Published on: 2011-03-31
Patients had improved early and sustained virological response (EVR and SVR) when treated with the current standard of care – pegylated Interferon-alpha and ribavirin (PegIFN/RBV) – and fluvastatin. The results show patients receiving fluvastatin and PegIFN/RBV achieve higher rates of EVR and SVR – 75.96% and 63.46% – to those receiving placebo and PegIFN/RBV – 61.9% and 49.52% respectively.
EASL's Secretary General, Professor Heiner Wedemeyer, said: "We know that metabolic syndrome (MS), the main treatment indication for statins, is associated with severe fibrosis and lower treatment responses in chronic HCV patients. The confirmation that the combination of fluvastatin and PegIFN/RBV could provide better clinical outcomes for those patients with co-morbid chronic HCV and MS is very exciting for clinicians".
Even in patients without MS, the study shows that responses to treatment are still higher in patients treated with fluvastatin and PegIFN/RBV (EVR 85.36% versus 71.42% and SVR 74.39% vs. 58.44).
"Today, healthcare professionals have to be mindful when considering health provision and treatment costs. We cannot overlook the importance of opportunities to maximise more affordable drugs' potential to complement the current standard of care for chronic HCV management," said Professor Wedemeyer.
This new study concludes that the synergistic effects between fluvastatin and PegIFN/RBV shows lipid lowering drugs may favour HCV clearance and be useful as a chronic HCV treatment, irrespective of the presence of metabolic syndrome.
###
Travis Taylor
easlpressoffice@cohnwolfe.com
44-784-306-9451
Source
April 4, 2011
EASL: REG-Novartis first-in-class antiviral DEB025 achieved sustained viral response in 76% of patients with chronic hepatitis C, new phase II study shows
Thu Mar 31, 2011 17:30 CET
◦ DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) showed superior viral cure vs standard of care alone (p=0.008)[1]
◦ A cyclophilin inhibitor, DEB025 belongs to a new class of medicines that limit hepatitis C virus replication and have the potential to reshape hepatitis C therapy
◦ Phase III study with DEB025 commenced recently with previously untreated patients infected by the most common form of hepatitis C virus
Basel, March 31, 2011 - Novartis announced today that a Phase II study with the first-in-class antiviral DEB025 (alisporivir) met its primary endpoint for achieving viral cure (24 weeks after stopping treatment) in 76% of patients with chronic hepatitis C[1]. The study involved nearly 300 previously untreated patients infected with the most common form of hepatitis C virus (HCV), the genotype 1 (G1)[1].
The data were presented today at the European Association for the Study of the Liver (EASL) congress in Berlin, Germany. The findings show that 76% of G1 chronic hepatitis C patients treated with DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) achieved superior viral cure (known as sustained viral response, or SVR) compared to 55% of patients on standard of care alone (p=0.008)[1]. Treatment with DEB025 demonstrated a low incidence of adverse events, with discontinuation rates comparable between treatment groups[1].
"Hepatitis C is difficult to treat and current therapies are only effective in about half of patients infected with the most prevalent genotype of HCV[2]," said Stefan Zeuzem, Professor of Medicine at the Goethe University Hospital in Frankfurt, Germany, and the study's principal investigator. "These results are exciting because a large majority of patients achieved sustained viral response with DEB025, with some who also benefited from a shorter duration of treatment compared to standard therapy[1]."
DEB025 is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the virus directly, DEB025 is a host targeting antiviral (HTA) that targets so-called host proteins which are essential for the replication of HCV. As these proteins play a key role in the replication of all types of HCV, DEB025 may offer an effective treatment option for a broad range of HCV forms. In other clinical trials, DEB025 has also shown effective antiviral activity against other common HCV genotypes (G2, G3 and G4)[3].
"There is a critical need for more effective drugs to treat chronic hepatitis C, and Novartis is dedicated to developing medicines that will reduce the burden of this disease for patients and physicians," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "DEB025 has a new mode of action that may stop the virus from replicating and could reshape the future approach to treatment of hepatitis C."
More than 170 million people worldwide are infected with HCV, which can cause serious liver disease leading to cirrhosis, liver cancer, and in some cases death. HCV is a blood borne virus that predominantly affects the liver[4],[5]. As an RNA (ribonucleic acid) virus, it mutates much more than DNA (deoxyribonucleic acid) viruses. This ability to change makes it harder for the immune system to clear (or eliminate) the virus. There are six major variations of HCV, known as genotypes and labelled from G1 to G6[5].
The study presented at EASL was a 48-week, global, double-blind, randomized, placebo-controlled trial in G1 treatment-naïve chronic hepatitis C patients. It evaluated the efficacy and safety of DEB025 combined with pegylated-interferon alfa 2a/ribavirin (PegIFN/RBV) vs. PegIFN/RBV alone. The primary endpoint was sustained viral response after 24 weeks (SVR24)[1].
Transient and reversible increase in bilirubin was observed in association with the initial DEB025 loading dose[1]. A small proportion of patients (4.2%) had a transient increase in bilirubin more than five times the upper limit of normal (ULN), but this was not associated with liver damage[1].
A pivotal Phase III study with DEB025 commenced recently to evaluate the efficacy and safety of DEB025 combined with standard of care and enrolling previously untreated HCV G1 patients. Other Phase II studies are ongoing in other patient populations i.e., G1 treatment-experienced patients and G2 and G3 treatment-naive patients.
Novartis in-licensed DEB025 from Debiopharm Group(TM), an independent biopharmaceuticals company based in Switzerland, under an agreement which gives Novartis exclusive worldwide development, manufacturing and marketing rights (excluding Japan).
Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "potential," "exciting," "may," "dedicated," "will," "could," "launched," or similar expressions, or by express or implied discussions regarding potential marketing submissions or approvals for DEB025, or the potential timing of any such submissions or approvals, or regarding potential future revenues from DEB025. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with DEB025 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that DEB025 will be submitted or approved for sale in any market. Nor can there be any guarantee that DEB025 will achieve any particular levels of revenue in the future. In particular, management's expectations regarding DEB025 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise
About Novartis
Novartis provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2010, the Group's continuing operations achieved net sales of USD 50.6 billion, while approximately USD 9.1 billion (USD 8.1 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 119,000 full-time-equivalent associates (including 16,700 Alcon associates) and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com/.
References
[1] Flisiak R, Pawlotsky JM, Crabbe R, Kryczka W, Haüssinger D, Mazella G, Romero-Gomez M, Purcea D, Vuagniaux G, Bao W, Zeuzem S. Once-daily alisporivir (DEB025) plus pegifnalfa2a/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naïve patients. Presented at European Association for Study of the Liver Congress, Berlin, March 2011.
