Gardasil

Treatment for Human Papillomavirus Prophylaxis

FDA Advisory Committee Votes Unanimously That Clinical Data Support the Efficacy and Safety of Gardasil

Merck's Investigational Cervical Cancer Vaccine; If Approved, Gardasil Will Be the First Cervical Cancer Vaccine in the U.S.

WHITEHOUSE STATION, N.J., May 18, 2006 - Merck & Co., Inc. announced today that the U.S. Food and Drug Administration's (FDA) Vaccines and Related Biological Products Advisory Committee voted unanimously that the data from Phase II and Phase III clinical trials support the efficacy and safety of Gardasil (quadrivalent human papillomavirus (Types 6, 11, 16, 18) recombinant vaccine) for the prevention of cervical cancer and for the prevention of cervical, vulvar and vaginal pre-cancers caused by human papillomavirus (HPV) types 16 and 18 in females. The Committee also agreed that data support the efficacy and safety of Gardasil for the prevention of other cervical, vulvar and vaginal lesions caused by HPV types 6, 11, 16 and 18 including genital warts.

The Committee's guidance will be considered by the FDA in its review of the Biologics License Application (BLA) that Merck submitted for Gardasil in December 2005. The FDA has informed Merck that the target date for completion of review is June 8, 2006. The Committee also recommended that Merck continue to develop and conduct post-licensure studies to assess the safety and efficacy of Gardasil if it is approved for use. The FDA is not bound by the committee's guidance, but takes its advice into consideration when reviewing investigational vaccines seeking approval.

"Merck is thrilled that the Advisory Committee has agreed that the extensive data from our decade-long, 27,000-patient clinical trial program support the use of Gardasil to reduce the burden of cervical cancer and other diseases caused by HPV," said Peter S. Kim, Ph.D., president, Merck Research Laboratories. "If approved, Gardasil will be the first and only vaccine to prevent cervical cancer and other serious HPV-related diseases. We look forward to bringing this vaccine to people to continue our legacy of bringing forward novel medicines and vaccines that address unmet medical needs for people around the world."

Diseases caused by HPV represent a major burden in the United States. Approximately 10,000 women are diagnosed with cervical cancer each year, and an average of 10 women die each day from this cancer. HPV also causes approximately 40 to 50 percent of the more than 3,500 cases of vulvar and vaginal cancer that are diagnosed each year in the U.S.; about three women die each day from these two cancers. HPV-related diseases cost about $5 billion per year in the United States.

Gardasil is Merck's investigational cervical cancer vaccine designed to protect against four types of human papillomavirus (HPV types 6, 11, 16 and 18). HPV types 16 and 18 account for an estimated 70 percent of cervical cancer cases and can lead to vulvar and vaginal cancers. HPV types 6 and 11 account for an estimated 90 percent of genital wart cases and can cause abnormal Pap tests and low-grade cervical abnormalities.

In studies, Gardasil prevented 100 percent of cervical cancers and pre-cancers caused by HPV types 16 and 18

Results from Merck's clinical trials, presented to the Advisory Committee, evaluated the efficacy, safety and immunogenicity of Gardasil in more than 27,000 females and males and from 33 countries around the world. In the key efficacy studies in 20,887 women aged 16 to 26, Gardasil prevented 100 percent of cervical, vaginal and vulvar pre-cancers caused by HPV types 16 and 18, prevented 95.2 percent of cervical lesions caused by HPV types 6, 11, 16 and 18, and prevented 99.1 percent of external genital lesions, including genital warts, caused by HPV types 6, 11, 16 and 18.

