.jpg)
Getz Pharma to launch therapy for Hepatitis C patients
* Biotechnology-based drug for hepatitis C will be manufactured by a Pakistani company for the first time
By Irfan Aligi
KARACHI: Getz Pharma would launch the Pegylated Interferon therapy for the treatment of hepatitis C in Pakistan. The new therapy would be highly cost-effective and easy to use as the manufacturer and presenters of the new therapy have considered patients? care and comfort. It would also be the first time that a biotechnology-based essential drug would be manufactured by Getz Pharma, a Pakistani company. It is pertinent to mention that approximately every 20th person in Pakistan is infected with hepatitis C.
The initiative taken by Getz Pharma to invest in the local manufacturing of Pegylated Interferon (Unipeg) in the country would substantially reduce the cost of treatment for a person suffering from hepatitis C. The company has invested in research and development to formulate this molecule with the help of a team of scientists from the Netherlands, led by Dr Ben Rademaker, a PhD-holder.
Getz Pharma Managing Director and Chief Executive Officer Khalid Mehmood, during a press conference on Thursday, said the size of the country?s pharmacy market is about Rs 119 billion, which is growing by 12 to 13 percent. Henceforth, they have been able to export pharmacy goods to 45 countries around the world. The pharmacy sector in the country is the largest employment provider, with around five million people employed. Pakistan?s pharmacy industry meets 90 percent of the needs of pharmacy goods.
Pharmaceutical exports are at their highest as compared to other corporate sectors in the country and have achieved a 29 percent growth, which is four times of the country?s textile exports. Still, the country?s spending on health according to annual budgetary allocations is just 0.4 percent of the GDP, while Bangladesh is spending 0.8 percent, Khalid said.
Investment: He said Getz Pharma was set up in 1995 as a small company with only 45 employees, while today the number of its employees exceeded 2,500 worldwide, and 1,850 people in Pakistan. Getz Pharma invested Rs 4 billion in revamping existing facilities, in purchasing state-of-the-art production, quality control from 2005 to 2009. It has a plan to meet the 54 percent target of exporting medicines. According to the Federal Bureau of Revenue, Getz Pharma was the second largest taxpayer unit in terms of taxes and duties with an estimated Rs 636 million in 2009, he added.
Khalid said the company?s total investment in Pakistan was Rs 4 billion in the last three years, including investment in manufacturing technology of the first locally manufactured recombinant human insulin. It plans to invest an equal amount in the coming two years in new technologies that would result in local manufacturing of drugs that are currently being imported at high costs. It may be mentioned that Getz Pharma is the single largest exporter of pharmaceutical products from the country. It was estimated that the company?s exports account for approximately 40 percent of the country?s total pharmaceutical exports.
Dr Bernardus Rademaker, speaking on the occasion, said the analytical, toxicological and pharmacokinetic studies for Unipeg (Pegylated Interferon Alpha 2a) had been carried out in Europe, comparing it to the existing research molecule.
New era: He said in addition, bioactivity and potency had also been evaluated at the Centre for Applied Molecular Biology in Lahore, a premier institute of the Science and Technology Ministry. Specialised manufacturing and testing technology is required for manufacturing the Unipeg. He said Getz Pharma had acquired the technology at a substantial investment and a number of these tests were not currently available in the country?s pharmaceutical industry. Through this molecule, Getz Pharma would herald a new biotech era in the country, he added.
To a question, Dr Rademaker said since the molecule was not available in the US, it was not necessary to seek approval form the US FDA. He also said collaboration with Getz Pharma was not business-oriented, but it had been overwhelmingly planned that the hepatitis C affected population of the country should be provided with a cost-effective and latest mode of treatment.
Dr Rademaker holds a PhD in biotechnology from the State University Utrecht, Holland. He is the founder and CEO of InProPharma, a company specialising in technology platforms for the production of biologically active proteins. Prior to setting up his own company, Rephartox BV, a contract research company for the pharmaceutical industry, he was the director of Corporate Drug Development at the Rhein Biotech NV, Maastricht and the Green Cross Vaccine Company, Seoul, Korea. He is a member of the Dutch Pharmacological Society and is a registered pharmacologist. He has authored more than 50 scientific publications, and many regulatory affairs documents.
Sunday, June 20, 2010
Blueberry Ameliorates Hepatic Fibrosis, Study Finds
Blueberry Ameliorates Hepatic Fibrosis, Study Finds
"In summary, in the present study, blueberries possessed a therapeutic effect on CCl4-induced hepatic fibrosis in rats through inhibiting liver inflammation and lipid peroxidation, and may be not related to the induction of phase-II enzymes through the activation of Nrf2 in rat liver during long-term of CCl4. More detailed study is needed." see link below to full text.
ScienceDaily (June 17, 2010) — Conventional drugs used in the treatment of liver diseases inevitably have side effects. An increasing number of natural substances have been studied to explore if they have protective effects on the liver. Blueberries have unique effects on human retinal, brain and tumor cells, but reports about the effects of blueberries on liver diseases are lacking.
A research article to be published on June 7, 2010 in the World Journal of Gastroenterology addresses this question. The research team led by Ming-Liang Cheng, MD, from Department of Infectious Diseases, Guiyang Medical College, Guiyang, presented some data from their research on the effectiveness of blueberries on liver fibrosis induced in laboratory animals.
Their study showed that blueberries could reduce liver indices, serum levels of hyaluronic acid and alanine aminotransferase, and increase levels of superoxide dismutase and decrease levels of malondialdehyde in liver homogenates compared with the model group. Meanwhile, the stage of hepatic fibrosis was significantly weakened. Blueberries increased the activity of glutathione-S-transferase in liver homogenates and the expression of Nrf2 and Nqo1 compared with the normal group, but there was no significant difference compared with the model group.
The authors suggest that blueberry consumption is beneficial for hepatic diseases (including fibrosis).
Journal Reference:
1. Wang YP, Cheng ML, Zhang BF, Mu M, Wu J. Effects of blueberry on hepatic fibrosis and transcription factor Nrf2 in rats. World J Gastroenterol, 2010; 16 (21): 2657-2663 DOI: http://www.wjgnet.com/1007-9327/full/v16/i21/2657.htm
"In summary, in the present study, blueberries possessed a therapeutic effect on CCl4-induced hepatic fibrosis in rats through inhibiting liver inflammation and lipid peroxidation, and may be not related to the induction of phase-II enzymes through the activation of Nrf2 in rat liver during long-term of CCl4. More detailed study is needed." see link below to full text.