[2] Hoofnagle JH. A step forward in therapy for hepatitis C. N Engl J Med. 2009; 360 (18):1899-901.
[3] Flisiak R, et al. The cyclophilin inhibitor Debio 025 combined with peg IFNa2a significantly reduces viral load in treatment-naïve hepatitis C patients. Hepatology. 2009; 49:1460-68.
[4] Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001; 345 (1):41-52.
[5] World Hepatitis Alliance, http://www.worldhepatitisalliance.org/, Last accessed March 2011
Novartis Media Relations
Central media line: +41 61 324 2200
Eric Althoff
Novartis Global Media Relations
+41 61 324 7999 (direct)
+41 79 593 4202 (mobile)
eric.althoff@novartis.com
Irina Ferluga
Novartis Pharma Communications
+41 61 324 2422 (direct)
+41 79 824 1121 (mobile)
irina.ferluga@novartis.com
e-mail: media.relations@novartis.com
Novartis Investor Relations
Central phone: +41 61 324 7944
Susanne Schaffert +41 61 324 7944
Pierre-Michel Bringer +41 61 324 1065
Thomas Hungerbuehler +41 61 324 8425
Isabella Zinck +41 61 324 7188
North America:
Richard Jarvis +1 212 830 2433
Edwin Valeriano +1 212 830 2456
Email: investor.relations@novartis.com e-mail: investor.relations@novartis.com
Source
◦ DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) showed superior viral cure vs standard of care alone (p=0.008)[1]
◦ A cyclophilin inhibitor, DEB025 belongs to a new class of medicines that limit hepatitis C virus replication and have the potential to reshape hepatitis C therapy
◦ Phase III study with DEB025 commenced recently with previously untreated patients infected by the most common form of hepatitis C virus
Basel, March 31, 2011 - Novartis announced today that a Phase II study with the first-in-class antiviral DEB025 (alisporivir) met its primary endpoint for achieving viral cure (24 weeks after stopping treatment) in 76% of patients with chronic hepatitis C[1]. The study involved nearly 300 previously untreated patients infected with the most common form of hepatitis C virus (HCV), the genotype 1 (G1)[1].
The data were presented today at the European Association for the Study of the Liver (EASL) congress in Berlin, Germany. The findings show that 76% of G1 chronic hepatitis C patients treated with DEB025 plus standard of care (pegylated-interferon alfa 2a/ribavirin) achieved superior viral cure (known as sustained viral response, or SVR) compared to 55% of patients on standard of care alone (p=0.008)[1]. Treatment with DEB025 demonstrated a low incidence of adverse events, with discontinuation rates comparable between treatment groups[1].
"Hepatitis C is difficult to treat and current therapies are only effective in about half of patients infected with the most prevalent genotype of HCV[2]," said Stefan Zeuzem, Professor of Medicine at the Goethe University Hospital in Frankfurt, Germany, and the study's principal investigator. "These results are exciting because a large majority of patients achieved sustained viral response with DEB025, with some who also benefited from a shorter duration of treatment compared to standard therapy[1]."
DEB025 is the first in a new class of drugs called cyclophilin inhibitors. Unlike other compounds in development that target the virus directly, DEB025 is a host targeting antiviral (HTA) that targets so-called host proteins which are essential for the replication of HCV. As these proteins play a key role in the replication of all types of HCV, DEB025 may offer an effective treatment option for a broad range of HCV forms. In other clinical trials, DEB025 has also shown effective antiviral activity against other common HCV genotypes (G2, G3 and G4)[3].
"There is a critical need for more effective drugs to treat chronic hepatitis C, and Novartis is dedicated to developing medicines that will reduce the burden of this disease for patients and physicians," said Trevor Mundel, MD, Global Head of Development at Novartis Pharma AG. "DEB025 has a new mode of action that may stop the virus from replicating and could reshape the future approach to treatment of hepatitis C."
More than 170 million people worldwide are infected with HCV, which can cause serious liver disease leading to cirrhosis, liver cancer, and in some cases death. HCV is a blood borne virus that predominantly affects the liver[4],[5]. As an RNA (ribonucleic acid) virus, it mutates much more than DNA (deoxyribonucleic acid) viruses. This ability to change makes it harder for the immune system to clear (or eliminate) the virus. There are six major variations of HCV, known as genotypes and labelled from G1 to G6[5].
The study presented at EASL was a 48-week, global, double-blind, randomized, placebo-controlled trial in G1 treatment-naïve chronic hepatitis C patients. It evaluated the efficacy and safety of DEB025 combined with pegylated-interferon alfa 2a/ribavirin (PegIFN/RBV) vs. PegIFN/RBV alone. The primary endpoint was sustained viral response after 24 weeks (SVR24)[1].
Transient and reversible increase in bilirubin was observed in association with the initial DEB025 loading dose[1]. A small proportion of patients (4.2%) had a transient increase in bilirubin more than five times the upper limit of normal (ULN), but this was not associated with liver damage[1].
A pivotal Phase III study with DEB025 commenced recently to evaluate the efficacy and safety of DEB025 combined with standard of care and enrolling previously untreated HCV G1 patients. Other Phase II studies are ongoing in other patient populations i.e., G1 treatment-experienced patients and G2 and G3 treatment-naive patients.
Novartis in-licensed DEB025 from Debiopharm Group(TM), an independent biopharmaceuticals company based in Switzerland, under an agreement which gives Novartis exclusive worldwide development, manufacturing and marketing rights (excluding Japan).
Disclaimer
The foregoing release contains forward-looking statements that can be identified by terminology such as "potential," "exciting," "may," "dedicated," "will," "could," "launched," or similar expressions, or by express or implied discussions regarding potential marketing submissions or approvals for DEB025, or the potential timing of any such submissions or approvals, or regarding potential future revenues from DEB025. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of management regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with DEB025 to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that DEB025 will be submitted or approved for sale in any market. Nor can there be any guarantee that DEB025 will achieve any particular levels of revenue in the future. In particular, management's expectations regarding DEB025 could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; the impact that the foregoing factors could have on the values attributed to the Novartis Group's assets and liabilities as recorded in the Group's consolidated balance sheet, and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise
About Novartis
Novartis provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2010, the Group's continuing operations achieved net sales of USD 50.6 billion, while approximately USD 9.1 billion (USD 8.1 billion excluding impairment and amortization charges) was invested in R&D throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 119,000 full-time-equivalent associates (including 16,700 Alcon associates) and operate in more than 140 countries around the world. For more information, please visit http://www.novartis.com/.
