HPV Vaccine Developers Racing to Marketplace

Merck and GlaxoSmithKline both hope to be first to win approval from regulators

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CEO SUMMARY: At least ten companies are working on an HPV vaccine that can prevent cervical cancer. The leading two companies have Phase III clinical trials under way and expect to earn regulatory approval within the next 24 to 30 months. The speedy arrival of an HPV vaccine in the market will not affect Pap smear testing volumes—in the short term. But it lays the groundwork for substantial long term change.

FOR THE LABORATORY INDUSTRY, development of an effective vaccine for Human Papillomavirus (HPV) is probably a financial good news/bad news story.

The good news is that, even following regulatory approval of an effective HPV vaccine, current cervical screening guidelines are unlikely to change for at least a decade. Moreover, the need to run a diagnostic test for HPV will increase the volumes of such tests performed annually in this country.

The bad news is that widespread vaccination of vulnerable populations will spell the end of Pap smear testing as it is practiced today. In the United States, that will mean a substantial reduction in the estimated 55 million Pap smears currently performed each year.

Many lab directors and pathologists saw headlines earlier this month reporting the results of human HPV vaccine trials. The findings were presented at a recent meeting of the American Society for Microbiology (ASM). Re- searchers at the University of Washington reported the results of this study, which was funded by Merck & Co. The study involved 755 women who had been part of an earlier HPV vaccine study. After their vaccination for HPV-16, these women were followed for a total of four years.

During this time, seven women became infected with HPV-16, but none developed pre-cancers. In the control group, 750 women received placebo shots and 111 became infected with HPV-16. Twelve women in this group formed pre-cancers.

HPV Vaccine Trials

Merck is one of two major pharmaceutical companies racing to be first to earn regulatory approval to market their HPV vaccine. Merck is in the final stages of testing an expanded vaccine that would protect against HPV strains 16, 18, 6, and 11. These four strains cause about 70% of all cervical cancers. About 90% of genital warts cases in men and women are also caused by these HPV strains.

Merck’s Phase III clinical trial is now underway, involving 25,000 men and women located in 34 countries. It expects the results of this study by mid-2005.

Sometime in the second half of 2005, Merck expects to submit an application for its quadrivalent HPV vaccine with the Food and Drug Administration (FDA). If approved without unexpected delays, Merck believes it will be first to market with an HPV vaccine.

GlaxoSmithKline’s Progress

Merck’s closest competitor is GlaxoSmithKline (GSK) Plc. It is developing its own HPV vaccine in collaboration with Medimmune, Inc. of Gathersburg, Maryland.

Studies of its two-strain HPV vaccine (HPV-16 and HPV-18) have involved about 1,100 women, ranging in age from 15 to 25 and living in 14 countries, including the United States, Canada, and Brazil. GSK is currently launching a Phase III trial that involves 25,000 women. It calls its vaccine “Cervarix.”

It had originally intended to file for regulatory approval in 2008. But, armed with favorable data from its clinical studies and feeling the pressure from Merck, GlaxoSmithKline recently announced that it was pushing up the probable filing date to 2006.

30 Months to Market

Assuming that both companies meet their announced timetables and regulators act with some dispatch, it is possible that HPV vaccines will be approved and available for clinical use within 24 to 30 months. However, the availability of HPV vaccines will not have much impact on Pap smear testing volumes for several years. That’s because it will take considerable time to inoculate enough people to statistically impact the rates of infection.

“If they started vaccinating only young people before the start of sexual activity, it would be about three to four decades before you saw major changes in cervical cancer rates,” stated Christopher P. Crum, M.D., Director of Women’s and Perinatal Pathology at Brigham and Women’s Hospital in Boston, Massachusetts. “But the changes would nonetheless be significant, and this would have a major impact, particularly in developing countries where you don’t have the Pap smear.”

Crum’s opinion was mirrored by that of Anne Szareski, M.D., a Clinical Consultant at Cancer Research UK. She is leading clinical trials in London, England. “This vaccine is the most exciting thing in cervical cancer research because it is mainly caused by a virus—so the obvious thing to do is get a vaccine,” she said. “It would have to protect against more than 70% to completely remove the need for [cervical cancer] screening. If we could get to 80% or more [protection], we could certainly stop [Pap] smears. Although we can only stop screening when we have reached the point where everyone’s been vaccinated.”

The HPV vaccine is given in three shots over six months. Researchers say that the vaccine would be most effective as a preventive measure if it is given to girls and young women before they become sexually active. Further, because the vaccine cannot prevent every virus that can cause disease, there would still be need to continue screening for cervical cancer. One unanswered question is how long immunity lasts and whether a booster shot or revaccination would be necessary in later years.

