June 28, 2011

P7 protein resistance mutations identified; represent drug targets for hepatitis C virus

Public release date: 28-Jun-2011

Contact: Dawn Peters
healthnews@wiley.com
781-388-8408
Wiley-Blackwell

Combination therapies inhibiting p7 could prevent spread of HCV in the body

British researchers have identified specific resistance mutations for two classes of p7 inhibitor, which may explain their lack of effectiveness in clinical trials combined with current standard of care. Study results support the role of p7 inhibitor combinations as potential components of future HCV-specific therapies and are available in the July issue of Hepatology, a journal published by Wiley-Blackwell on behalf of the American Association for the Study of Liver Diseases.

More than 3% of the world population is infected with HCV, which causes severe liver disease. HCV is the leading cause of liver-related mortality and most common cause for liver transplantation in the U.S. Studies have shown that the current treatment of PEGylated interferon alpha (IFN) and ribavirin (Rib) does not adequately achieve a sustained virological response in many HCV patients. This, coupled with the high cost and poor patient compliance, continues to drive demand for new virus-specific therapies.

"The HCV p7 ion channel plays a critical role in infectious virus production, representing an important new therapeutic target," said lead researcher Dr. Stephen Griffin with the Institute of Molecular Medicine at the University of Leeds in the UK. Previously, Dr. Griffin and colleagues determined that p7 acts as a proton channel within HCV infected cells, and that its function could be blocked by small molecule inhibitors, resulting in a blockade of infectious virus production.

In the present study, the team set out to expand on their prior work by predicting inhibitor binding sites using molecular modeling, which were then validated by the identification of resistance mutations. This allowed the researchers to define the mode of action for two prototype p7 inhibitor classes—adamantanes (amantadine and rimantadine) and alkylated imino-sugars (IS). This confirmed not only specific, but distinct effects for these inhibitors on the p7 protein. As these drugs are known to be safe in humans, they could rapidly be combined with new direct-acting HCV drugs, while paving the way for the development of novel, more potent compounds.

Dr. Griffin explains, "Our study confirms that single amino acid changes can mediate resistance to p7 inhibitor drugs." The study describes that low fitness cost for the observed mutations suggest that a minimal genetic barrier to their selection exists, which explains the perceived lack of p7 inhibitor efficacy in clinical trials combined with IFN/Rib. "Further investigation into the molecular basis of p7 drug resistance will aid in the design of novel, more effective therapies to combat HCV," concluded Dr. Griffin.

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This study was conducted in collaboration with the laboratories of Professor Mark Harris, Professor Colin Fishwick and Dr. Richard Foster (University of Leeds), as well as Professor Steven Weinman (University of Kansas). Funding was through the UK Medical Research Council, Yorkshire Cancer Research and the University of Leeds Biomedical Health Research Centre.

Additional Media Contact:
Paula Gould
University of Leeds Communications & Press Office
+44 (0)113 343 8059
p.a.gould@leeds.ac.uk

This study is published in Hepatology. Media wishing to receive a PDF of the article may contact healthnews@wiley.com.

Full Citation:

Article: "Resistance Mutations Define Specific Antiviral Effects for Inhibitors of the Hepatitis C Virus (HCV) P7 Ion Channel." Toshana L. Foster, Mark Verow, Ann L. Wozniak, Matthew J. Bentham, Joseph Thompson, Elizabeth Atkins, Steven A. Weinman, Colin Fishwick, Richard Foster, Mark Harris and Stephen Griffin. Hepatology; Published Online: June 24, 2011 (DOI: 10.1002/hep.24371); Print Issue Date: July 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24371/abstract.

About the Journal

Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350 .

About Wiley-Blackwell

Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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Also See: Will new drugs block hepatitis C virus in its tracks?

Will new drugs block hepatitis C virus in its tracks?

Public release date: 28-Jun-2011

Contact: Paula Gould
p.a.gould@leeds.ac.uk
44-113-343-8059
University of Leeds

Targeted multi-drug treatments for hepatitis C patients that could stop the virus in its tracks have come a step closer, thanks to researchers at the University of Leeds, UK.

The study by Dr Stephen Griffin and colleagues, published in the journal Hepatology, reveals how two prototype small molecule drugs, known as p7 inhibitors, can each attack different parts of the hepatitis C virus. Their findings suggest that p7 inhibitors could be a powerful way of suppressing hepatitis C, when used together with the latest generation of 'direct-acting' drugs.