References
[1] Flisiak R, Pawlotsky JM, Crabbe R, Kryczka W, Haüssinger D, Mazella G, Romero-Gomez M, Purcea D, Vuagniaux G, Bao W, Zeuzem S. Once-daily alisporivir (DEB025) plus pegifnalfa2a/ribavirin results in superior sustained virologic response (SVR24) in chronic hepatitis C genotype 1 treatment naïve patients. Presented at European Association for Study of the Liver Congress, Berlin, March 2011.
[2] Hoofnagle JH. A step forward in therapy for hepatitis C. N Engl J Med. 2009; 360 (18):1899-901.
[3] Flisiak R, et al. The cyclophilin inhibitor Debio 025 combined with peg IFNa2a significantly reduces viral load in treatment-naïve hepatitis C patients. Hepatology. 2009; 49:1460-68.
[4] Lauer GM, Walker BD. Hepatitis C virus infection. N Engl J Med. 2001; 345 (1):41-52.
[5] World Hepatitis Alliance, http://www.worldhepatitisalliance.org/, Last accessed March 2011
Novartis Media Relations
Central media line: +41 61 324 2200
Eric Althoff
Novartis Global Media Relations
+41 61 324 7999 (direct)
+41 79 593 4202 (mobile)
eric.althoff@novartis.com
Irina Ferluga
Novartis Pharma Communications
+41 61 324 2422 (direct)
+41 79 824 1121 (mobile)
irina.ferluga@novartis.com
e-mail: media.relations@novartis.com
Novartis Investor Relations
Central phone: +41 61 324 7944
Susanne Schaffert +41 61 324 7944
Pierre-Michel Bringer +41 61 324 1065
Thomas Hungerbuehler +41 61 324 8425
Isabella Zinck +41 61 324 7188
North America:
Richard Jarvis +1 212 830 2433
Edwin Valeriano +1 212 830 2456
Email: investor.relations@novartis.com e-mail: investor.relations@novartis.com
Source
EASL: Results show benefits in using acute kidney injury criteria in the diagnosis of cirrhosis
Public release date: 31-Mar-2011
Contact: Dimple Natali
easlpressoffice@cohnwolfe.com
44-797-160-8315
European Association for the Study of the Liver
Recent study may change future approach to diagnosis
The first clinical study investigating the use of the AKIN criteria (Acute Kidney Injury Network) in cirrhosis has shown significant benefits that have the potential to change future diagnosis, according to results from a Spanish study presented today at the International Liver Congress.
As screening and differential diagnosis is becoming increasingly important in relation to managing health service provision, if these results are confirmed in larger studies, the AKIN criteria has the potential to replace current screening and diagnosis criteria in hospitalised cirrhotic patients.
This prospective study aimed to assess the value of the AKIN criteria in predicting outcomes in hospitalised cirrhotic patients. Out of 300 patients admitted to hospital for complications of cirrhosis 88 (29%) developed renal failure according to the AKIN criteria. Three-month survival of these patients was 38%, compared with 87% of patients who did not develop renal failure (p< 0.01).
Renal failure in cirrhosis is currently defined as serum creatinine greater than 1.5 mg/dL. According to the study investigators this definition has two shortcomings: firstly it represents a very low glomerular filtration rate (GFR), and secondly it may not detect significant changes in GFR because it does not take into account variations in creatinine values. In contrast, the AKIN criteria is much more sensitive and considers renal failure as an increase in serum creatinine greater than or equal to a 0.3ml/dL (≥50% increase) compared to baseline within 48 hours.
Mark Thursz, EASL's Vice-Secretary commented: "Liver disease is associated with a high mortality due to renal failure, especially in end stage cirrhosis. As experts and clinicians in the field of hepatology, defining more sensitive tests that help to identify patients at risk of renal failure or death earlier is critical to enable us to intervene and ensure the patient has the best possible outcome".
Furthermore, when the AKIN criteria were combined with the current definition of renal failure, patients meeting the AKIN criteria in whom serum creatinine reached a peak value of >1.5 mg/dL (n=60) had a significantly lower survival compared to patients with a peak value ≤ 1.5 mg/dL (n=28) (29% vs 58%, respectively; p=0.026). Out of the 300 patients, 30 patients had serum creatinine >1.5 mg/dL but did not meet the AKIN criteria. However, three-month survival of these patients was 80%.
###
Notes to Editors
About EASL
EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.
EASL's main focus on education and research is delivered through numerous events and initiatives, including:
• The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
• Journal of Hepatology published monthly
• Participation in a number of policy initiatives at European level
About The International Liver CongressTM 2011
The International Liver Congress™ 2011, the 46th annual meeting of the European Association for the study of the Liver, is being held at the Internationales Congress Centrum, Berlin, Germany from March 30 – April 3, 2011. The congress annually attracts over 7,500 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.
References
1. Fagundes C et al. Acute Kidney Injury Network (AKIN) Criteria for Acute Renal Failure Predicts Outcome in Hospitalized Cirrhotic Patients. A Prospective Study. Presented at The International Liver CongressTM 2011
Source
Contact: Dimple Natali
easlpressoffice@cohnwolfe.com
44-797-160-8315
European Association for the Study of the Liver
Recent study may change future approach to diagnosis
The first clinical study investigating the use of the AKIN criteria (Acute Kidney Injury Network) in cirrhosis has shown significant benefits that have the potential to change future diagnosis, according to results from a Spanish study presented today at the International Liver Congress.
As screening and differential diagnosis is becoming increasingly important in relation to managing health service provision, if these results are confirmed in larger studies, the AKIN criteria has the potential to replace current screening and diagnosis criteria in hospitalised cirrhotic patients.
This prospective study aimed to assess the value of the AKIN criteria in predicting outcomes in hospitalised cirrhotic patients. Out of 300 patients admitted to hospital for complications of cirrhosis 88 (29%) developed renal failure according to the AKIN criteria. Three-month survival of these patients was 38%, compared with 87% of patients who did not develop renal failure (p< 0.01).
Renal failure in cirrhosis is currently defined as serum creatinine greater than 1.5 mg/dL. According to the study investigators this definition has two shortcomings: firstly it represents a very low glomerular filtration rate (GFR), and secondly it may not detect significant changes in GFR because it does not take into account variations in creatinine values. In contrast, the AKIN criteria is much more sensitive and considers renal failure as an increase in serum creatinine greater than or equal to a 0.3ml/dL (≥50% increase) compared to baseline within 48 hours.