The number of people infected with HPV is significant. It is believed that 50% of sexually active men and women acquire genital HPV at some point in their lives. More than 80% of women will have acquired an HPV infection by the age of 50. In the United States, it is estimated that 6.2 million people acquire genital HPV infections each year.

Most people will naturally clear their HPV infection. Women who do not clear their HPV infection are at highest risk for cervical cancer. About 15,000 new cases of cervical cancer are diagnosed annually in the United States. In this country, about 4,400 women die annually from cervical cancer and it is widely recognized that the majority of these women did not have a Pap smear in the five years prior to their diagnosis of cervical cancer.

Billion-Dollar Market

At least ten companies are known to be developing a vaccine for HPV. That’s because the market potential for such a vaccine is immense. Research Analyst Tim Anderson at Prudential Equity Group characterizes Merck’s HPV vaccine as possibly “one of the most important drugs to emerge” from a pharma company “in recent memory.” He projects HPV vaccine sales of $2.3 billion in 2008, just 48 months away.

Adrian Howd, an Analyst at ABN AMRO, called GlaxoSmithKline’s Cervarix a “sleeper” drug that has attracted little attention within the financial community. Howd believes sales of Cervarix could top $1.8 billion after it hits the marketplace in 2007.

The race to bring an HPV vaccine to market is driving two areas of science and medicine which will influence and shape laboratory testing in future years. First is the science behind developing vaccines for infectious diseases. This science centers around advances in proteomics. Researchers are learning how to create non-virulent virus-like particles (VLPs). These mimic, in important ways, the virus and stimulate an immune response in the body.

Using New Technology

Second is the new technology which enables this type of scientific approach in vaccine development. The ability to create VLPs is just one element. Researchers have a variety of tools to help them identify even subtle immune system responses and understand them.

Another dimension of the HPV vaccine development effort which can have a longer-term impact on laboratory medicine is this fact. The HPV vaccine’s therapeutic value is that it prevents cervical cancer. “This is the first time we have shown that there is a vaccine that protects against the only cause of [cervical] cancer and can actually prevent 70% of all cervical cancer worldwide,” declared Diane Harper, a researcher at Dartmouth Medical School in Hanover, New Hampshire who helped conduct one of the HPV clinical trial sites.

Vaccine To Prevent Cancer

Cancer prevention has been one effect from the use of the vaccine for Hepatitis B (HBV). This vaccine has reduced the number of people whose infections progress to liver cancer. Collectively, the HBV and HPV vaccines point to new medical strategies which aim to prevent cancer, not treat it after it is diagnosed.

If these types of vaccines are discovered to have the ability to prevent other cancers, it will certainly have an impact on anatomic pathology and cancer diagnostics. It also is an early demonstration of how proteomics may provide new ways to prevent disease. As that happens, laboratory tests will evolve to serve prevention, not detection.

Eat a Banana, Vaccinate Against the HPV Virus

EVEN AS RESEARCHERS RACE TO DEVELOP an effective vaccine for HPV, a parallel research effort is under way to develop an edible vaccine against the same disease.

Edible vaccine research is ongoing at the University of Rochester, Cornell University, and Tulane University. Two years ago, researchers developed a genetically-altered potato that stimulated an immune in mice.

The goal is to create an oral vaccine that eliminates needles. “The beauty of an oral vaccine is that you don’t need a needle,” observed Robert Rose, Ph.D., a virologist involved in this research project at the University of Rochester in Rochester, New York. “You don’t need sterile injection equipment or highly-skilled medical personnel who know how to inject a vaccine. You just need to put a couple of drops on someone’s tongue. Part of the reason that polio has been virtually stamped out is because of development of an oral vaccine.”

HPV is not the only oral vaccine target for this research. Other diseases include hepatitis B, rotavirus, tooth decay, and respiratory syncytial virus. Potential foods that could deliver an oral virus are bananas, potatoes, and apples.

The work centers around VLPs—virus-like particles. These look like viral particles, but are not infectious. VLPs can trigger an immune response by the body. Researchers use genetic splicing techniques to insert VLPs into plants. As a plant grows, it then produces VLPs in its fruit and leaves.

Rose says that the banana is a preferred food. Because heat often destroys protein, a food that is eaten uncooked and is tasty, such as a banana, is preferred as the delivery vehicle for vaccines that can protect against HPV and other diseases.

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