ScienceDaily (June 17, 2010) — Conventional drugs used in the treatment of liver diseases inevitably have side effects. An increasing number of natural substances have been studied to explore if they have protective effects on the liver. Blueberries have unique effects on human retinal, brain and tumor cells, but reports about the effects of blueberries on liver diseases are lacking.
A research article to be published on June 7, 2010 in the World Journal of Gastroenterology addresses this question. The research team led by Ming-Liang Cheng, MD, from Department of Infectious Diseases, Guiyang Medical College, Guiyang, presented some data from their research on the effectiveness of blueberries on liver fibrosis induced in laboratory animals.
Their study showed that blueberries could reduce liver indices, serum levels of hyaluronic acid and alanine aminotransferase, and increase levels of superoxide dismutase and decrease levels of malondialdehyde in liver homogenates compared with the model group. Meanwhile, the stage of hepatic fibrosis was significantly weakened. Blueberries increased the activity of glutathione-S-transferase in liver homogenates and the expression of Nrf2 and Nqo1 compared with the normal group, but there was no significant difference compared with the model group.
The authors suggest that blueberry consumption is beneficial for hepatic diseases (including fibrosis).
Journal Reference:
1. Wang YP, Cheng ML, Zhang BF, Mu M, Wu J. Effects of blueberry on hepatic fibrosis and transcription factor Nrf2 in rats. World J Gastroenterol, 2010; 16 (21): 2657-2663 DOI: http://www.wjgnet.com/1007-9327/full/v16/i21/2657.htm
Community Testimony at Hepatitis Congress Hearing Yesterday
Community Testimony at Hepatitis Congress Hearing Yesterday
Viral Hepatitis Prevention
6/17/2010, 12:14 p.m. EDT
The Associated Press
(AP) — xfdte VIRAL-HEPATITIS sked
TESTIMONY June 17, 2010 MR. MICHAEL NINBURG EXECUTIVE DIRECTOR HEPATITIS EDUCATION PROJECT HOUSE Oversight and Government Reform VIRAL HEPATITIS PREVENTION Roll Call, Inc. 1255 22nd Street N.W. Washington, D.C. 20037 Transcript/Programming: Tel. 301-731-1728 Sales: Tel. 202-419-8500 ext 599 sales@cqrollcall.com www.cqrollcall.com Roll Call, Inc. is a private firm not affiliated with the U.S. Government. Copyright 2010 by Roll Call, Inc. Washington, D.C. U.S.A. All materials herein are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcast without the prior written permission of Roll Call, Inc. You may not alter or remove any trademark, copyright or other notice from copies of the content.Statement of Mr. Michael Ninburg Executive Director Hepatitis Education Project.
June 17, 2010
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
As Executive Director of the Hepatitis Education Project and a Steering Committee Member of the National Viral Hepatitis Roundtable, I respectfully submit testimony for the record for the hearing "Viral Hepatitis: The Secret Epidemic" and in response to the Institute of Medicine's recent report, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.
Since 2001, I have had the privilege of managing the Hepatitis Education Project (HEP), a national nonprofit organization based in Seattle, Washington dedicated to improving the lives of those affected by hepatitis. HEP works with populations most affected by viral hepatitis and often least connected to the health care system. Our partners include local, state and federal agencies as well as other community-based organizations. In this testimony, I will address the urgency of the hepatitis B and hepatitis C epidemics; the role of community-based organizations in addressing this crisis; and my personal experience.
Two Viruses, One Crisis
The urgency of the public health threat posed by hepatitis B and hepatitis C to our country cannot be overstated. More than 5 million Americans are living with chronic viral hepatitis, or almost 2 percent of the U.S. population. Most of those living with hepatitis B or hepatitis C are unaware of their infection and often remain asymptomatic for decades. Those who remain undiagnosed can unwittingly transmit the viruses to others and unknowingly do things to exacerbate their own liver damage. Many will be diagnosed only when their liver is failing. Sadly, thirty percent or more will eventually develop cirrhosis of the liver and some of those will die from endstage liver disease. Others will die from liver cancer.
Much of the disease burden from viral hepatitis is preventable. Hepatitis B is preventable through a simple series of vaccinations. For those who are already living with chronic viral hepatitis, the prognosis is usually very good when diagnosis is made early. Hepatitis B and hepatitis C are treatable conditions; and hepatitis C is often curable. For people to be treated for hepatitis, however, they have to be diagnosed. This remains one of our greatest challenges.
Viral hepatitis in the U.S. must also be viewed through the lens of health disparities. Hepatitis B disproportionately affects Asian Americans and Pacific Islanders (API) at rates more than twenty times that of their non-API counterparts. A staggering 1 in 10 foreign-born APIs has chronic hepatitis B. For new hepatitis B infections, there are racial, behavioral and geographic disparities. African American men and injection drug users have the highest rates of those newly infected with hepatitis B; and southern states have a disproportionate number of those new infections.
Hepatitis C disproportionately affects African Americans and Hispanics. And the majority of new hepatitis C infections occur in injection drug users. The real ticking time-bomb, though, is the prevalence of chronic hepatitis C among baby boomers, those born between 1946 -1964. It is estimated that 2-3 million boomers are currently living with hepatitis C. Most of these men and women were infected more than 30 years ago; the overwhelming majority remains unaware of their status. For the fortunate minority who get diagnosed, many will already have advanced liver disease that is more difficult to treat and manage and leads to progressively worsening and costly health outcomes such as end- stage liver disease and liver cancer. These outcomes are preventable but not if we maintain the current programs, policies and levels of funding for prevention.
Addressing the Epidemics - the Role of Community-Based Organizations Community-based organizations like the Hepatitis Education Project do much of the work related to viral hepatitis prevention, testing, education and referral to medical care. Programs at my agency include hepatitis A and B vaccination; hepatitis C antibody testing; a national support hotline; education programs for at-risk youth, prisoners, public health workers and medical providers. HEP also operates one of the few walk-in resource centers for hepatitis patients in the country.
Unlike many other disease states, there is very little federal support for these efforts. In FY2010, for example, the Division of Viral Hepatitis (DVH) at the Centers for Disease Control and Prevention (CDC) received $19.3 million. By way of comparison, the budget for domestic HIV prevention for the same period was more than $600 million. Of the $19.3 budget CDC allocated in FY 2010, about $5 million went to states and some city health departments, or about $90,000 for each state and each of five cities. This is a woefully inadequate amount to address epidemics that affect more than 5 million people less than $1 per patient per year.
