Cervical Cancer: Endangered Species

IT'S BUSY AT MERCK THESE DAYS— and not just in the Vioxx legal department. Instead, the entire office buzzes with activity: Executives work late hours, finalizing the regulatory submission; conference calls echo throughout the Whitehouse Station compound, dialed in to local affiliates around the world. In other offices, scientists write up scientific papers, while communications execs buzz in on intercoms, patching the flood of media calls to top scientists.

One could witness the rattle and hum of this sort from almost any company awaiting regulatory approval for a drug. But, in fact, Merck's human papillomavirus (HPV) vaccine Gardasil is unique. Rather then a cancer treatment, Merck has taken the monumental step forward in science and developed a vaccine that prevents HPV, the virus that causes cervical cancer. FDA is now expected to review the application in June.

"A major advance like this one would be very heartening," says Digene's chief scientific officer Attila L�cz, who was the first to clone several HPV subtypes. "We haven't had any huge victories against cancer."

At Long Last, Vaccine Victories: GSK's Gary Dubin

Small advances typically characterize oncology drug development. But Gardasil, and GlaxoSmithKline's Ceravix—which GSK expects to file with FDA by the end of 2006—are 100 percent effective at blocking the virus, and as such, offer for the first time new hope in stopping cervical cancer.

There are more than 100 different strains of HPV. However, only a few types are linked to cancer: HPV-16, HPV-18, HPV-31, and HPV-45. Of those, types 16 and 18 are responsible for 70 percent of cervical cancer cases, while types 31 and 45 cause about 10 percent. Women develop cervical cancer when infections from these high-risk HPV types persist. Although it could take a decade, those persistent infections cause pre-cancerous—and finally, cancerous—cells in the cervix.

HPV is the top sexually transmitted disease in the world. And it affects nearly everyone—men and women—with an estimated 80 percent of the population expected to contract the virus by age 50, according to the American Social Health Association. It used to be a big problem in the United States, before the introduction and widespread use of PAP smears, which test for cervical cancer. (Since the introduction of the PAP smear in the 1950s, the numbers of US cases of cervical cancer have dropped by almost 75 percent.) Still, many women fall through the cracks, explains Pam Rasmussen, vice president of corporate communications at Digene. Many women don't receive PAP smears, and in other cases, the tests don't catch pre-cancerous cells until it's too late. As a result, 15,000 US women are diagnosed with cervical cancer each year and 4,100 die, according to the National Cancer Institute. But the prevalence of the disease in the US pales in comparison to that in developing countries with weak medical infrastructure. Each year, worldwide, 500,000 cases of cervical cancer are diagnosed and 250,000 women die from the disease.

To turn the hope of a cancer vaccine into reality will take substantial investment. Certainly, companies must foster a national, and even supernational, understanding of the disease and the vaccine if they are to successfully carry out the steps needed to begin to eliminate cervical cancer. On order: mass vaccinations of pre-teen girls, and that's just to start.

Eliav Barr, MD, Merck's head of clinical development for Gardasil, and Gary Dubin, GSK's head clinical developer of Ceravix, have both been involved with the development of the HPV vaccines from the earliest research.

"I see this as a once-in-a-lifetime opportunity," says Dubin. "To actually be able to help in the development of a vaccine from the beginning to widescale use is not an opportunity that many of us have. I think this is going to be a vaccine that hundreds of millions of women around the world will ultimately get, that will change the way women's healthcare will be administered in many countries."

Here, we share the tale of the two vaccines, Gardasil and Ceravix—particularly through the eyes of Barr and Dubin, who have painstakingly toiled for almost a decade over these vaccines. For those men, there is little time to sit and reflect on their accomplishments given the big implementation challenges that lie ahead. To that end, we also provide some analysis of the obstacles they face in ensuring the vaccines live up to their promise and potential.

100% EFFECTIVE

Dr. Eliav Barr remembers the first confirmation that Gardasil was going to be a winner. "The first real 'a-ha' moment came in June 2001, when we [got the results of] a blinded interim analysis of a study that looked at the HPV-16 component of Gardasil," says Barr. Merck had decided to conduct a full-fledged efficacy study of this prototype vaccine. "The study was blinded, and only one person got to see the data," continues Barr. "But when he came out [from analyzing the study], he told us to go home and to enjoy a really good dinner and celebrate—and plan on moving the vaccine forward."

Merck's Eliav Barr have followed the development of Ceravix and Gardasil, respectively, since those drugs were licensed into their companies.

