Merck Looks To Mid-June FDA Decision On Expanded Use Of Gardasil To Older Women

Company unveils data at European conference supporting use in women ages 27 through 45; data was sent to FDA late last year.

Merck anticipates receiving an FDA decision by mid-June on expanding use of its human papillomavirus Gardasil to women aged 27 through 45.

The company submitted 48-month end-of-trial data from the FUTURE III study to FDA in late 2009, the company said in an email exchange. It released those findings Feb. 17 at the European Research Organization on Genital Infection and Neoplasia conference in Monte Carlo.

At the meeting, scientists also presented data from a study in men that Merck plans to use to support an indication for preventing HPV-related anal disease in both men and women.

Gardasil currently is approved in the U.S. for girls and women aged 9 through 26 to prevent cervical, vulvar and vaginal cancers caused by HPV16/18, as well as genital warts caused by HPV6/11, and precancerous or dysplastic lesions caused by HPV6/11/16/18.

Merck submitted the FUTURE III data following an FDA "complete response" letter seeking additional data to support the sBLA for using Gardasil in the 27-45 age group. The original application included 24 month data from FUTURE III (Also see "Gardasil Label Expansion To Women 27-45 Delayed Until 2010, At The Earliest" - Pink Sheet, 9 Jan, 2009.). The submission has been challenging for Merck; this was the second CR on the application.

Merck expects the agency to complete its review of the new submission - a Class 2 response - prior to the June 22-23 meeting of CDC's Advisory Committee on Immunization Practices, the company said. ACIP makes recommendations on using vaccines to prevent disease.

The final FUTURE III data presented at the European conference shows the quadrivalent HPV vaccine to be 95.7 percent effective in preventing HPV6/11/16/18-related cervical intraepithelial neoplasia and external genital lesions in patients aged 24 to 45, study investigators reported at EUROGIN.

The 95.7 percent efficacy for CIN or EGL prevention (95% CI: (73.4, 99.9) is derived from occurrence of the diseases in 23 patients receiving placebo and one receiving Gardasil.

Efficacy against HPV6/11/16/18-related persistent infection was 89.6 percent (95% CI: 79.3, 95.4), based on occurrence in 85 placebo recipients versus nine in vaccinated patients.

The FUTURE III study was a double-blind, placebo-controlled trial that enrolled 3,817 women aged 24-45 with no history of cervical disease, Loop Electrosurgical Excision Procedures, hysterectomy or genital warts in the previous five years. Participants received a series of three injections of Gardasil (n=1,910) or placebo (n=1907) and were monitored for HPV-related infection, cervical and genital disease every six months.

Mean follow-up time in the study was 3.8 years, representing an additional 1.6 years of follow-up when compared to earlier analyses, according to Merck.

The vaccine already is approved for women up to age 45 in the European Union, and women ages 27 to 45 in Mexico, Ecuador, the Philippines and Australia. In 2009, it generated worldwide sales of $1.1 billion, a sizable market, but down 20 percent from 2008. Merck would not estimate the size of the potential expanded market for Gardasil.

Substudy In Homosexual Men Finds Efficacy Against Anal Disease

Merck also is looking to expand the vaccine's indication to include prevention of HPV-related anal disease. A study of Gardasil use in 16 to 26 year-old men who have sex with men found the vaccine to be 77.5 percent (95% CI: 39.6, 93.3) effective in preventing HPV6/11/16/18-related anal intraepithelial neoplasia (AIN) and anal cancer, Joel Palefsky, University of California, San Francisco, reported to EUROGIN.

AIN or anal cancer occurred in five vaccinated patients and in 24 placebo recipients. Efficacy against high-grade AIN (AIN 2+) was 74.9 percent (95% CI: 8.8, 95.4). No anal cancer was seen in either treatment group, he said.

The study is in fact a substudy of Merck's pivotal Phase III trial of Gardasil in males. Because HPV infections are the primary cause of anal cancer and men who have sex with men are at higher risk for anal infection and disease, studying Gardasil in this population provides a good opportunity to define the vaccine's impact on these disease endpoints in a reasonable timeframe, the firm explained.

Participants in the substudy were 598 men aged 16-26 who were randomized to receive three doses of the vaccine or placebo and were monitored at six-month intervals. The per-protocol efficacy population was not infected with the relevant HPV vaccine type at the start of the study and through the vaccination series to month seven. Median follow-up was 2.5 years (post-dose three, which was administered six months after enrollment).

FDA approved Gardasil in October 2009 for prevention of genital warts caused by HPV6/11 in boys and men aged 9 to 26 (Also see "Gardasil For Males Gets FDA OK; Next Up, Cost-Effectiveness Questions" - Pink Sheet, 16 Oct, 2009.).

Gardasil has demonstrated duration of protection for five years with no disease breakthrough against all four of the targeted HPV types, Merck said. A follow-up study of the HPV16 component demonstrated an average 8.5 years of protection and long-term studies are on-going, the company added. Duration of the drug's immunity was raised as an issue at a Sept. 9, 2009, FDA Vaccines and Related Biological Products Advisory Committee meeting (Also see "Merck Proposes 27,000-Patient Observational Trial As Follow-up for Male Use of Gardasil" - Pink Sheet, 9 Sep, 2009.).

-Cathy Dombrowski ([email protected] )