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
Viral Hepatitis Prevention
6/17/2010, 12:14 p.m. EDT
The Associated Press
(AP) — xfdte VIRAL-HEPATITIS sked
TESTIMONY June 17, 2010 MR. MICHAEL NINBURG EXECUTIVE DIRECTOR HEPATITIS EDUCATION PROJECT HOUSE Oversight and Government Reform VIRAL HEPATITIS PREVENTION Roll Call, Inc. 1255 22nd Street N.W. Washington, D.C. 20037 Transcript/Programming: Tel. 301-731-1728 Sales: Tel. 202-419-8500 ext 599 sales@cqrollcall.com www.cqrollcall.com Roll Call, Inc. is a private firm not affiliated with the U.S. Government. Copyright 2010 by Roll Call, Inc. Washington, D.C. U.S.A. All materials herein are protected by United States copyright law and may not be reproduced, distributed, transmitted, displayed, published or broadcast without the prior written permission of Roll Call, Inc. You may not alter or remove any trademark, copyright or other notice from copies of the content.Statement of Mr. Michael Ninburg Executive Director Hepatitis Education Project.
June 17, 2010
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
As Executive Director of the Hepatitis Education Project and a Steering Committee Member of the National Viral Hepatitis Roundtable, I respectfully submit testimony for the record for the hearing "Viral Hepatitis: The Secret Epidemic" and in response to the Institute of Medicine's recent report, Hepatitis and Liver Cancer: A National Strategy for Prevention and Control of Hepatitis B and C.
Since 2001, I have had the privilege of managing the Hepatitis Education Project (HEP), a national nonprofit organization based in Seattle, Washington dedicated to improving the lives of those affected by hepatitis. HEP works with populations most affected by viral hepatitis and often least connected to the health care system. Our partners include local, state and federal agencies as well as other community-based organizations. In this testimony, I will address the urgency of the hepatitis B and hepatitis C epidemics; the role of community-based organizations in addressing this crisis; and my personal experience.
Two Viruses, One Crisis
The urgency of the public health threat posed by hepatitis B and hepatitis C to our country cannot be overstated. More than 5 million Americans are living with chronic viral hepatitis, or almost 2 percent of the U.S. population. Most of those living with hepatitis B or hepatitis C are unaware of their infection and often remain asymptomatic for decades. Those who remain undiagnosed can unwittingly transmit the viruses to others and unknowingly do things to exacerbate their own liver damage. Many will be diagnosed only when their liver is failing. Sadly, thirty percent or more will eventually develop cirrhosis of the liver and some of those will die from endstage liver disease. Others will die from liver cancer.
Much of the disease burden from viral hepatitis is preventable. Hepatitis B is preventable through a simple series of vaccinations. For those who are already living with chronic viral hepatitis, the prognosis is usually very good when diagnosis is made early. Hepatitis B and hepatitis C are treatable conditions; and hepatitis C is often curable. For people to be treated for hepatitis, however, they have to be diagnosed. This remains one of our greatest challenges.
Viral hepatitis in the U.S. must also be viewed through the lens of health disparities. Hepatitis B disproportionately affects Asian Americans and Pacific Islanders (API) at rates more than twenty times that of their non-API counterparts. A staggering 1 in 10 foreign-born APIs has chronic hepatitis B. For new hepatitis B infections, there are racial, behavioral and geographic disparities. African American men and injection drug users have the highest rates of those newly infected with hepatitis B; and southern states have a disproportionate number of those new infections.
Hepatitis C disproportionately affects African Americans and Hispanics. And the majority of new hepatitis C infections occur in injection drug users. The real ticking time-bomb, though, is the prevalence of chronic hepatitis C among baby boomers, those born between 1946 -1964. It is estimated that 2-3 million boomers are currently living with hepatitis C. Most of these men and women were infected more than 30 years ago; the overwhelming majority remains unaware of their status. For the fortunate minority who get diagnosed, many will already have advanced liver disease that is more difficult to treat and manage and leads to progressively worsening and costly health outcomes such as end- stage liver disease and liver cancer. These outcomes are preventable but not if we maintain the current programs, policies and levels of funding for prevention.
Addressing the Epidemics - the Role of Community-Based Organizations Community-based organizations like the Hepatitis Education Project do much of the work related to viral hepatitis prevention, testing, education and referral to medical care. Programs at my agency include hepatitis A and B vaccination; hepatitis C antibody testing; a national support hotline; education programs for at-risk youth, prisoners, public health workers and medical providers. HEP also operates one of the few walk-in resource centers for hepatitis patients in the country.
Unlike many other disease states, there is very little federal support for these efforts. In FY2010, for example, the Division of Viral Hepatitis (DVH) at the Centers for Disease Control and Prevention (CDC) received $19.3 million. By way of comparison, the budget for domestic HIV prevention for the same period was more than $600 million. Of the $19.3 budget CDC allocated in FY 2010, about $5 million went to states and some city health departments, or about $90,000 for each state and each of five cities. This is a woefully inadequate amount to address epidemics that affect more than 5 million people less than $1 per patient per year.
As a result of this inadequate government response, organizations like the Hepatitis Education Project are vaccinating more people against hepatitis A and B, and testing more people for hepatitis C than any public health district in our state. We are proud of the work we do, but the efforts of community-based organizations like ours should complement, not substitute, the work of governmental and public health agencies. I am hopeful that this hearing and the IOM report will help to outline and stimulate an appropriate governmental response to these twin epidemics and provide the rationale needed to increase funding for critical programs and services.
Two Viruses, One Family
Until very recently I was a hepatitis patient, an experience that is often fraught with uncertainty. When I was diagnosed with hepatitis C relatively little was known about the virus. Hepatitis C was only discovered in 1989, and from the early through the late 90's this new epidemic was often compared to HIV except that it attacked the liver, not the immune system. Through the mid-90's, reports about hepatitis C grew increasingly dire. People with hepatitis C were dying from their disease. Some people were lucky enough to get a liver transplant, but that was thought to just delay the inevitable.
I sought medical care for my hepatitis C in 2000. By then, the medical community had a better understanding of the natural history of the disease, but there was still much that they did not know. In 2002, I had a liver biopsy which showed that I had some liver damage, but not enough to warrant immediate treatment. I had the kind of hepatitis C that responded to treatment about 50% of the time. With newer, more effective treatments thought to be commercially available within 5 years I decided to wait for the next class of drugs and in the meantime monitor the health of my liver. Five years came and went and so did the expected due date for the next class of drugs. Now, I was looking at 2010 at the earliest. I had my second liver biopsy in 2007 and the results were not what I wanted to hear. My liver damage was progressing and if I didn't do something, it was likely that I would progress to cirrhosis relatively soon. Once I had progressed to cirrhosis, there would be other potential complications.