It wasn't until five months later that Merck unblinded the study results, and Barr could see the data. "It took my breath away," recalls Barr. "Vaccines tend to be much higher in terms of efficacy than drugs, but even there, there are very few vaccines that are 100 percent efficacious: Measles, mumps, rubella, and Merck's hepatitis A vaccine—but that's about it."

GSK's Gary Dubin shared a similar experience—a feeling of awe in light of the data. "No one thought a vaccine targeting cancer had the potential to be that highly effective," says Dubin. "Typically, improvements in cancer therapies tend to be small and incremental. Something that improves on an existing therapy by five or 10 percent is considered a big step forward. Of course, we had high hopes when we started, but in this case, we've seen numbers that go beyond what we had imagined."

COMPETITION: WARTS AND ALL

Most media reports have boiled down the similarities and differences between Merck's and GSK's vaccines into simple terms. Gardasil and Ceravix both offer protection against the two HPV types that cause about 70 percent of cervical cancer, types 16 and 18. But while Gardasil also protects against HPV types 6 and 11, which cause genital warts, GSK's doesn't. Taken together, analysts forecast the market for HPV vaccines to reach $4 billion by 2010.

If things go as expected, Merck's Gardasil will be the first to market and, as such, will achieve some of the advantages associated with being a front-runner. In particular, the company is banking on the fact that physicians will achieve a level of familiarity with the vaccine, and will be unlikely to switch to Ceravix when it debuts. Merck will also capture the "catch-up" vaccination market—that is, HPV-negative women from 15-49 who decide they want to be vaccinated—for at least one year, says Datamonitor analyst Holger Rovini.

"After that, it will be down to who is better at communicating their marketing message and the perceived advantages of differentiating product attributes: duration of immunity, breadth of HPV-subtype coverage, side effects," says Rovini.

Pamela Rasmussen Digene

It is in this way that the competitive landscape is shaping up. "They're going to be competing very sharply with each other," says Digene's Rasmussen. "GSK is behind, but it will be out there soon. I think you'll find they are doing some education out there, but that it's going to quickly get into a lot of competition—and not just unbranded disease education.

Gardasil and Ceravix can't compete against one another in their primary and most important indications—preventing the cancer-causing HPV types 16 and 18—because they have the same efficacy. Instead, the war for market share will be waged on the back of other benefits.

It's not yet clear whether Gardasil's ability to treat genital warts will remain an outstanding positive for the company. Certainly, it opens up a wider market for Merck by enabling the potential for male vaccination. However, that can come at a price, given the sensitivity of some conservative groups.

"Vaccines for hepatitis B, another often sexually transmitted disease, only gained widespread public acceptance in the US as a cancer vaccine preventing liver cancer," says Rovini. "Gardasil may have more trouble here since it does not just prevent cancer but also genital warts, an STD."

Perhaps because of that, Barr points to the other benefits of targeting HPV types 6 and 11 for genital warts, like saving the US system money. After all, these HPV types often pass for pre-cancerous cells. Each year, 150,000 women are told, after a PAP smear, that they may have pre-cancerous cervical cells and must undergo additional testing, when in reality they were infected with the HPV types that do not cause cancer.

Barr also notes the ability to prevent recurrent respiratory papillomatosis, a condition that occurs when pregnant mothers with genital warts give birth, resulting in newborns' with sizeable tumors in their throats, which are just "total disaster cases," says Barr.

On the other hand, GSK's studies show their vaccine provides cross protection against other oncogenic HPV types 45 and 31, which are less agressive but still cause about 10 percent of cervical cancers.

The company has also begun building its body of data to show long-term effectiveness—a big question mark facing both vaccine makers, given the potential need to develop booster shots. Recently, GSK published a study in the Lancet that showed Ceravix maintained protection for the 4.5 year study period without any sign of waning. Dubin credits the use of an adjuvant called ASO4, instead of the standard adjuvant alum that is used in most vaccines, including Gardasil.

"It was very encouraging that by using adjuvant, it would be possible to have longer-term protection," says Dubin.

THE CHALLENGE OF MASS INOCULATION

Now that the science is in order, Merck and GSK face several important challenges in conditioning the market.

The court of public opinion There is some pushback against the HPV vaccines from religious-based organizations, which are concerned that these vaccines promote promiscuity. But how prevalent is that criticism?

The court of public opinion There is some pushback against the HPV vaccines from religious-based organizations, which are concerned that these vaccines promote promiscuity. But how prevalent is that criticism?