More than 170 million people - or 3% of the world's population - are infected with the hepatitis C virus. The virus causes severe liver disease and is a leading cause of liver-related deaths, organ transplants and liver cancer.

At the moment, patients are typically treated with PEGylated interferon alpha (IFN) and ribavirin (Rib) - drugs that work by boosting the patient's immune system. However, the effects of these drugs can depend on the individual patient's genetic make-up. To make matters worse, hepatitis C is often resistant to the therapy and fails to suppress the virus for long enough. The treatment is also expensive and can trigger unpleasant side effects. Many patients stop taking the drugs or do not take them when they should.

To address this, researchers are looking at new classes of drugs that work in a different way to either IFN or Rib and target the virus directly. The aim is to find groups of these 'direct-acting' drugs that each attack a different target, making it much, much harder for the virus to fight back.

University of Leeds researchers are focusing on drugs that target the p7 ion channel - a protein made by hepatitis C that allows the virus to continue spreading. In previous studies, Dr Griffin and colleagues worked out how the p7 ion channel could be blocked by certain types of small molecule, stopping the hepatitis C virus in its tracks. Their latest work looks at two particular classes of p7 inhibitor - adamantanes and alkylated imino-sugars – and confirms that these molecules do, indeed, attack their intended target through separate mechanisms.

The researchers used a combination of molecular modelling and lab-based experiments to study the drugs' interaction with hepatitis C. Importantly they observed how the virus responded to the two types of drug and determined that each of these responses was very different. This suggests that the drugs would work well in combination, tackling the virus on a number of fronts.

Lead author, researcher Dr Stephen Griffin, from the University of Leeds' School of Medicine, said: "Hepatitis C has always been an extremely difficult condition to treat effectively because the virus evolves so quickly and develops resistance to drugs that are used to treat it. This new class of small molecule drugs, the p7 inhibitors, attack the virus directly. As we have discovered here, they each do so in quite a different way which allows us to combine their effects.

"By learning how the hepatitis C virus reacts to these molecules, we can design drugs that are likely to be more effective for longer. We can also see how such drugs could be used together with other 'direct-acting' drugs that target alternative viral targets, rather than individually or with IFN/Rib. In other words, a similar approach to treatment as that used for HIV."

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The study was conducted in collaboration with Professor Mark Harris (University of Leeds, Faculty of Biological Sciences), Professor Colin Fishwick and Dr Richard Foster (University of Leeds, School of Chemistry) and Professor Steven Weinman (University of Kansas).

The work was funded by the UK Medical Research Council, Yorkshire Cancer Research and the University of Leeds Biomedical and Health Research Centre.

For further information:

Paula Gould, University of Leeds Communications & Press Office: Tel +44 (0)113 343 8059 , email p.a.gould@leeds.ac.uk

Dawn Peters, Wiley-Blackwell PR Consultant: Tel: +1 781 388 8408 , email: healthnews@wiley.com

Notes to editors:

1. Approximately 3% (170 million) of the world's population has been infected with the hepatitis C virus (HCV). For most countries, the prevalence of HCV infection is less than 3%. The prevalence is higher (up to 15%) in some countries in Africa and Asia, and highest (over 15%) in Egypt.

2. Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. Researchers estimate that at least 20 percent of patients with chronic hepatitis C develop cirrhosis. Hepatitis C is the cause of about half of cases of primary liver cancer in the developed world. Men, alcoholics, patients with cirrhosis, people over age 40, and those infected for 20 to 40 years are at higher risk of developing HCV-related liver cancer.

3. A copy of the paper is available on request (Resistance Mutations Define Specific Antiviral Effects for Inhibitors of the Hepatitis C Virus (HCV) P7 Ion Channel. Toshana L et al. Hepatology; Published Online AOP (DOI: 10.1002/hep.24371); Print Issue Date: July 2011. http://onlinelibrary.wiley.com/doi/10.1002/hep.24371/abstract

4. One of the UK's largest medical, health and bioscience research bases, the University of Leeds delivers world leading research in medical engineering, cancer, cardiovascular studies, epidemiology, molecular genetics, musculoskeletal medicine, dentistry, psychology and applied health. Treatments and initiatives developed in Leeds are transforming the lives of people worldwide with conditions such as diabetes, HIV, tuberculosis and malaria. http://www.leeds.ac.uk/