In January, 2009, I was very fortunate to enter a clinical trial looking at a promising experimental new drug to treat hepatitis C. The virus rapidly became undetectable in my body and I completed treatment in December, 2009. Just last month I received my final lab results and learned that I am cured. I happily use the past tense now when I say that I was a hepatitis patient.
I talk about my hepatitis story because it the story I know best. It is not, however, the story that is most important to me - that would be the story of my wife, Lily, and our little boy, Sacha. Shortly after I met Lily, I told her that I had hepatitis C and explained to her what that meant and how it was transmitted. Later I explained that there was another epidemic that was equally invisible to the general public - hepatitis B. I knew that among the groups at greatest risk were people born in countries where hepatitis B is endemic. One of those countries is China - where Lily was born. I asked Lily if she had ever been tested for hepatitis B and she said she didn't know. I suggested that it would be a good idea to find out her status. She didn't seem to think it was that important. After some cajoling - and close to another year - Lily was tested for hepatitis B. The results showed that she had chronic hepatitis B, likely contracted at birth from her mother. Fortunately it was inactive, the doctor said, but as she gets older she would need to be monitored regularly and checked for early signs of liver cancer. She took the news almost as stoically as she had when I suggested she get tested in the first place.
Confronting the Crisis - A Time for Leadership
I would like to end this testimony on a note of optimism. There are gaping holes in this country's response to viral hepatitis - that's why we're here. There are, however, examples of successful, life-saving initiatives we can look to for inspiration. Since the early 90's there has been a recommendation in the U.S. that all pregnant women get tested for hepatitis B, and all babies born to hepatitis B positive mothers be given a series of protective vaccinations beginning within 12 hours of birth. A pregnant woman with hepatitis B will transmit the virus to her newborn about 90% of the time. However, if the newborn gets this series of shots, including the hepatitis B vaccine, the child will almost always develop immunity and not develop chronic hepatitis B. As a result of this initiative, we have seen new hepatitis B infections contracted in the U.S. plummet.
Also, as a result of this initiative, my little boy was given life-saving vaccinations that spared him the potential fate of dying young from complications related to chronic hepatitis B. I am encouraged by recent events that show a growing awareness of this public health crisis. Promising developments include the IOM report on Viral Hepatitis and Liver Cancer, the introduction last year of the Viral Hepatitis and Liver Cancer Control and Prevention Act (HR 3794) and the new Interagency Workgroup on Viral Hepatitis headed by Asst. Secretary of Health Koh.
We have an opportunity and we have a responsibility to use this momentum and act now. It should be a collaborative effort - government, industry, payors, health care providers, advocates and patients - but government needs to lead. We need strong leadership within the U.S. government to coordinate a comprehensive response that uses the information we have now, seeks to collect additional information on best practices and effective interventions and implements nationwide programs that include and build upon the core elements of public health to provide information, services and referral into quality care for everyone at risk for, and infected with, hepatitis B and hepatitis C. If we wait, hundreds of thousands of Americans will die unnecessarily premature deaths. If we act now, we can save many of those lives.
Benitec Limited (ASX:BLT) Granted Hepatitis C RNA Interference Patent In US
Benitec Limited (ASX:BLT) Granted Hepatitis C RNA Interference Patent In US
Melbourne, June 18, 2010 (ABN Newswire) - Benitec Limited (ASX:BLT) (PINK:BNIKF) are pleased to announce that US Patent 7727970 "Multiple promoter expression cassettes for simultaneous delivery of RNAi agents targeted to Hepatitis C virus" has been granted by the United States Patent and Trademark Office (USPTO). The granted claims cover the use of an RNA interference construct (with multiple promoters) to inhibit the level of Hepatitis C virus in animal cells, tissues and organs. Moreover, the USPTO has granted Benitec an additional 805 days patent term in recognition of the delays in examining the patent application. Additional related applications remain pending to extend the scope of protection.
Benitec has licensed the rights to use this patent for Hepatitis C exclusively to Tacere Therapeutics, Inc., who recently announced that Pfizer has exercised its option to further develop and commercialise Tacere's Hepatitis C Virus (HCV) compounds.
Benitec's Chief Scientific Officer, Dr Peter French said, "The grant of this patent is an important further recognition of our dominant global position in the transformational DNA-directed RNA interference field and provides increased depth and breadth to our patent portfolio. Benitec's ddRNAi-related patent estate (solely owned or licensed exclusively for humans from CSIRO) currently comprises over 100 patents and patent applications covering 20 jurisdictions, of which more than 30 are granted, accepted or allowed."
Link: http://www.abnnewswire.net/media/en/docs/63116-ASX-BLT-596073.pdf
About Benitec Limited
Benitec Limited (ASX:BLT) (PINK:BNIKF) is an Australian biotechnology company focused on licensing its extensive intellectual property portfolio and developing therapeutics to treat serious diseases using its proprietary ddRNAi technology. For additional information, please visit www.benitec.com.
Contact
Mel Bridges
Executive Director
Mob: +61-413-051-600
Email: mbridges@benitec.com
Peter French
Chief Executive Officer
Mob: +61-412-457-595
Email: pfrench@benitec.com
Melbourne, June 18, 2010 (ABN Newswire) - Benitec Limited (ASX:BLT) (PINK:BNIKF) are pleased to announce that US Patent 7727970 "Multiple promoter expression cassettes for simultaneous delivery of RNAi agents targeted to Hepatitis C virus" has been granted by the United States Patent and Trademark Office (USPTO). The granted claims cover the use of an RNA interference construct (with multiple promoters) to inhibit the level of Hepatitis C virus in animal cells, tissues and organs. Moreover, the USPTO has granted Benitec an additional 805 days patent term in recognition of the delays in examining the patent application. Additional related applications remain pending to extend the scope of protection.
Benitec has licensed the rights to use this patent for Hepatitis C exclusively to Tacere Therapeutics, Inc., who recently announced that Pfizer has exercised its option to further develop and commercialise Tacere's Hepatitis C Virus (HCV) compounds.
Benitec's Chief Scientific Officer, Dr Peter French said, "The grant of this patent is an important further recognition of our dominant global position in the transformational DNA-directed RNA interference field and provides increased depth and breadth to our patent portfolio. Benitec's ddRNAi-related patent estate (solely owned or licensed exclusively for humans from CSIRO) currently comprises over 100 patents and patent applications covering 20 jurisdictions, of which more than 30 are granted, accepted or allowed."
