Tag Archives: Merck

Can HPV Vaccination Be Simplified?

The human papillomavirus vaccine was recommended for routine use in 11-12 year old girls in 2007. But by 2010, the most recent year for which data are available, less than half had received one dose of the three-dose series and fewer than a third had received all three. The inconvenience of the need for three separate office visits along with the vaccine’s price – about $130 per Gardasil dose, as of July 2011 – have certainly contributed to the low uptake.

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Now, some parts of the world – including Mexico, Switzerland, and parts of Canada have moved to either a two-dose schedule, or a so-called “extended dose” schedule, in which the third dose is delayed until 5 years after the second one. (In the current U.S. three-dose schedule, doses two and three are given at 2 and 6 months, respectively, after dose one.)

“There has been emerging interest in HPV vaccine schedules with fewer than three doses, for a variety of reasons. These schedules could facilitate implementation, they may be more convenient for providers, parents, and vaccinees, and of course they would be cost-saving,” said Dr. Lauri Markowitz, of the Centers for Disease Control and Prevention, at a recent meeting of the CDC’s Advisory Committee on Immunization Practices.

No data on the efficacy of fewer than three doses have been published by either Merck or GlaxoSmithKline from their pivotal trials of Gardasil and Cervarix, respectively. But some other data are available for both vaccines. A nonrandomized study in Costa Rica that included more than 1,100 women who had received just one or two doses of Cervarix suggested that two doses or maybe even just one – could be as protective as three doses against infection at 4 years.

And in an as-yet unpublished study done in Canada, immune responses against both HPV 16 and 18 at 3 years were similar between two doses of Gardasil given at age 9-13 years and three doses given at age 16-26 years. But, there are limited efficacy data and no long-term data, Dr. Markowitz said.

Electron micrograph of human papillomavirus (HPV) / Courtesy of the National Cancer Institute

In an e-mail, Deb Wambold of Merck Vaccines said that, while the company does support studies of alternative dosing schedules for HPV vaccination including two-dose regimens, so far those studies are “interesting preliminary explorations in select subpopulations of vaccinees,” and “It is important to note that there are no data on the clinical efficacy or durability of effectiveness with two doses of either of the HPV vaccines, as we have for the recommended three-dose vaccination regimen.”

Dr. Joseph A. Bocchini Jr., who chairs the ACIP HPV vaccine working group, concurred. In an interview at the ACIP meeting, he noted that the long-term efficacy of two doses is “worth looking at,” as is the varying of three-dose schedules. “But, at this point, there are too few data to apply this to recommendations in the United States.”

More data from ongoing trials will be available in the next few years, Dr. Markowitz said.

-Miriam E. Tucker (@MiriamETucker on Twitter)

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Filed under Allergy and Immunology, Epidemiology, Family Medicine, IMNG, Infectious Diseases, Internal Medicine, Obstetrics and Gynecology, Oncology, Pediatrics, Primary care, Uncategorized

HPV Changes the Face of Head/Neck Cancer

Just a few years ago, tobacco and alcohol use were presumed to be the main causes of head and neck cancers. Evidence of oropharyngeal cancer associated with human papillomavirus (HPV) first appeared about 10 years ago, but it wasn’t until 2010, with the publication of 2 papers showing far greater survival among HPV-positive patients with head and neck cancer, that oncologists suddenly realized that they were likely dealing with two distinct diseases.

“It’s become clear that the disease we thought was one disease related to tobacco and alcohol is now being parsed into two major categories,” Dr. Maura L. Gillison said last week in Phoenix at the 2012 Multidisciplinary Head and Neck Cancer Symposium. At the meeting, she presented her group’s data showing that the overall prevalence of oral HPV infection in people aged 14-69 years is 6.9%, and that the prevalence is much higher among men than women. The Merck-supported trial paper was published online in JAMA on January 26, coinciding with her presentation.

Tissue section from a head and neck cancer patient / Courtesy of Tom Carey, Ph.D.

In a separate talk, Dr. Gillison summarized previous work from her group showing that the incidence of HPV-related cancer is rising while HPV-negative cancer is declining, consistent with the decline in tobacco use and changes in sexual behavior that increase HPV transmission. Overall survival of head and neck cancer has improved over the last decade, a trend that is likely due both to the improved prognosis among HPV-positive patients and to the decline in tobacco use rather than to advances in treatment, she said.

This recently heightened role of HPV in head and neck cancer  – and the awareness of it – has impacted the field of oncology in several ways. For one, it has dramatically changed the way research is done, conference chair Dr. Ezra Cohen told me. “It has made a tremendous difference in the way clinical trials are conducted, because it makes absolutely no sense to lump these patients together. Now all clinical trials will either stratify for HPV status or design completely separate studies, because they truly are two biologically different diseases.”

Clinically, patients with head and neck cancers are now routinely tested for HPV. This wasn’t the case prior to 2010. And those who test positive are counseled differently, since their prognosis is better. Indeed, Dr. Cohen said, HPV-positive head/neck cancer patients appear to respond better to just about every type of treatment, including surgery.