5. For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. http://www.mrc.ac.uk/

6. Harrogate-based Yorkshire Cancer Research (YCR), the UK's largest regional medical research charity, funds around £7m a year of internationally recognised cancer research. The 200 plus scientists and clinicians, funded by Yorkshire Cancer Research are among the world leaders in the fight against cancer and the charity has committed a further £15 million over the next few years to continue funding them. http://www.yorkshirecancerresearch.org.uk/

7. Hepatology is the premier publication in the field of liver disease, publishing original, peer-reviewed articles concerning all aspects of liver structure, function and disease. Each month, the distinguished Editorial Board monitors and selects only the best articles on subjects such as immunology, chronic hepatitis, viral hepatitis, cirrhosis, genetic and metabolic liver diseases and their complications, liver cancer, and drug metabolism. Hepatology is published on behalf of the American Association for the Study of Liver Diseases (AASLD). For more information, please visit http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1527-3350.

8. Wiley-Blackwell is the international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons, Inc., with strengths in every major academic and professional field and partnerships with many of the world's leading societies. Wiley-Blackwell publishes nearly 1,500 peer-reviewed journals and 1,500+ new books annually in print and online, as well as databases, major reference works and laboratory protocols. For more information, please visit http://www.wileyblackwell.com/ or our new online platform, Wiley Online Library (wileyonlinelibrary.com), one of the world's most extensive multidisciplinary collections of online resources, covering life, health, social and physical sciences, and humanities.

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Vertex Tops Merck in Early Hep C Drug Launch

By Adam Feuerstein 06/28/11 - 09:01 AM EDT

CAMBRIDGE, Mass. (TheStreet) --Vertex Pharmaceuticals'(VRTX_) new hepatitis C drug Incivek is outselling Victrelis, a rival drug from Merck(MRK_), in the early weeks of their respective commercial launches.

U.S. regulators approved Incivek and Victrelis in May just 10 days apart, which means Vertex and Merck began marketing the competing hepatitis C drugs essentially at the same time. Investors rarely get to watch companies launch two similar drugs simultaneously -- particular two drugs tapping into a multi-billion dollar market like hepatitis C -- so investors are paying close attention to the early prescriptions written for Incivek and Victrelis.

So far, Vertex is beating Merck, which means the marketing battle between Incivek and Victrelis is playing out largely as expected.

For the week ended June 17 (the most current data available), doctors wrote 460 prescriptions for Vertex's Incivek compared to 160 prescriptions written for Merck's Victrelis, according to weekly prescription data compiled by IMS Health. Weekly IMS drug prescription data tracks retail pharmacy, mail order and long-term care distribution channels.

That puts Incivek's market share at 75% compared to Victrelis' 25% with about five weeks of prescription data available. Even before the two drugs launched, investors were expecting Incivek to garner more prescriptions, with some analysts forecasting a 75% market share split for Incivek at peak.

The current consensus 2011 sales forecast for Incivek is $490 million, according to the sell-side analysts who cover Vertex. Buyside investors are expecting more. A survey of 188 investors in early June yielded a 2011 consensus sales estimate of $568 million, including $43 million in the second quarter that ends June 30, according to ISI Group biotech analyst Mark Schoenebaum, who conducted the survey.

Bank of America Merrill Lynch, through IMS, is tracking daily prescriptions of Incivek for those investor clients who are totally obsessed with the launch of the new hepatitis C drugs. Those daily IMS reports, culled from prescriptions reported by retail pharmacies only, also show Incivek topping Victrelis to date.

Doctors are showing a preference for Incivek over Victrelis so far, but that advantage isn't yet translating into a higher Vertex stock price. At Monday's close of $48.73, Vertex is down 15% from May 23, the day Incivek was approved, and down 21% from the stock's 52-week high reached on May 12.

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New Vertex ads focus on disease, not treatment

One Vertex ad on MBTA buses features an aging rocker. Vertex ads direct consumers to a website and a free nurses helpline. (Vertex Pharmaceuticals Inc.)

By Robert Weisman
Globe Staff / June 28, 2011
 
CAMBRIDGE — The ads began popping up this spring.

An aging rocker, guitar in hand, peers from a poster mounted inside MBTA buses. “I survived disco,’’ the text reads. “I can fight hepatitis C.’’

On the radio, a reassuring voice says: “Hepatitis C is a serious disease, but it can be cured. You can fight it. Now there’s a program to help you get ready.’’