Link: http://www.abnnewswire.net/media/en/docs/63116-ASX-BLT-596073.pdf
About Benitec Limited
Benitec Limited (ASX:BLT) (PINK:BNIKF) is an Australian biotechnology company focused on licensing its extensive intellectual property portfolio and developing therapeutics to treat serious diseases using its proprietary ddRNAi technology. For additional information, please visit www.benitec.com.
Contact
Mel Bridges
Executive Director
Mob: +61-413-051-600
Email: mbridges@benitec.com
Peter French
Chief Executive Officer
Mob: +61-412-457-595
Email: pfrench@benitec.com
Lawmakers urge quick passage of bill to boost detection, treatment of hepatitis
Lawmakers urge quick passage of bill to boost detection, treatment of hepatitis
By Julian Pecquet - 06/17/10 03:01 PM ET
Lawmakers on the House Oversight panel on Thursday urged Congress to quickly pass legislation to boost the detection and treatment of viral hepatitis, the leading cause of liver cancer in the United States.
The Oversight and Government Reform Committee held the first hearing in several years on the deadly disease, which disproportionately affects blacks and Asians, and pressed for passage of a bipartisan bill that would boost funding by $600 million over the next five years.
The hearing comes on the heels of an Institute of Medicine (IOM) report that highlighted deficiencies with the federal government's response to the epidemic. The report contains two dozen expert recommendations for improvement, including enhanced screening, physician education and the creation of a coordinated system to identify people who have the disease and refer them to care.
About 5.3 million Americans are believed to have hepatitis — the disease causes 12,000 to 15,000 deaths a year — though many don’t know it.
"The current approach [...] is not working," the IOM report says.
The legislation under consideration, introduced in October by Rep. Mike Honda (D-Calif.), has 52 bipartisan co-sponsors. The "Viral Hepatitis and Liver Cancer Control and Prevention Act" is currently in the Energy and Commerce Committee.
The bill would charge the secretary of Health and Human Services with developing and implementing a plan for the prevention, control and medical management of hepatitis B and C; it would also provide federal funding for state-based screening and early intervention programs.
Honda said the bill would eventually save billions of dollars by identifying sick people early. A study by the research firm Milliman found that without federal leadership, the cost of treating hepatitis C alone could more than triple, to $85 billion a year, by 2024.
"We can do a whole lot better than what we're doing," said Oversight panel chairman Edolphus Towns (D-N.Y.). "I think it's a disgrace to have a problem of this nature and to not commit resources."
The panel heard testimony from Honda and Reps. Bill Cassidy (R-La.) and Hank Johnson (D-Ga.). Cassidy is a hepatologist who co-sponsored the bill, and Johnson last year acknowledged he was undergoing treatment for hepatitis C.
Cassidy applauded former President Bill Clinton's children’s vaccination program and said the Honda bill would "similarly save lives." But debate quickly descended into budgetary politics.
Oversight ranking member Darrell Issa (R-Calif.) said Republicans would not vote for any new directed spending unless it's part of the budget bill, which has stalled.
Meanwhile, Democrats bristled at Issa's description of the word "earmark" to describe the bill.
A coalition of more than 175 public and private organizations launched a print ad campaign on Tuesday to coincide with the hearing. The National Viral Hepatitis Roundtable ad is made to look like a movie poster and reads "Mission: Possible."
"If Congress gets on the case now," the ad says, "the leading cause of liver cancer won't stand a chance."
Patient advocates say the Honda bill will help boost funding for hepatitis prevention efforts, which currently only get 2 percent — $19.3 million — of the budget allocated to the Centers for Disease Control and Prevention's National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. Advocates hope the Honda bill will eventually allow them to get $150 million a year.
By Julian Pecquet - 06/17/10 03:01 PM ET
Lawmakers on the House Oversight panel on Thursday urged Congress to quickly pass legislation to boost the detection and treatment of viral hepatitis, the leading cause of liver cancer in the United States.
The Oversight and Government Reform Committee held the first hearing in several years on the deadly disease, which disproportionately affects blacks and Asians, and pressed for passage of a bipartisan bill that would boost funding by $600 million over the next five years.
The hearing comes on the heels of an Institute of Medicine (IOM) report that highlighted deficiencies with the federal government's response to the epidemic. The report contains two dozen expert recommendations for improvement, including enhanced screening, physician education and the creation of a coordinated system to identify people who have the disease and refer them to care.
About 5.3 million Americans are believed to have hepatitis — the disease causes 12,000 to 15,000 deaths a year — though many don’t know it.
"The current approach [...] is not working," the IOM report says.
The legislation under consideration, introduced in October by Rep. Mike Honda (D-Calif.), has 52 bipartisan co-sponsors. The "Viral Hepatitis and Liver Cancer Control and Prevention Act" is currently in the Energy and Commerce Committee.
The bill would charge the secretary of Health and Human Services with developing and implementing a plan for the prevention, control and medical management of hepatitis B and C; it would also provide federal funding for state-based screening and early intervention programs.
Honda said the bill would eventually save billions of dollars by identifying sick people early. A study by the research firm Milliman found that without federal leadership, the cost of treating hepatitis C alone could more than triple, to $85 billion a year, by 2024.
"We can do a whole lot better than what we're doing," said Oversight panel chairman Edolphus Towns (D-N.Y.). "I think it's a disgrace to have a problem of this nature and to not commit resources."
The panel heard testimony from Honda and Reps. Bill Cassidy (R-La.) and Hank Johnson (D-Ga.). Cassidy is a hepatologist who co-sponsored the bill, and Johnson last year acknowledged he was undergoing treatment for hepatitis C.
Cassidy applauded former President Bill Clinton's children’s vaccination program and said the Honda bill would "similarly save lives." But debate quickly descended into budgetary politics.
Oversight ranking member Darrell Issa (R-Calif.) said Republicans would not vote for any new directed spending unless it's part of the budget bill, which has stalled.
Meanwhile, Democrats bristled at Issa's description of the word "earmark" to describe the bill.
A coalition of more than 175 public and private organizations launched a print ad campaign on Tuesday to coincide with the hearing. The National Viral Hepatitis Roundtable ad is made to look like a movie poster and reads "Mission: Possible."
"If Congress gets on the case now," the ad says, "the leading cause of liver cancer won't stand a chance."
Patient advocates say the Honda bill will help boost funding for hepatitis prevention efforts, which currently only get 2 percent — $19.3 million — of the budget allocated to the Centers for Disease Control and Prevention's National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention. Advocates hope the Honda bill will eventually allow them to get $150 million a year.