Mark Thursz, EASL's Vice-Secretary commented: "Liver disease is associated with a high mortality due to renal failure, especially in end stage cirrhosis. As experts and clinicians in the field of hepatology, defining more sensitive tests that help to identify patients at risk of renal failure or death earlier is critical to enable us to intervene and ensure the patient has the best possible outcome".
Furthermore, when the AKIN criteria were combined with the current definition of renal failure, patients meeting the AKIN criteria in whom serum creatinine reached a peak value of >1.5 mg/dL (n=60) had a significantly lower survival compared to patients with a peak value ≤ 1.5 mg/dL (n=28) (29% vs 58%, respectively; p=0.026). Out of the 300 patients, 30 patients had serum creatinine >1.5 mg/dL but did not meet the AKIN criteria. However, three-month survival of these patients was 80%.
###
Notes to Editors
About EASL
EASL is the leading European scientific society involved in promoting research and education in hepatology. EASL attracts the foremost hepatology experts and has an impressive track record in promoting research in liver disease, supporting wider education and promoting changes in European liver policy.
EASL's main focus on education and research is delivered through numerous events and initiatives, including:
• The International Liver CongressTM which is the main scientific and professional event in hepatology worldwide
• Meetings including Monothematic and Special conferences, Post Graduate courses and other endorsed meetings that take place throughout the year
• Clinical and Basic Schools of Hepatology, a series of events covering different aspects in the field of hepatology
• Journal of Hepatology published monthly
• Participation in a number of policy initiatives at European level
About The International Liver CongressTM 2011
The International Liver Congress™ 2011, the 46th annual meeting of the European Association for the study of the Liver, is being held at the Internationales Congress Centrum, Berlin, Germany from March 30 – April 3, 2011. The congress annually attracts over 7,500 clinicians and scientists from around the world and provides an opportunity to hear the latest research, perspectives and treatments of liver disease from principal experts in the field.
References
1. Fagundes C et al. Acute Kidney Injury Network (AKIN) Criteria for Acute Renal Failure Predicts Outcome in Hospitalized Cirrhotic Patients. A Prospective Study. Presented at The International Liver CongressTM 2011
Source
April 3, 2011
EASL: Innovation in science
March 31st, 2011 New data presented at the International Liver CongressTM today show the existence of novel interactions between T cells and hepatocytes that are regulated by HCV infection, providing a novel understanding of how HCV persists in the liver.
The nature of the T cell-hepatocyte interactions alter CD4+ T-cell trafficking and cytokine expression, and may have an impact on T-cell effector function and the outcome of anti-viral immune responses.
Innate and adaptive immune responses play a critical role in clearing acute HCV infection. Evidence from models suggest that CD4+ T cells play a critical role in controlling acute HCV infection, but the mechanism(s) behind their failure to control chronic HCV replication are still unknown.
More information:
1. Stamataki, Z.et al. Lymphocyte-hepatocyte interactions: hepatitis C virus changes the rules. Abstract presented at The International Liver CongressTM 2011. http://www1.easl.eu/easl2011/program/Posters/Abstract14.htm
Provided by European Association for the Study of the Liver
Source
The nature of the T cell-hepatocyte interactions alter CD4+ T-cell trafficking and cytokine expression, and may have an impact on T-cell effector function and the outcome of anti-viral immune responses.
Innate and adaptive immune responses play a critical role in clearing acute HCV infection. Evidence from models suggest that CD4+ T cells play a critical role in controlling acute HCV infection, but the mechanism(s) behind their failure to control chronic HCV replication are still unknown.
More information:
1. Stamataki, Z.et al. Lymphocyte-hepatocyte interactions: hepatitis C virus changes the rules. Abstract presented at The International Liver CongressTM 2011. http://www1.easl.eu/easl2011/program/Posters/Abstract14.htm
Provided by European Association for the Study of the Liver
Source
Hope for liver patients
Thursday, March 31, 2011
UMASS SEEKS TO STOP TRANSPLANT RE-INFECTION
By Karen Nugent TELEGRAM & GAZETTE STAFF
WORCESTER — A new liver does not mean the end of hepatitis C.
The virus, which can go undetected for years, is the leading cause of liver failure in the United States, and for many patients, a transplant is the only life-saving treatment. But the hepatitis C virus circulates in the blood, and during transplant surgery, infected blood immediately gets into a donated liver.
“One-hundred percent (of transplanted livers) get re-infected,” said Dr. Donna M. Ambrosino, executive director of Massachusetts Biologic Laboratories, a division of the University of Massachusetts Medical School. “The virus stays in the blood for a couple of days, if not longer. You cannot be without your liver, and you can't put the new liver in without blood spilling on it and getting into it. So we're between a rock and a hard place.”
A re-infected liver, while giving patients perhaps five more years of life, she said, accelerates the course of the disease, and standard antiviral medications are not well-tolerated in transplant patients.
The medical school, along with five hospitals in Boston, New York and Connecticut, is entering the second phase of a clinical trial of a new treatment for the prevention of hepatitis C re-infection in liver transplant patients. The treatment, a monoclonal antibody, is different from the usual antiviral drugs in that it binds the virus and blocks its ability to get into the liver, Dr. Ambrosino said.
There are 10 patients currently in the study, with a target enrollment of 16 patients. Half are given the antibody, so far known only as MBL-HCV1, and half are given a placebo.
Dr. Ambrosino, who is also a professor of pediatrics at the medical school, said results will likely be available in the summer. If the virus is not found in patients 42 days after transplantation, it will be deemed a success. If the virus is found, a trial with a higher dose of antibody will begin.
The antibody — or the placebo — is administered to patients by infusion, in phases.
The first dose is given a few hours before transplant surgery, and another is given during surgery between when the diseased liver is removed and the donor liver is implanted. A third infusion is given just after surgery, followed by daily infusions during the first week of recovery. A final infusion is given on the 14th day after surgery.
A 2009 study of the antibody in 31 healthy volunteers showed no serious side effects.
Dr. Ambrosino said it generally takes 10 years of development and trials before a new medication becomes available.
According to the U.S. Centers for Disease Control and Prevention, hepatitis C virus infection is the most common chronic blood-borne infection in the United States, with approximately 3.2 million people chronically infected, and about 10,000 deaths per year. Of 6,000 or so liver transplants each year in the United States, half are the result of hepatitis C infection.