The poster and radio spots appear to be public service messages about a liver-destroying virus few are aware of. But if you look or listen carefully, you’ll notice the name of the sponsor — Cambridge biotechnology company Vertex Pharmaceuticals Inc., which recently won federal approval to sell a new hepatitis C drug.

Its pill, being sold under the brand name Incivek (pronounced inn-see-veck), is expected to quickly become the biggest selling drug from a Massachusetts company in nearly a decade, with annual sales projected to hit $2 billion within three years. But rather than drum up consumer interest in the product itself, Vertex is conducting a so-called unbranded campaign that doesn’t mention Incivek. The idea, company officials say, is to let more people know about hepatitis C.

Educating the public about the disease also is a priority for pharmaceutical giant Merck & Co., which is selling a hepatitis C drug to compete with Vertex’s and has enlisted legendary rocker Gregg Allman for a similar awareness campaign.

The two companies are promoting information about the illness over their brand-name medicines — at least for now — because many of the 3.2 million Americans believed to carry the virus don’t realize they are infected, according to numbers from the Centers for Disease Control and Prevention in Atlanta.

“Three quarters of the people don’t know they have the disease, and most of the people who know don’t get treated,’’ said Pamela Stephenson, Vertex’s vice president for marketing excellence.

“People out there are searching for information. They can be scared. They can be alone,’’ Stephenson said. “At the core of what we’re trying to do is to find people who have hepatitis C and help them lead a better life.’’

Untreated, hepatitis C can eventually cause cancer or liver scarring, and about 10,000 people die from the disease every year in the United States. Many of those at risk are baby boomers who contracted the virus through intravenous drug use or blood transfusions in the 1960s or 1970s, before the blood supply was safeguarded, and have lived for decades without symptoms.

Incivek is the first drug the 22-year-old Vertex brought to market and sold on its own. While the pill is positioned to become a major success for the company — which last week broke ground for a massive corporate headquarters on the South Boston Waterfront — it will compete with a Merck’s drug, which won Food and Drug Administration approval 10 days before Incivek last month.

Both treatments work by blocking the enzyme that allows the hepatitis C virus to replicate. Though Merck’s drug got out of the gate first, Vertex’s did better in clinical trials and is projected to win a larger market share.

The decision to forgo a purple-pill-style marketing blitz in favor of a campaign focused squarely on hepatitis C is somewhat unusual. While drug makers have used unbranded campaigns in the past, it’s typically done when they are first to market with a treatment and don’t have to worry about a rival product. By contrast, drugs for hepatitis C have been around for years, though the new class of drugs — used with existing therapies — promises a more effective treatment with shorter duration.

Vertex ads direct consumers to a website, http://www.bettertoknowc.com/, and a free nurses helpline, 1-855-HEPCINFO , where they can learn more about the virus and treatments. But the focus of the ads is squarely on introducing hepatitis C to the public.

“A lot of drug companies are trying to expand sales of their products even to people who don’t need it,’’ said Rajendra Sisodia, professor of marketing at Bentley University in Waltham. “This campaign is more of a service to the public, promoting awareness of a hidden killer, a hidden disease people aren’t aware of. Companies that come from a place of service can add value and ultimately help themselves. Sales of the drug are a byproduct.’’

Merck, based in Whitehouse Station, N.J., also has launched a consumer awareness website, http://www.allabouthepc.com/. Like Vertex, Merck does not directly promote its new product, Victrelis, but urges consumers to get more information about the disease and consult doctors or nurses. Merck has also teamed with Allman, who was infected with hepatitis C and received a liver transplant. The Allman Brothers Band will perform a World Hepatitis Day benefit concert in New York on July 27.

Though the companies have not collaborated, by increasing the pool of people seeking treatment, both will benefit. Merck and Vertex also run parallel campaigns to educate doctors and nurses about their products.

Another push to educate the public about hepatitis C is being readied by the CDC, which is writing new guidelines that will recommend one-time screenings of people born between 1946 and 1964. Currently, people are tested for hepatitis C only if they are considered high risk.

Given that about 3 percent of that age group — one out of 33 people — is thought to be infected, broader screening makes sense, said Dr. John W. Ward, director of the CDC’s division of viral hepatitis. “These people are aging into a risk period for this disease,’’ he said.

Ward said government officials are not explicitly coordinating their education efforts with the drug makers, though he said they are working toward the same goal. “There’s a huge need to increase awareness about hepatitis,’’ he said. “What’s important is that all these campaigns provide accurate information about the disease, the modes of transmission, and who’s at risk.’’

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