Deep sequencing analysis of baseline and on-treatment samples from HCV genotype-1
Deep sequencing analysis of baseline and on-treatment samples from HCV genotype-1 patients treated for 5 days with TMC435 monotherapy and subsequently re-treated with TMC435 in combination with PegIFNα-2a/ribavirin - poster presentation
Reported by Jules Levin
O Lenz,1 L Vijgen,1 T Verbinnen,1 H van Marck,1 I Vandenbroucke,1 M Peeters,1 G De Smedt,1 K Simmen,1 G Fanning,1 H Reesink,2 G Picchio3 1Tibotec BVBA, Mechelen, Belgium; 2Academic Medical Center, Amsterdam, The Netherlands; 3Tibotec Inc., Yardley, PA, USA
Author Conclusions
Treatment with TMC435 200 mg QD resulted in potent antiviral activity in study TMC435-C101, during five days of monotherapy, and subsequently in the same patients when combined with PegIFN/RBV in the OPERA-1 study.
Emerging viral variants were associated with a high fold change in EC50 values to TMC435 in in vitro replicon assays.
Viral variants that emerged during first exposure to TMC435 in study TMC435-C101 were no longer detectable in most cases over time, while in some they persisted at low frequencies based on ultra-dee sequencing analysis.
Persistence of viral variants in two patients at low frequency was associated with slightly reduced antiviral activity of TMC435 during the first seven days of the OPERA-1 study.
The newly identified F169L mutation reduced activity of TMC435 in vitro when combined with the Q80R and/or D168E mutation in a genotype-1b replicon.
Introduction
· TMC435 is a potent and selective macrocyclic inhibitor of the hepatitis C virus (HCV) NS3/4A protease with an in vitro 50% effective concentration (EC50) of 8 nM (6 ng/mL) in a genotype-1b replicon cell line.1 TMC435 is currently in Phase IIb development.
· In vitro resistance studies identified changes at amino acid positions 43, 80, 155, 156 and 168 within the NS3 protease domain that confer variable degrees of reduced susceptibility to TMC435.2
· In a Phase I study (TMC435-C101), six HCV genotype-1-infected patients who failed previous interferon (IFN)-based therapy received TMC435 200 mg once daily (QD) for 5 days.3 Approximately 1.5 years later, 5/6 patients were enrolled into Cohort 5 of the Phase IIa Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA)-1 study (TMC435-C201; NCT00561353) and were re-treated withTMC435 (200 mg QD) in combination with pegylated (Peg)IFNα-2a/ribavirin (RBV) for 28 days followed by PegIFNα-2a/RBV up to Week 48.4
· Median/mean trough TMC435 concentrations observed following doses of 75 mg and 200 mg QD ranged from approximately 25-50 and 350-950 fold, respectively, of the EC50 values obtained in the genotype-1b replicon cell line (6 ng/mL).3,5,6
· Here we present a detailed genotypic and phenotypic analysis of HCV isolates obtained from patients participating in the TMC435-C101 study who were re-treated in OPERA-1.
METHODS
· Plasma samples were collected during the TMC435-C101 and OPERA-1 studies.
· HCV ribonucleic acid (RNA) was extracted from plasma samples and the NS3/4A region was sequenced using standard population sequencing. In addition, selected samples were analysed using clonal single genome sequencing (20-80 clones per sample) or were subjected to massive parallel pyrosequencing (deep sequencing) using the 454 life science platform (GS-FLX, Roche Applied Science).
· For phenotypic analysis, selected mutations or patient-derived NS3 protease regions were introduced into a genotype-1b replicon backbone and the antiviral activity of TMC435 was tested and compared with the parental replicon in a standard transient replicon assay.
Figure 1. Schematic representation of genotypic and phenotypic assessments.
RESULTS
Antiviral activity and genotypic/phenotypic changes in the HCV NS3 region
· A consistent and rapid drop in plasma HCV RNA was observed in all six patients, with a maximal median reduction from baseline of 3.9 log10 IU/mL at Day 6 in study TMC435-C101. All four subjects who completed the 28-day treatment in the OPERA-1 study reached HCV RNA levels of <25 IU/mL.
· Although overall changes in HCV RNA were similar between studies, in two patients the RNA decrease from baseline was slower in OPERA-1 compared with study TMC435-C101: in patient 142 at Day 3 (-2.9 versus -3.7 log10 IU/mL) and patient 141 at Day 7 (-2.8 versus -3.5 log10 IU/mL).
· At baseline of study TMC435-C101, four patients had no detectable variations at positions identified in vitro to confer reduced susceptibility to TMC435, while in two patients (177 and 140), a Q80K and D168D/E variation was observed, respectively. Initial HCV RNA reductions in these two patients were comparable to those observed in patients without baseline variations. Change from baseline to Day 3 was 3.1 and 3.6 log10 IU/mL for these two patients in study TMC435-C101, respectively.
· Mutations at one or more of the amino acid positions 80, 155, 156 and 168 were newly detected in all subjects as early as Day 3 of study TMC435-C101.
· Population sequencing and phenotypic analysis of the HCV isolates obtained from 5/6 patients at baseline of OPERA-1 suggested that the viral variants returned to the characteristics observed prior to study TMC435-C101 in all five patients.
· Emerging mutations R155K, and Q80R/K, D168E plus F169L, were detected in two subjects in OPERA-1, respectively.
· The in vitro activity of TMC435 against the treatment emerging NS3 variants identified revealed fold changes in EC50 values (FC) >100 in all patients in study TMC435-C101 and in patient 141 in OPERA-1.
Figure 2. A) Individual changes in plasma HCV RNA from baseline in genotype-1-infected IFN-experienced patients during five days of dosing with 200 mg QD of TMC435 alone in study TMC435-C101 and in combination with PegIFNα-2a/RBV in OPERA-1. B) Mutations detected in the NS3 protease domain defined as changes from reference sequence (Con1 for genotype-1b and H77 for genotype-1a). C) Fold changes in EC50 values compared with wild-type assessed in a transient replicon assay using chimeric replicons harbouring the NS3 protease domain derived from patient samples. Day 1 = Baseline; FUP1 = follow-up 1 (2 weeks after end of dosing); FUP2 = follow-up 2 (4 weeks after end of dosing).
*Patient discontinued TMC435 due to adverse event at Day 14 (dose reduction to 100 mg at Day 10)
C201=OPERA-1
Mutations T40A, S91T/A and L153I were found in all HCV genotype-1a patients at all time points analysed; the mutation R26K was found in all HCV genotype-1b patients at all time points analysed; A156A/V was present in patient 143 at Day 4.
