection site the most commonly reported. There were no discontinuations due to serious vaccine-related adverse events.