July 30, 2012 4:33 pm

Merck’s Gardasil, GSK’s Cervarix HPV vaccines see poor adherence, experts question overall response

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Merck’s Gardasil, a human papillomavirus (HPV) vaccine, has poor adherence and more data is required on the effects of receiving fewer than the full three-dose regimen, according to experts interviewed by BioPharm Insight.

A recent Centers for Disease Control and Prevention (CDC) report indicated only 32% of US females aged 13 to 17 received all three doses of an HPV vaccine in 2010. GlaxoSmithKline’s Cervarix is the other marketed HPV vaccine and is also administered as a three-dose regimen.

HPV is a sexually transmitted infection spread via skin that can lead to genital warts or cancers of the genitals or anus. Almost all cases of cervical cancers are caused by HPV, although 90% of HPV infections clear on their own. HPV vaccines prevent infection against the specific HPV genotypes included in the vaccine.

While Gardasil and Cervarix are both approved for use in females, Gardasil is also approved for use in males. The overarching reason to vaccinate males is to prevent them from transmitting HPV to females, an investigator on Merck’s HPV vaccines said.

To further its reach in HPV, Merck is developing another vaccine, V503, which protects against five more cancer-causing HPV genotypes than the two in Gardasil and Cervarix. Merck, however, recently had to extend the late-stage human trial, comparing V503 to Gardasil, by one year, a Merck spokesperson said.

The trial extension was due to a lack of HPV infections seen among patients given Gardasil, she added. This raises questions about whether there is a need to protect against these additional HPV genotypes.

Cervarix and Gardasil both protect against HPV-16 and -18, two of the “high-risk” strains that account for 70% of cervical cancers. The additional HPV genotypes in V503 are less prevalent in the population than HPV-16 and -18, noted Dr Connie Mao, associate professor, University of Washington.

Adherence to all three doses of HPV vaccines is “dismal” in the US, said Mao. This is largely due to the fact that HPV vaccination is not mandated in the US, explained Dr Mark Einstein, associate professor, Albert Einstein College of Medicine.

Vaccination is currently recommended in the US but only mandated in Virginia and Washington, DC, which have “generous opt-out clauses,” added Dr Lauri Markowitz, medical epidemiologist, National Center for HIV, Viral, Hepatitis, STD and TB Prevention, CDC.

Adherence rates in the US are much worse than in the UK or Australia, where vaccination is routinely given in school-based programs, added Einstein.

We will not see a marked decrease in cervical cancer rates until there is better uptake of the vaccines, said Dr Rick Haupt, head, Adult Vaccine Clinical Research, Merck.

Better uptake of the vaccines will allow us to shift costs from pap smears and HPV-related biopsies and procedures to preventative medicine, said Dr Michelle Lally, associate professor, Brown University.

Expansion into males

Since Gardasil is not reaching a large proportion of females in the US, vaccinating males may help increase protection on a population level. Vaccinating men is cost-effective because protecting males against HPV will subsequently protect females as well, said Dr Stanley Grogg, associate dean of clinical research, Oklahoma State University College of Osteopathic Medicine.

In October 2011, the CDC recommended routine use of Gardasil for males aged 11 to 21 years. Gardasil also protects against HPV-6 and -11, which are noncancerous and cause around 95% of genital warts.

The FDA would only approve Gardasil for males if the vaccine could be proven to provide them with direct benefit, noted an investigator. Hence, the benefit to males was pitched as protection against genital warts and later anal cancer. A Merck spokesperson noted the company pursued these indications in men because men can also be at risk for acquiring HPV infections and HPV-related cancers.

Genital warts may not cause death or major morbidity, but it is a common problem that adds “substantial cost to the healthcare system,” said Markowitz. According to CDC data, there are roughly 250,000 cases of males genital warts per year, meaning about 1% of sexually active men have genital warts in the US.

While many public health problems are more severe than genital warts, “we don’t have vaccines for them, so we spend our money on the available therapies,” said Dr James Colgrove, assistant professor, Mailman School of Public Health, Columbia University.

Incidence rates of anal cancers are on the rise, and there are currently no recommended screening methods, said Mao. No specific data has been released yet, but Mao expects to see significant drops in rates of anal cancers, as most of these cancers are caused by HPV-16.

Assessing efficacy of two-dose regimens

With poor compliance to the three-dose regimen of HPV vaccines, it is tough to assess the vaccine’s impact on HPV-related cancers. Data shows response with two doses of Cervarix is “almost as good as with three doses,” said Haupt. He noted Studies of Cervarix in Costa Rica that included a subpopulation of women who received only two doses.

This trial, however, had a short follow-up period of four years and included a small number of women, noted Dr Anne Szarewski, clinical senior lecturer, Centre for Cancer Prevention, Queen Mary University of London. Data from those who received two doses demonstrated that the vaccine elicits a response, but we do not know the duration of protection, she added.

Receiving fewer than three doses is “not optimal, but it is better to get one or two shots than none at all,” added Lally.

GSK discourages any other regimen than what is in the product labeling, according to a GSK spokesperson. “We also have no plans at this time to seek a two-dose indication,” the spokesperson added.

In 2011, Cervarix and Gardasil achieved sales of GBP 506m and USD 1.2bn, respectively.

Next-gen HPV vaccine in development

Merck’s strategy with V503 is to extend protection to more HPV types. The new vaccine is expected to protect against 80-85% of cervical cancers, said Mao.

Patients already given Gardasil will not be required to get revaccinated with V503, said Mao, but after US approval, the new vaccine will be given in place of Gardasil – assuming V503’s protection against HPV-16 and -18 is proven to be as efficacious as that of Gardasil.

Gardasil protects against the HPV strains that cost the most to the healthcare system, said Dr Mark Steben, director, Risk Management Biological and Occupational Health, The National Public Health Institute of Quebec. The additional five genotypes in V503 are “the next most-important genotypes that cause cervical cancer,” added Haupt.

Yet the lack of new HPV infections seen among patients only given Gardasil in the V503 trial raises questions about the value of a new vaccine that protects against these additional HPV genotypes that occur less frequently than HPV-16 and -18.

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