C201=OPERA-1
EC50, 50% effective concentration; FC, fold change; FUP, follow-up; HCV, hepatitis C virus; NR, non-responder; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy; PegIFN, pegylated interferon; QD, once daily; RBV, ribavirin; R, relapser; RNA, ribonucleic acid; wt, wild type
Presence of viral variants at baseline in studies TMC435-C101 and OPERA-1 based on ultra-deep sequencing
· No additional pre-existing NS3 mutations were detected at baseline of TMC435-C101 using ultra-deep sequencing (Q80K and D168D/E were also detected by population sequencing).
· At baseline of OPERA-1, additional mutations were observed at low frequency (<2%) in three patients: Q80L, R155G and R155K, respectively.
· Alternative codon usage was noted for wild-type and mutated amino acid, respectively.
Figure 3. The sequence of the HCV NS3 protease domain was determined for baseline samples of study TMC435-C101 and OPERA-1 using ultra-deep sequencing. Percentage of codon frequency at NS3 positions 80, 155, 156 and 168 are shown. Grey dots represent codons encoding wild-type amino acids. Coloured dots represent codons encoding mutations (defined as changes from reference sequence: Con1 for genotype-1b and H77 for genotype-1a).
C201=OPERA-1
HCV, hepatitis C virus; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy
Single genome (clonal) sequencing of NS3 protease domain and effect of isolated mutations on in vitro activity of TMC435
· In addition to single mutations, variants harbouring double and triple mutations were observed.
· In general, when introduced into the replicon, most of the single mutations detected resulted in lower fold change in EC50 values than double or triple mutations.
· Mutation F169L, which has no effect on TMC435 activity alone, further decreased susceptibility to TMC435 when combined with Q80R and/or D168E.
Figure 4. A) NS3 protease domain was amplified, cloned into standard cloning vectors and sequenced to determine linkage of mutations. Mutations at position 80, 155, 156 and 168 (169) were considered for this analysis. Frequency of clones is represented. B) Single and multiple mutations were introduced in a genotype-1b replicon backbone and EC50 values were determined using a standard transient replicon assay. Fold change in EC50 values versus the parental wild-type replicon are indicated.
Evolution of amino acid changes over time
· In patient 141, ultra-deep sequencing detected a Q80R and D168E mutation four weeks after end of dosing for study TMC435-C101, which were no longer detectable at baseline of the OPERA-1 study
- These two mutations emerged as major variants upon re-exposure to TMC435 in the OPERA-1 study.
· Different mutational patterns were observed in response to exposure to TMC435.
· Variants with different mutations at a given position were detected.
Figure 5. The sequence of the HCV NS3 domain was analysed from multiple samples using ultra-deep sequencing. Changes of codon frequency over time for NS3 at positions 80, 155, 156 and 168 are shown for patient 142 (A) and 141 (B).
C201=OPERA-1
FUP, follow-up; HCV, hepatitis C virus; AA, amino acid
References
1. Lin TI et al. Antimicrob Agents Chemother 2009;53:1377-1385.
2. Lenz O et al. Antimicrob Agents Chemother 2010;54:1878-1887.
3. Reesink HW et al. Gastroenterology 2010;138:913-921.
4. Reesink HW et al. Presented at the 60th American Association for the Study of Liver Diseases (AASLD) meeting, Boston, MA, USA, 30 October-3 November, 2009.
5. Sekar V et al. Presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna, Austria, 14-18 April, 2010.
6. Data on file. Tibotec Inc. 2010.
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Reported by Jules Levin
O Lenz,1 L Vijgen,1 T Verbinnen,1 H van Marck,1 I Vandenbroucke,1 M Peeters,1 G De Smedt,1 K Simmen,1 G Fanning,1 H Reesink,2 G Picchio3 1Tibotec BVBA, Mechelen, Belgium; 2Academic Medical Center, Amsterdam, The Netherlands; 3Tibotec Inc., Yardley, PA, USA
Author Conclusions
Treatment with TMC435 200 mg QD resulted in potent antiviral activity in study TMC435-C101, during five days of monotherapy, and subsequently in the same patients when combined with PegIFN/RBV in the OPERA-1 study.
Emerging viral variants were associated with a high fold change in EC50 values to TMC435 in in vitro replicon assays.
Viral variants that emerged during first exposure to TMC435 in study TMC435-C101 were no longer detectable in most cases over time, while in some they persisted at low frequencies based on ultra-dee sequencing analysis.
Persistence of viral variants in two patients at low frequency was associated with slightly reduced antiviral activity of TMC435 during the first seven days of the OPERA-1 study.
The newly identified F169L mutation reduced activity of TMC435 in vitro when combined with the Q80R and/or D168E mutation in a genotype-1b replicon.
Introduction
· TMC435 is a potent and selective macrocyclic inhibitor of the hepatitis C virus (HCV) NS3/4A protease with an in vitro 50% effective concentration (EC50) of 8 nM (6 ng/mL) in a genotype-1b replicon cell line.1 TMC435 is currently in Phase IIb development.
· In vitro resistance studies identified changes at amino acid positions 43, 80, 155, 156 and 168 within the NS3 protease domain that confer variable degrees of reduced susceptibility to TMC435.2
· In a Phase I study (TMC435-C101), six HCV genotype-1-infected patients who failed previous interferon (IFN)-based therapy received TMC435 200 mg once daily (QD) for 5 days.3 Approximately 1.5 years later, 5/6 patients were enrolled into Cohort 5 of the Phase IIa Optimal Protease inhibitor Enhancement of Response to TherApy (OPERA)-1 study (TMC435-C201; NCT00561353) and were re-treated withTMC435 (200 mg QD) in combination with pegylated (Peg)IFNα-2a/ribavirin (RBV) for 28 days followed by PegIFNα-2a/RBV up to Week 48.4
· Median/mean trough TMC435 concentrations observed following doses of 75 mg and 200 mg QD ranged from approximately 25-50 and 350-950 fold, respectively, of the EC50 values obtained in the genotype-1b replicon cell line (6 ng/mL).3,5,6
· Here we present a detailed genotypic and phenotypic analysis of HCV isolates obtained from patients participating in the TMC435-C101 study who were re-treated in OPERA-1.
METHODS
· Plasma samples were collected during the TMC435-C101 and OPERA-1 studies.
· HCV ribonucleic acid (RNA) was extracted from plasma samples and the NS3/4A region was sequenced using standard population sequencing. In addition, selected samples were analysed using clonal single genome sequencing (20-80 clones per sample) or were subjected to massive parallel pyrosequencing (deep sequencing) using the 454 life science platform (GS-FLX, Roche Applied Science).
· For phenotypic analysis, selected mutations or patient-derived NS3 protease regions were introduced into a genotype-1b replicon backbone and the antiviral activity of TMC435 was tested and compared with the parental replicon in a standard transient replicon assay.