"My sense is that it's not a widespread opposition, just a few vocal opponents," says Duke University Medical Center's Evan Myers, MD. "They are arguing that if a teenage girl knows she got the HPV vaccine, that it is somehow going to remove a barrier against her having intercourse. That argument assumes a.) teenagers make rational decisions, b.) drugs and alcohol are never involved in adolescent sex, and c.) there's widespread knowledge of the consequences of HPV—and most kids don't know anything about HPV."

Coverage concerns The vaccines are likely to be pricey, with estimates ranging between $150 and $500 for the three-dose vaccine; analysts are expecting good coverage. "Cost is going to be a major factor, but you've had more expensive vaccines like Prevnar that have shown good uptake," says Decision Resources analyst John Lebbs. "If you have the clinical justification and the public health issue and rationale—which you do for these vaccines—there's a very good likelihood that the vaccine will be integrated into the [CDC's Advisory Committee on Immunization Practices] immunization schedule." The ACIP is supposed to vote on this in June.

Getting onto the schedule—and obtaining that "universal vaccination" recommendation—is critical. "It means they feel the intervention is important enough for the public health of this country that everyone should get it, and there should be funds available for those children without insurance to get the vaccine," says Barr. "When universal vaccinations are made, uptake is quite a bit more robust because people expend the efforts to make sure the people who need it have access."

One of the convincing arguments for coverage is one based on cost effectiveness. PAP smear screening costs between $4 and $6 billion annually. However, much of that cost can be eliminated—GSK says 40 percent, or $2.4 billion—by using HPV vaccines to prevent the likelihood of abnormal PAP smears in the first place.

Understanding long-term protection Both Merck and GSK have pledged to conduct large-scale studies that follow women throughout their lives to definitively assess how the vaccines act in real-world populations. Such undertakings will take time and immense resources, but are necessary in creating the foundation of data to ensure maximum uptake of the vaccines. Already, some physicians have voiced their wish for this data. "If we vaccinate 12-year-old girls, will it still offer protection at age 25?" asks Myers. "A lot of follow-up, at least from Merck, is going to be in Denmark, Norway, and Iceland, which have electronic records that can link people and allow them to study how long the protection from the vaccine lasts, and if a booster is needed."

THE IMPACT FACTOR

Cervical cancer tends to strike women in their later years because it is so slow growing. And given that Merck and GSK plan to target the 9-15 year-olds, the benefits of vaccination won't be seen for some time. But the industry will see their impact in other areas.

First, Gardasil and Ceravix both rely on, and thus have validated, the use of "virus-like particle" technology, which stimulate immunity to the viruses by mimicking only the surface proteins of the viruses, but don't contain any genetic information. Some say the technology will be applicable for other viral infections with relatively small, simple viruses.

The use of adjuvants is also validated. Says Dubin, "Adjuvant technologies can make a difference. One example, beyond HPV, is a malaria vaccine in development where we have convincing evidence that the reason it appears to be effective is due to the adjuvant being used."

Still others view the introduction of these cancer vaccines in a much broader context, such as helping spark renewed interest in vaccines to treat viral infection or helping lay down needed physician and educational infrastructure that might one day be needed for an AIDS vaccine.

It is for this last point that Barr and Dubin envision more busy nights. "The greatest burden of disease lies in countries with undeveloped medical structures," says Dubin. "The more 'developing' the country, the more cases of cervical cancer. We have been gearing up for this. It requires a huge amount of manufacturing capacity—not to mention working with governments and NGOs, and dealing with the political environment in different countries. These are implementation issues, and where a majority of the challenges for us now lies."

OUT IN FRONT

As per FDA regulations, drug companies must wait until launch to market a product. And PhRMA guidelines advise waiting at least six months after launch to market to consumers. But Digene, a diagnostics company which has had an HPV test on the market since 1999, has already rolled out a glossy consumer advertising campaign to educate women about HPV. "You want to first educate physicians," says Digene's Pamela Rasmussen. "We have a huge amount of data, we're in all the guidelines, we had the thoughtleaders, yet some doctors told us they weren't going to change their habit [and use the HPV test] unless women were asking for it." Rasmussen also said that doctors, surprisingly, were forgoing the test because they didn't feel comfortable educating patients about HPV from scratch. "The DTC ads do a little bit of that job already for the doctors, so women are already aware when they go into the office." It also makes vaccine manufacturers' marketing efforts easier, in that a baseline of knowledge among the public is currently being established.