What’s more, Dr. Gillison told me, HPV has essentially upended some of the tools oncologists use to predict outcomes in head and neck cancer patients. One example is the current tumor staging system, which doesn’t take into account HPV status. A Stage 3 or 4 cancer which carries a poor prognosis among HPV-negative patients might carry the prognosis now associated with Stage 1 cancer among those who are HPV-positive. And another factor that has been shown to predict poor outcome in HPV-negative patients, the presence of extracapsular extension, appears to have little impact in those who are HPV-positive.

“So all these things that we take as firmly established and drivers of treatment decisions in this new setting are all in question,” she said.

Tissue section from the same head/neck cancer, with brown stain of an HPV marker protein called p16 / Courtesy of Tom Carey, Ph.D.

Thus far there have been no major changes in treatment, but Dr. Cohen believes that is likely to change as more data become available. He is currently leading a clinical trial  in collaboration with Novartis Pharmaceuticals looking at treatment with reduced radiation doses – and thereby reduced toxicity – for patients who have a good response to induction chemotherapy. Such patients are usually HPV positive.

Another study, funded by the National Cancer Institute, randomizes HPV positive patients to radiation combined with either chemotherapy or a monoclonal antibody, with the hypothesis that the latter will be better tolerated.

Dr. Cohen cautioned that treatment changes won’t come immediately. “Many of us in the field believe that there will be different therapies developed for [HPV-positive] patients, but it takes time to do that. It’s hard to make those changes, especially when we are curing the majority of these patients.”

-Miriam E. Tucker (@MiriamETucker on Twitter)

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Filed under Allergy and Immunology, Family Medicine, Geriatric Medicine, IMNG, Infectious Diseases, Internal Medicine, Neurology and Neurological Surgery, Oncology, Ophthalmology, Otolaryngology, Primary care, Uncategorized

Can Crowdsourcing Speed Diabetes Drug Discovery?

When it comes to finding treatments and cures for complicated conditions such as diabetes, why not cast the widest net possible for new ideas? That’s the thinking behind the Juvenile Diabetes Research Foundation’s new collaboration with an organization called Innocentive to seek innovative proposals from the general public for a novel glucose-responsive insulin drug. The “Challenge,” which offers a $100,000 reward, is an example of crowdsourcing in drug discovery, a recent concept that has been gaining momentum.

manbeastextraordinaire (Jake Brown) / Wikimedia Commons

“Originally, crowdsourcing was defined as a mechanism by which specific problems are communicated to an unknown group of potential solvers in the form of an open call, usually via the Internet; the community (the “crowd”) is asked to provide solutions and the ‘winners’ are rewarded,” Dr. Monika Lessl and Dr. Khusssru Asadullah, of Global Drug Discovery Bayer Healthcare Pharmaceuticals, Berlin, wrote earlier this year in Nature Reviews/Drug Discovery.

Eli Lilly was the first company to introduce the crowdsourcing concept in drug discovery by establishing the InnoCentive platform in 2001. Now an independent organization, InnoCentive has a “solver” community of more than 200,000 experts from 20 countries. In Innocentive’s “Challenge Platform” model, intellectual property (IP) is transferred from the solver to the “seeker” in return for a financial reward. In contrast, with Bayer Healthcare’s Grants4Targets, IP remains fully with the applicants initially, and subsequent collaborative agreements are negotiated for promising agents. In yet another crowdsourcing model sponsored by the UK’s Medical Research Council, IP is jointly owned and revenue is split between the parties.

Drs. Lessl and Asadullah write that in order for drug discovery crowdsourcing to be successful, “it is critical that the questions or challenges to be addressed are suitable, precisely defined and clearly presented, and that what is expected from potential solvers and offered by the searching organizations is clearly communicated.” Indeed, the expectation is clearly spelled out for the JDRF/InnoCentive initiative: “What we need is a sophisticated insulin that will take the guesswork out of managing diabetes by working the same way insulin works in people without diabetes,” Aaron Kowalski, Ph.D., assistant vice president of Treatment Therapies at JDRF, said in a press statement.

This isn’t JDRF’s first support of research on glucose-responsive insulin. Back in 2008, JDRF formed a $1 million partnership with a company called SmartCells, Inc. to advance the preclinical development of a product called SmartInsulin. SmartCells has since been acquired by Merck, which is continuing the product’s development. As Dr. Kowalski told me, “JDRF remains interested and excited in the clinical development of SmartInsulin by Merck.”

Photo by Miriam E. Tucker

So why is JDRF now simultaneously crowdsourcing the concept? Again, it’s about that wide net. First, Dr. Kowalski said, there may be multiple innovative ways to design glucose-responsive insulins. Second, it’s possible that not all insulin-dependent diabetes patients would respond the same way to a single type of insulin. “Therefore, we aim to stimulate more approaches that we hope will provide multiple options to patients with diabetes.”

Third, because the approval process for new drugs is highly variable, “The more options that are available, the more likely it is that one of them will make its way through the regulatory process.” Bottom line: “Insulin-dependent diabetes remains an urgent, unmet medical need, and it is important for JDRF to take a multi-pronged approach to tackle this challenge.” By opening up the challenge to the entire world, crowdsourcing would seem to be the ultimate “multi-pronged” approach.

Anyone with a solution that fits the proposed criteria is eligible to enter the Challenge, which requires only a written proposal. Submissions will be accepted through November 9, 2011.

—Miriam E. Tucker (@MiriamETucker on Twitter)

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