No. 4: Success of HPV Vaccine

In the May 10 issue of The New England Journal of Medicine, results from an international phase 3 trial showed that a quadrivalent human papilloma virus (HPV) vaccine (Gardasil; Merck) was 98% efficacious for reducing the composite risk of precancerous cervical lesions or HPV-related cervical cancer in young women who demonstrated no evidence of being infected with the most common causes of cervical cancer. A related study, reported in the same issue, indicated that the same vaccine was 100% efficacious for reducing the composite risk of genital warts and neoplastic cervical lesions in a similar group.

In the Females United to Unilaterally Reduce Endo/Ectocervical Disease (FUTURE) II Study,* 12,167 women between the ages of 15 and 26 years received 3 doses of randomly assigned quadrivalent HPV vaccine (n = 5305) or placebo (n = 5260) in double-blind fashion at day 1, month 2, and month 6. The primary analysis was performed in the “per-protocol susceptible population,” which consisted of women who demonstrated no evidence of infection with HPV types 16 or 18 at 1 month after the third dose of vaccine. In this study population, the vaccine was 99% efficacious for reducing the composite endpoint of cervical intraepithelial neoplasia grade 2 or 3, adenocarcinoma in situ, or cervical cancer related to HPV-16 or HPV-18 at a mean of 3 years. In the intent-to-treat population, the vaccine demonstrated 44% efficacy for the composite endpoint and 17% efficacy for the endpoint of high-grade cervical lesions.

In the companion study (FUTURE I), 5455 young women between the ages of 16 and 24 years received the same randomly assigned regimen of vaccine (n = 2723) or placebo (n = 2732). The vaccine demonstrated 100% efficacy in the per-protocol study population (as defined) for reducing the composite risk of genital warts, vulvar or vaginal intraepithelial neoplasia, or cancer, as well as the composite risk of cervical intraepithelial neoplasia, adenocarcinoma in situ, or cancer associated with HPV type 6, 11, 16, or 18 at a mean of 3 years. The vaccine reduced the rate of any vulvar or vaginal perianal lesions by 34% and the rate of cervical lesions by 20%. Lesions were reduced regardless of the causative HPV type.

The Merck vaccine is a noninfectious, recombinant vaccine containing highly purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV types 6, 11, 16, and 18. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (amorphous aluminum hydroxyphosphate sulfate). HPV is known to cause essentially all cervical cancers, with types 16 and 18 accounting for approximately 70% of cervical cancers globally. Although HPV types 6 and 11 are rarely detected in high-grade cervical lesions, they are the causative agents of most anogenital warts.

On the basis of these phase 3 data and prior phase 2 data, Gardasil was approved by the FDA in June 2006 for administration to girls and women aged 9-26 years. The uptake of the vaccine has been robust, with 2007 sales reported at blockbuster status—$1.5 billion, and projected annual sales have been estimated at a whopping $3 billion. In addition, data presented November 7 at the 24th International Papillomavirus Conference in Beijing, China, indicated an approximate 90% efficacy of the vaccine in women aged 24-45 years, and Merck states that it plans to submit these data to the FDA for an expanded indication.

In related news, GlaxoSmithKline suffered a setback regarding US approval of its cervical cancer vaccine (Cervarix) on December 17 after the FDA requested additional information. The bivalent vaccine, which has been approved in the European Union, Mexico, and Australia, is designed to prevent cervical cancer related to HPV types 16 and 18 and is promoted as being formulated with a “novel proprietary adjuvant system” that is intended to prolong the duration of HPV immunity.

*Oy. Don't get me started on these study acronyms.