However, it is a slow-growing infection that may not show symptoms for 20 years — until liver failure becomes apparent, or abnormal laboratory tests are found.
Dr. Ambrosino said because the average age of a hepatitis C patient is 55 — smack in the middle of the baby boomer generation — they will probably make up the next wave of patients.
“So that's a large group, and there will be more people needing liver transplants,” she said.
While many boomers unknowingly carry the virus, Dr. Ambrosino said it is not entirely because of bad behavior such as drug use and multiple sex partners in the 1970s.
Hepatitis C can be transmitted through drug use via contaminated needles, and rarely through sexual contact, but she said the majority of cases were contracted through blood transfusions prior to the late 1970s when the virus was first identified. Since 1990, all donated blood has been tested for hepatitis C.
“It was not known in the '70s,” Dr. Ambrosino said.
The virus differs from hepatitis A, a largely food-borne illness, and hepatitis B, a more obvious illness, which is also transmitted through blood but was identified earlier and for which there is a vaccine.
The Massachusetts Biologic Institute was part of the state Department of Public Health until 1997, when it became aligned with UMass. Its main focus is public health — especially infectious diseases — and its major source of revenue is manufacturing tetanus-diphtheria vaccine and other medications. Monoclonal antibodies are the latest products, Dr. Ambrosino said.
Contact Karen Nugent via email at knugent@telegram.com
Source
UMASS SEEKS TO STOP TRANSPLANT RE-INFECTION
By Karen Nugent TELEGRAM & GAZETTE STAFF
WORCESTER — A new liver does not mean the end of hepatitis C.
The virus, which can go undetected for years, is the leading cause of liver failure in the United States, and for many patients, a transplant is the only life-saving treatment. But the hepatitis C virus circulates in the blood, and during transplant surgery, infected blood immediately gets into a donated liver.
“One-hundred percent (of transplanted livers) get re-infected,” said Dr. Donna M. Ambrosino, executive director of Massachusetts Biologic Laboratories, a division of the University of Massachusetts Medical School. “The virus stays in the blood for a couple of days, if not longer. You cannot be without your liver, and you can't put the new liver in without blood spilling on it and getting into it. So we're between a rock and a hard place.”
A re-infected liver, while giving patients perhaps five more years of life, she said, accelerates the course of the disease, and standard antiviral medications are not well-tolerated in transplant patients.
The medical school, along with five hospitals in Boston, New York and Connecticut, is entering the second phase of a clinical trial of a new treatment for the prevention of hepatitis C re-infection in liver transplant patients. The treatment, a monoclonal antibody, is different from the usual antiviral drugs in that it binds the virus and blocks its ability to get into the liver, Dr. Ambrosino said.
There are 10 patients currently in the study, with a target enrollment of 16 patients. Half are given the antibody, so far known only as MBL-HCV1, and half are given a placebo.
Dr. Ambrosino, who is also a professor of pediatrics at the medical school, said results will likely be available in the summer. If the virus is not found in patients 42 days after transplantation, it will be deemed a success. If the virus is found, a trial with a higher dose of antibody will begin.
The antibody — or the placebo — is administered to patients by infusion, in phases.
The first dose is given a few hours before transplant surgery, and another is given during surgery between when the diseased liver is removed and the donor liver is implanted. A third infusion is given just after surgery, followed by daily infusions during the first week of recovery. A final infusion is given on the 14th day after surgery.
A 2009 study of the antibody in 31 healthy volunteers showed no serious side effects.
Dr. Ambrosino said it generally takes 10 years of development and trials before a new medication becomes available.
According to the U.S. Centers for Disease Control and Prevention, hepatitis C virus infection is the most common chronic blood-borne infection in the United States, with approximately 3.2 million people chronically infected, and about 10,000 deaths per year. Of 6,000 or so liver transplants each year in the United States, half are the result of hepatitis C infection.
However, it is a slow-growing infection that may not show symptoms for 20 years — until liver failure becomes apparent, or abnormal laboratory tests are found.
Dr. Ambrosino said because the average age of a hepatitis C patient is 55 — smack in the middle of the baby boomer generation — they will probably make up the next wave of patients.
“So that's a large group, and there will be more people needing liver transplants,” she said.
While many boomers unknowingly carry the virus, Dr. Ambrosino said it is not entirely because of bad behavior such as drug use and multiple sex partners in the 1970s.
Hepatitis C can be transmitted through drug use via contaminated needles, and rarely through sexual contact, but she said the majority of cases were contracted through blood transfusions prior to the late 1970s when the virus was first identified. Since 1990, all donated blood has been tested for hepatitis C.
“It was not known in the '70s,” Dr. Ambrosino said.
The virus differs from hepatitis A, a largely food-borne illness, and hepatitis B, a more obvious illness, which is also transmitted through blood but was identified earlier and for which there is a vaccine.
The Massachusetts Biologic Institute was part of the state Department of Public Health until 1997, when it became aligned with UMass. Its main focus is public health — especially infectious diseases — and its major source of revenue is manufacturing tetanus-diphtheria vaccine and other medications. Monoclonal antibodies are the latest products, Dr. Ambrosino said.
Contact Karen Nugent via email at knugent@telegram.com
Source
EASL: Data From Phase 3 Studies Showed Substantial Improvements in SVR (Viral Cure) Rates With Telaprevir-Based Therapy Compared to Currently Available Medicines in People With Hepatitis C, Regardless of Their IL28B Genotype Status
- 90% of people with the 'CC' variation of IL28B who were new to treatment and received a telaprevir-based regimen achieved a viral cure, 78% of them were eligible to stop all treatment at 24 weeks -
- Nearly three-fold improvement in viral cure rates was observed among people with the 'CT' and 'TT' variations compared to the control group, regardless of prior treatment experience -
BERLIN--(March 31 2011 press release Vertex)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced new data from retrospective analyses that evaluated the relationship between variations at the IL28B gene and a patient's response to treatment with telaprevir in combination with pegylated-interferon and ribavirin from two of its pivotal Phase 3 studies (ADVANCE and REALIZE) for a group of people who were tested for IL28B genotype. These analyses showed that people in these studies had substantial improvements in sustained viral response (SVR, or viral cure) rates across all IL28B genotypes (CC, CT or TT) for those treated with telaprevir-based combination therapy compared to those treated with pegylated-interferon and ribavirin alone. Telaprevir is a medicine in development for the treatment of genotype 1 chronic hepatitis C. Safety and tolerability results were consistent across the Phase 3 studies of telaprevir. Data from these IL28B analyses were presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.