Figure 1. Schematic representation of genotypic and phenotypic assessments.
RESULTS
Antiviral activity and genotypic/phenotypic changes in the HCV NS3 region
· A consistent and rapid drop in plasma HCV RNA was observed in all six patients, with a maximal median reduction from baseline of 3.9 log10 IU/mL at Day 6 in study TMC435-C101. All four subjects who completed the 28-day treatment in the OPERA-1 study reached HCV RNA levels of <25 IU/mL.
· Although overall changes in HCV RNA were similar between studies, in two patients the RNA decrease from baseline was slower in OPERA-1 compared with study TMC435-C101: in patient 142 at Day 3 (-2.9 versus -3.7 log10 IU/mL) and patient 141 at Day 7 (-2.8 versus -3.5 log10 IU/mL).
· At baseline of study TMC435-C101, four patients had no detectable variations at positions identified in vitro to confer reduced susceptibility to TMC435, while in two patients (177 and 140), a Q80K and D168D/E variation was observed, respectively. Initial HCV RNA reductions in these two patients were comparable to those observed in patients without baseline variations. Change from baseline to Day 3 was 3.1 and 3.6 log10 IU/mL for these two patients in study TMC435-C101, respectively.
· Mutations at one or more of the amino acid positions 80, 155, 156 and 168 were newly detected in all subjects as early as Day 3 of study TMC435-C101.
· Population sequencing and phenotypic analysis of the HCV isolates obtained from 5/6 patients at baseline of OPERA-1 suggested that the viral variants returned to the characteristics observed prior to study TMC435-C101 in all five patients.
· Emerging mutations R155K, and Q80R/K, D168E plus F169L, were detected in two subjects in OPERA-1, respectively.
· The in vitro activity of TMC435 against the treatment emerging NS3 variants identified revealed fold changes in EC50 values (FC) >100 in all patients in study TMC435-C101 and in patient 141 in OPERA-1.
Figure 2. A) Individual changes in plasma HCV RNA from baseline in genotype-1-infected IFN-experienced patients during five days of dosing with 200 mg QD of TMC435 alone in study TMC435-C101 and in combination with PegIFNα-2a/RBV in OPERA-1. B) Mutations detected in the NS3 protease domain defined as changes from reference sequence (Con1 for genotype-1b and H77 for genotype-1a). C) Fold changes in EC50 values compared with wild-type assessed in a transient replicon assay using chimeric replicons harbouring the NS3 protease domain derived from patient samples. Day 1 = Baseline; FUP1 = follow-up 1 (2 weeks after end of dosing); FUP2 = follow-up 2 (4 weeks after end of dosing).
*Patient discontinued TMC435 due to adverse event at Day 14 (dose reduction to 100 mg at Day 10)
C201=OPERA-1
Mutations T40A, S91T/A and L153I were found in all HCV genotype-1a patients at all time points analysed; the mutation R26K was found in all HCV genotype-1b patients at all time points analysed; A156A/V was present in patient 143 at Day 4.
C201=OPERA-1
EC50, 50% effective concentration; FC, fold change; FUP, follow-up; HCV, hepatitis C virus; NR, non-responder; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy; PegIFN, pegylated interferon; QD, once daily; RBV, ribavirin; R, relapser; RNA, ribonucleic acid; wt, wild type
Presence of viral variants at baseline in studies TMC435-C101 and OPERA-1 based on ultra-deep sequencing
· No additional pre-existing NS3 mutations were detected at baseline of TMC435-C101 using ultra-deep sequencing (Q80K and D168D/E were also detected by population sequencing).
· At baseline of OPERA-1, additional mutations were observed at low frequency (<2%) in three patients: Q80L, R155G and R155K, respectively.
· Alternative codon usage was noted for wild-type and mutated amino acid, respectively.
Figure 3. The sequence of the HCV NS3 protease domain was determined for baseline samples of study TMC435-C101 and OPERA-1 using ultra-deep sequencing. Percentage of codon frequency at NS3 positions 80, 155, 156 and 168 are shown. Grey dots represent codons encoding wild-type amino acids. Coloured dots represent codons encoding mutations (defined as changes from reference sequence: Con1 for genotype-1b and H77 for genotype-1a).
C201=OPERA-1
HCV, hepatitis C virus; OPERA, Optimal Protease inhibitor Enhancement of Response to TherApy
Single genome (clonal) sequencing of NS3 protease domain and effect of isolated mutations on in vitro activity of TMC435
· In addition to single mutations, variants harbouring double and triple mutations were observed.
· In general, when introduced into the replicon, most of the single mutations detected resulted in lower fold change in EC50 values than double or triple mutations.
· Mutation F169L, which has no effect on TMC435 activity alone, further decreased susceptibility to TMC435 when combined with Q80R and/or D168E.
Figure 4. A) NS3 protease domain was amplified, cloned into standard cloning vectors and sequenced to determine linkage of mutations. Mutations at position 80, 155, 156 and 168 (169) were considered for this analysis. Frequency of clones is represented. B) Single and multiple mutations were introduced in a genotype-1b replicon backbone and EC50 values were determined using a standard transient replicon assay. Fold change in EC50 values versus the parental wild-type replicon are indicated.
Evolution of amino acid changes over time
· In patient 141, ultra-deep sequencing detected a Q80R and D168E mutation four weeks after end of dosing for study TMC435-C101, which were no longer detectable at baseline of the OPERA-1 study
- These two mutations emerged as major variants upon re-exposure to TMC435 in the OPERA-1 study.
· Different mutational patterns were observed in response to exposure to TMC435.
· Variants with different mutations at a given position were detected.
Figure 5. The sequence of the HCV NS3 domain was analysed from multiple samples using ultra-deep sequencing. Changes of codon frequency over time for NS3 at positions 80, 155, 156 and 168 are shown for patient 142 (A) and 141 (B).
C201=OPERA-1
FUP, follow-up; HCV, hepatitis C virus; AA, amino acid
References
1. Lin TI et al. Antimicrob Agents Chemother 2009;53:1377-1385.
2. Lenz O et al. Antimicrob Agents Chemother 2010;54:1878-1887.
3. Reesink HW et al. Gastroenterology 2010;138:913-921.
4. Reesink HW et al. Presented at the 60th American Association for the Study of Liver Diseases (AASLD) meeting, Boston, MA, USA, 30 October-3 November, 2009.
5. Sekar V et al. Presented at the 45th Annual Meeting of the European Association for the Study of the Liver (EASL), Vienna, Austria, 14-18 April, 2010.
6. Data on file. Tibotec Inc. 2010.
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