Specifically, in women aged 16 to 26 who were free from infection with HPV types 16 and 18 at the start of the study and who received all three doses of Gardasil:

  • Prevention of cervical pre-cancers and non-invasive cancers caused by HPV 16 and HPV 18: Gardasil prevented 100 percent of HPV 16- or 18-related CIN 2/3 (cervical intraepithelial neoplasia) or adenocarcinoma in situ (AIS). There were no cases in the 8,487 women who received Gardasil compared to 53 cases in the 8,460 women who received placebo. National and international health agencies including the FDA and the World Health Organization have maintained that demonstrated efficacy against pre-cancers (CIN 2/3) is the most clinically relevant measure of a cervical cancer vaccine's effectiveness.
  • Prevention of vaginal and vulvar pre-cancers caused by HPV 16 and HPV 18: Gardasil prevented 100 percent of HPV 16- or 18-related VIN 2/3 (vulvar pre-cancers) or VaIN 2/3 (vaginal pre-cancers). There were no cases in the 8,641 women who received Gardasil compared to 24 cases in 8,667 women who received placebo.

In women aged 16 to 26 who were free from infection with HPV types 6, 11, 16 and 18 at the start of the study and who received all three doses of the vaccine:

  • Prevention of cervical lesions caused by HPV 6, HPV 11, HPV 16, and HPV 18: Gardasil prevented 95.2 percent of HPV 6-, 11-, 16- or 18-related cervical lesions (CIN 1), CIN 2/3 or AIS. There were 4 cases in the 7,858 women who received Gardasil compared to 83 cases in the 7,861 women who received placebo.
  • Prevention of external genital lesions caused by HPV 6, HPV 11, HPV 16, and HPV 18: Gardasil prevented 99.1 percent of HPV 6-, 11-, 16- or 18-related external genital lesions, including genital warts, vulvar intraepithelial neoplasia (VIN) or vaginal intraepithelial neoplasia (VaIN). There was one case in the 7,897 women who received Gardasil compared to 113 cases in the 7,899 women who received placebo.

Merck also presented a secondary analysis that assessed the effect of Gardasil in women who were free from infection from vaccine HPV types at baseline but who became infected with vaccine HPV types during the vaccination period, women who might have violated the study protocols in significant ways (for example, by missing certain protocol visits), and women who received fewer than three doses of vaccine. In these groups, Gardasil prevented 94 percent or more of HPV diseases related to HPV types 6, 11, 16 and 18.

Merck also presented results from immunogenicity studies in males and females aged nine to 15. The immune response in this age group was higher than in older adolescents and adults. The Advisory Committee agreed that the immunogenicity data for the younger female population support the bridging of the efficacy data from the older female population to the younger female population. Efficacy trials to evaluate Gardasil in males are still ongoing.

Compared with placebo subjects, a higher proportion of subjects who received Gardasil reported experiencing an injection site adverse experience (mostly mild- to moderate in intensity) or a low-grade fever (temperature of 102-degree F or lower). The most common adverse events reported were injection site pain, swelling and redness, as well as fever. Few subjects (0.2%) discontinued vaccination due to an adverse experience.

Merck also has filed for licensure of Gardasil in a number of countries worldwide, including Australia, Brazil, Mexico and Taiwan, and in the European Union through the joint venture Sanofi-Pasteur MSD.

In 1995, Merck entered into a license agreement and collaboration with CSL Limited relating to technology used in Gardasil. Gardasil also is the subject of other third-party licensing agreements.

About HPV Disease

In the United States approximately 20 million people are infected with HPV, and for most people, HPV goes away on its own. In some, however, certain high-risk types of HPV, if unrecognized and untreated, can lead to cervical, vaginal and vulvar cancers. Cervical cancer is the second most common cause of cancer death in women worldwide, resulting in nearly a half-million diagnoses and 240,000 deaths each year. In addition, certain low-risk types of HPV cause genital warts and can lead to abnormal Pap results. Approximately 1 million cases of genital warts occur each year in the United States and an estimated 32 million cases occur worldwide. Additionally, there are an estimated 4.7 million abnormal Pap results that require follow-up each year in the United States. At least 3 million of these results are caused by some type of HPV.

Source: Merck & Co., Inc.

Posted: May 2006

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