A specific genetic region near the IL28B gene is referred to as an IL28B genotype. The three variations of IL28B genotypes have been associated with a person's response to hepatitis C treatment with pegylated-interferon and ribavirin. The CC variation is associated with better responses to these medicines.
"Doctors sometimes use IL28B genotype status to decide which patients should be treated with currently available medicines because people with the CT and TT variations of IL28B tend to have substantially lower viral cure rates compared to those with the CC variation," said Ira Jacobson, M.D., Chief of the Division of Gastroenterology and Hepatology at New York-Presbyterian Hospital/Weill Cornell Medical Center, and the Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College and principal investigator for the ADVANCE study. "In this study, telaprevir was associated with a substantial improvement over currently available medicines, regardless of IL28B status, and the greatest improvement was observed in patients with the CT and TT variations."
In ADVANCE, patients were randomized 1:1:1 to receive telaprevir (eight weeks or 12 weeks) in combination with pegylated-interferon and ribavirin, followed by pegylated-interferon and ribavirin alone for a total of either 24 weeks or 48 weeks of treatment. Eligibility for the shorter treatment duration was based on having undetectable hepatitis C virus at weeks four and 12. Among patients in this study tested for their IL28B genotype, 90 percent (45/50) of CC patients who received a 12-week telaprevir-based combination regimen, achieved a viral cure and 78 percent (39/50) of them were eligible to stop all treatment at 24 weeks. These results were compared to 64 percent (35/55) of patients who achieved a viral cure with pegylated-interferon and ribavirin alone for 48 weeks.
"The 90 percent viral cure rate among people with the CC variation of IL28B in this study is significant, but the fact that nearly 80 percent of them were eligible for the shorter course of treatment is an equally important finding," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Vertex plans to conduct a study evaluating a short-duration, 12-week telaprevir-based regimen in people who have not been treated for hepatitis C who have the CC variation of IL28B."
Data from the ADVANCE study showed that patients with the CC variation of IL28B who were new to treatment and received a telaprevir-based combination regimen had the highest viral cure rates compared to those with the CT and TT variations. Data from both ADVANCE and REALIZE showed a nearly three-fold improvement in viral cure rates among patients with the CT and TT variations of IL28B who received telaprevir-based combination therapy compared to those who received pegylated-interferon and ribavirin. These differences were observed among patients who were new to treatment as well as those whose prior treatment for hepatitis C was unsuccessful.
Retrospective Analysis from ADVANCE
The Phase 3 ADVANCE study evaluated people who were new to treatment for hepatitis C. The retrospective analysis of IL28B status presented today includes people tested for IL28B genotype (454/1088; 42 percent). Of the patients in ADVANCE who were tested for their IL28B genotype, the distribution of the variations was consistent with previously published studies in people new to treatment.1 Data from the subanalysis of IL28B status in the control and telaprevir treatment arms (12 weeks) of the study are shown in the table.
Due to the de-identification procedure, only samples from Caucasian patients were included in this analysis.
*RVR: rapid viral response; undetectable (<25 IU/mL undetectable by Roche COBAS Taqman HCV test) at week 4.
**eRVR: extended rapid viral response; undetectable (<25 IU/mL undetectable by Roche COBAS Taqman HCV test) at weeks 4 and 12.
***SVR: defined as the proportion of people who had undetectable hepatitis C virus 24 weeks after the end of all treatment; <25 IU/mL, undetectable by Roche COBAS Taqman HCV test.
TVR+: 12 weeks of telaprevir (TVR, 750 mg, q8h), Pegasys(R) (PEG, pegylated-interferon alfa-2a) and Copegus(R) (RBV, ribavirin) followed by 12 weeks or 36 weeks of only PEG & RBV, based on response to treatment at week 4 and week 12.
Control++: 12 weeks of placebo, PEG & RBV, followed by 36 weeks of PEG & RBV alone.
----------------------
Retrospective Analysis from REALIZE
The Phase 3 REALIZE study evaluated people whose prior treatment with pegylated-interferon and ribavirin was unsuccessful (prior relapsers, prior partial responders and prior null responders). Of the patients in REALIZE who were tested for their IL28B genotype (527/662; 80 percent), the distribution of patients with the CT variation was over-represented and the distribution of those with the CC variation was under-represented. This is consistent with expectations for a population that has not responded to a prior course of treatment.
TVR+: Since there was no difference between the two telaprevir groups studied, SVR rates reflect the combined telaprevir-based treatment groups. (a) 12 weeks of telaprevir (750 mg, q8h), Pegasys® (PEG, pegylated-interferon alfa-2a) & Copegus® (RBV, ribavirin), followed by 36 weeks of PEG & RBV alone and (b) 4 weeks of PEG & RBV alone followed by 12 weeks of telaprevir (750 mg, q8h), PEG & RBV, followed by 32 weeks of PEG & RBV alone.
Control++: 12 weeks of placebo, PEG & RBV, followed by 36 weeks of PEG & RBV alone.
Relapser: Defined as a person whose hepatitis C virus was undetectable at the completion of at least 42 weeks of a prior course of therapy but whose virus became detectable during the follow-up period.
Partial Responder: Defined as a person who achieved at least a 2 log10 reduction in HCV RNA at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy.
Null Responder: Defined as a person who achieved a less than 2 log10 reduction in HCV RNA at week 12 of a prior course of therapy.
----------------------
Safety and Tolerability Information from Phase 3 Studies of Telaprevir
The safety and tolerability results of the telaprevir-based combination regimens were consistent across the Phase 3 studies. The most common adverse events were fatigue, pruritus, nausea, headache, rash, anemia, flu-like symptoms, insomnia and diarrhea with the majority being mild to moderate. Rash and anemia occurred more frequently in the telaprevir-based treatment arms compared to the control groups.
Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. More than 90 percent of rash was mild to moderate and was primarily managed with the use of topical corticosteroids and/or antihistamines. Anemia was primarily managed by reducing the dose of ribavirin.
To optimize each patient's opportunity to achieve viral cure in the Phase 3 studies, sequential discontinuation of the medicines was recommended as a strategy to manage certain adverse events. This strategy allowed patients to continue on pegylated-interferon and ribavirin after stopping telaprevir. Discontinuation of all medicines due to either rash or anemia during the telaprevir/placebo treatment phase was 1 percent to 3 percent in the telaprevir treatment arms.
About IL28B
IL28B is a gene related to the interferon system. A genetic region near the IL28B gene is referred to as an IL28B genotype. There are three variations of IL28B genotypes: CC, CT or TT. These variations have been associated with a person's response to treatment for hepatitis C with pegylated-interferon and ribavirin. Studies have shown that people with the CC variation respond better to treatment with pegylated-interferon and ribavirin than those with the CT or TT variations. The CC variation is more frequent in Caucasians compared to African Americans (39 percent versus 16 percent), which may partially explain the lower response to treatment observed among African Americans in most clinical trials of pegylated-interferon and ribavirin.1
About the Phase 3 ADVANCE and REALIZE Studies
ADVANCE was a pivotal Phase 3, randomized, double-blind, placebo-controlled, global study of 1,088 people who were new to hepatitis C treatment. The primary endpoint of ADVANCE was SVR (defined as the proportion of people who had undetectable hepatitis C virus 24 weeks after the end of all treatment; <25 IU/mL, undetectable by Roche COBAS Taqman HCV test). The secondary endpoint evaluated the safety of telaprevir when dosed in combination with pegylated-interferon and ribavirin.
REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled study conducted globally with the majority of clinical trial sites in Europe and North America. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based combination regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one course of prior treatment with interferon-based therapy.
Patients were randomized 2:2:1 to two telaprevir-based treatment arms (simultaneous start and lead-in) and a control arm of pegylated-interferon and ribavirin alone. The primary endpoint of the REALIZE study was SVR in each of the two telaprevir treatment arms compared to the control arm and for the three groups of people included in the study.
Status of Telaprevir Regulatory Applications
The regulatory applications for the approval of telaprevir have been granted Priority Review by the U.S. Food and Drug Administration (FDA) and Health Canada and accelerated assessment by the European Medicines Agency for the treatment of people with genotype 1 chronic hepatitis C. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA). The applications include data from three registration studies, ADVANCE, ILLUMINATE and REALIZE, which evaluated telaprevir in combination with pegylated-interferon and ribavirin in people with hepatitis C who were new to treatment as well as those who did not achieve a viral cure after treatment with currently available medicines. For complete information on the telaprevir clinical trials or a fact sheet on the trial designs visit: www.vrtx.com/press.cfm.
About the Telaprevir Development Program
Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 chronic hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.
Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.2 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2 Approximately 60 percent of people who undergo treatment with an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,3,4,5 or viral cure.6 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8
More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10
PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.
Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) Vertex's plan to conduct a study evaluating a short-duration, 12-week telaprevir-based regimen in people how have not been treated for hepatitis C who have the CC variation of IL28B, (ii) the date of the scheduled meeting of the FDA's Antivirial Advisory Committee and (iii) the FDA's target review date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
For more information and to view Vertex's press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
1 Ge D, Fellay J, Thomspon AH, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009; 461:399-401
2 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.
3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
9 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.
10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
11 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
12 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
Source
- Nearly three-fold improvement in viral cure rates was observed among people with the 'CT' and 'TT' variations compared to the control group, regardless of prior treatment experience -
BERLIN--(March 31 2011 press release Vertex)-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced new data from retrospective analyses that evaluated the relationship between variations at the IL28B gene and a patient's response to treatment with telaprevir in combination with pegylated-interferon and ribavirin from two of its pivotal Phase 3 studies (ADVANCE and REALIZE) for a group of people who were tested for IL28B genotype. These analyses showed that people in these studies had substantial improvements in sustained viral response (SVR, or viral cure) rates across all IL28B genotypes (CC, CT or TT) for those treated with telaprevir-based combination therapy compared to those treated with pegylated-interferon and ribavirin alone. Telaprevir is a medicine in development for the treatment of genotype 1 chronic hepatitis C. Safety and tolerability results were consistent across the Phase 3 studies of telaprevir. Data from these IL28B analyses were presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.
A specific genetic region near the IL28B gene is referred to as an IL28B genotype. The three variations of IL28B genotypes have been associated with a person's response to hepatitis C treatment with pegylated-interferon and ribavirin. The CC variation is associated with better responses to these medicines.
"Doctors sometimes use IL28B genotype status to decide which patients should be treated with currently available medicines because people with the CT and TT variations of IL28B tend to have substantially lower viral cure rates compared to those with the CC variation," said Ira Jacobson, M.D., Chief of the Division of Gastroenterology and Hepatology at New York-Presbyterian Hospital/Weill Cornell Medical Center, and the Vincent Astor Distinguished Professor of Medicine at Weill Cornell Medical College and principal investigator for the ADVANCE study. "In this study, telaprevir was associated with a substantial improvement over currently available medicines, regardless of IL28B status, and the greatest improvement was observed in patients with the CT and TT variations."
In ADVANCE, patients were randomized 1:1:1 to receive telaprevir (eight weeks or 12 weeks) in combination with pegylated-interferon and ribavirin, followed by pegylated-interferon and ribavirin alone for a total of either 24 weeks or 48 weeks of treatment. Eligibility for the shorter treatment duration was based on having undetectable hepatitis C virus at weeks four and 12. Among patients in this study tested for their IL28B genotype, 90 percent (45/50) of CC patients who received a 12-week telaprevir-based combination regimen, achieved a viral cure and 78 percent (39/50) of them were eligible to stop all treatment at 24 weeks. These results were compared to 64 percent (35/55) of patients who achieved a viral cure with pegylated-interferon and ribavirin alone for 48 weeks.
"The 90 percent viral cure rate among people with the CC variation of IL28B in this study is significant, but the fact that nearly 80 percent of them were eligible for the shorter course of treatment is an equally important finding," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Vertex plans to conduct a study evaluating a short-duration, 12-week telaprevir-based regimen in people who have not been treated for hepatitis C who have the CC variation of IL28B."
Data from the ADVANCE study showed that patients with the CC variation of IL28B who were new to treatment and received a telaprevir-based combination regimen had the highest viral cure rates compared to those with the CT and TT variations. Data from both ADVANCE and REALIZE showed a nearly three-fold improvement in viral cure rates among patients with the CT and TT variations of IL28B who received telaprevir-based combination therapy compared to those who received pegylated-interferon and ribavirin. These differences were observed among patients who were new to treatment as well as those whose prior treatment for hepatitis C was unsuccessful.
Retrospective Analysis from ADVANCE
The Phase 3 ADVANCE study evaluated people who were new to treatment for hepatitis C. The retrospective analysis of IL28B status presented today includes people tested for IL28B genotype (454/1088; 42 percent). Of the patients in ADVANCE who were tested for their IL28B genotype, the distribution of the variations was consistent with previously published studies in people new to treatment.1 Data from the subanalysis of IL28B status in the control and telaprevir treatment arms (12 weeks) of the study are shown in the table.
*RVR: rapid viral response; undetectable (<25 IU/mL undetectable by Roche COBAS Taqman HCV test) at week 4.
**eRVR: extended rapid viral response; undetectable (<25 IU/mL undetectable by Roche COBAS Taqman HCV test) at weeks 4 and 12.
***SVR: defined as the proportion of people who had undetectable hepatitis C virus 24 weeks after the end of all treatment; <25 IU/mL, undetectable by Roche COBAS Taqman HCV test.
TVR+: 12 weeks of telaprevir (TVR, 750 mg, q8h), Pegasys(R) (PEG, pegylated-interferon alfa-2a) and Copegus(R) (RBV, ribavirin) followed by 12 weeks or 36 weeks of only PEG & RBV, based on response to treatment at week 4 and week 12.
Control++: 12 weeks of placebo, PEG & RBV, followed by 36 weeks of PEG & RBV alone.
----------------------
Retrospective Analysis from REALIZE
The Phase 3 REALIZE study evaluated people whose prior treatment with pegylated-interferon and ribavirin was unsuccessful (prior relapsers, prior partial responders and prior null responders). Of the patients in REALIZE who were tested for their IL28B genotype (527/662; 80 percent), the distribution of patients with the CT variation was over-represented and the distribution of those with the CC variation was under-represented. This is consistent with expectations for a population that has not responded to a prior course of treatment.
Control++: 12 weeks of placebo, PEG & RBV, followed by 36 weeks of PEG & RBV alone.
Relapser: Defined as a person whose hepatitis C virus was undetectable at the completion of at least 42 weeks of a prior course of therapy but whose virus became detectable during the follow-up period.
Partial Responder: Defined as a person who achieved at least a 2 log10 reduction in HCV RNA at week 12, but whose hepatitis C virus never became undetectable by week 24 of a prior course of therapy.
Null Responder: Defined as a person who achieved a less than 2 log10 reduction in HCV RNA at week 12 of a prior course of therapy.
----------------------
Safety and Tolerability Information from Phase 3 Studies of Telaprevir
The safety and tolerability results of the telaprevir-based combination regimens were consistent across the Phase 3 studies. The most common adverse events were fatigue, pruritus, nausea, headache, rash, anemia, flu-like symptoms, insomnia and diarrhea with the majority being mild to moderate. Rash and anemia occurred more frequently in the telaprevir-based treatment arms compared to the control groups.
Rash was primarily characterized as eczema-like, manageable and resolved upon stopping telaprevir. More than 90 percent of rash was mild to moderate and was primarily managed with the use of topical corticosteroids and/or antihistamines. Anemia was primarily managed by reducing the dose of ribavirin.
To optimize each patient's opportunity to achieve viral cure in the Phase 3 studies, sequential discontinuation of the medicines was recommended as a strategy to manage certain adverse events. This strategy allowed patients to continue on pegylated-interferon and ribavirin after stopping telaprevir. Discontinuation of all medicines due to either rash or anemia during the telaprevir/placebo treatment phase was 1 percent to 3 percent in the telaprevir treatment arms.
About IL28B
IL28B is a gene related to the interferon system. A genetic region near the IL28B gene is referred to as an IL28B genotype. There are three variations of IL28B genotypes: CC, CT or TT. These variations have been associated with a person's response to treatment for hepatitis C with pegylated-interferon and ribavirin. Studies have shown that people with the CC variation respond better to treatment with pegylated-interferon and ribavirin than those with the CT or TT variations. The CC variation is more frequent in Caucasians compared to African Americans (39 percent versus 16 percent), which may partially explain the lower response to treatment observed among African Americans in most clinical trials of pegylated-interferon and ribavirin.1
About the Phase 3 ADVANCE and REALIZE Studies
ADVANCE was a pivotal Phase 3, randomized, double-blind, placebo-controlled, global study of 1,088 people who were new to hepatitis C treatment. The primary endpoint of ADVANCE was SVR (defined as the proportion of people who had undetectable hepatitis C virus 24 weeks after the end of all treatment; <25 IU/mL, undetectable by Roche COBAS Taqman HCV test). The secondary endpoint evaluated the safety of telaprevir when dosed in combination with pegylated-interferon and ribavirin.
REALIZE was a pivotal Phase 3, randomized, double-blind, placebo-controlled study conducted globally with the majority of clinical trial sites in Europe and North America. The study was designed to evaluate the efficacy, safety and tolerability of telaprevir-based combination regimens in people infected with genotype 1 chronic hepatitis C who did not achieve a viral cure after at least one course of prior treatment with interferon-based therapy.
Patients were randomized 2:2:1 to two telaprevir-based treatment arms (simultaneous start and lead-in) and a control arm of pegylated-interferon and ribavirin alone. The primary endpoint of the REALIZE study was SVR in each of the two telaprevir treatment arms compared to the control arm and for the three groups of people included in the study.
Status of Telaprevir Regulatory Applications
The regulatory applications for the approval of telaprevir have been granted Priority Review by the U.S. Food and Drug Administration (FDA) and Health Canada and accelerated assessment by the European Medicines Agency for the treatment of people with genotype 1 chronic hepatitis C. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA). The applications include data from three registration studies, ADVANCE, ILLUMINATE and REALIZE, which evaluated telaprevir in combination with pegylated-interferon and ribavirin in people with hepatitis C who were new to treatment as well as those who did not achieve a viral cure after treatment with currently available medicines. For complete information on the telaprevir clinical trials or a fact sheet on the trial designs visit: www.vrtx.com/press.cfm.
About the Telaprevir Development Program
Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with hepatitis C have received telaprevir-based therapy as part of Phase 2 studies and the Phase 3 ADVANCE, ILLUMINATE and REALIZE studies. Together, these studies enrolled people with genotype 1 chronic hepatitis C who had not been treated for their disease previously as well as people who had been treated before but did not achieve a viral cure.
Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.2 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.2 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.2 Approximately 60 percent of people who undergo treatment with an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,3,4,5 or viral cure.6 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.7,8
More than 170 million people worldwide are chronically infected with hepatitis C.6 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.9 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.10 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.11,12 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.10
PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.
Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) Vertex's plan to conduct a study evaluating a short-duration, 12-week telaprevir-based regimen in people how have not been treated for hepatitis C who have the CC variation of IL28B, (ii) the date of the scheduled meeting of the FDA's Antivirial Advisory Committee and (iii) the FDA's target review date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that there may be varying interpretations of the data from the telaprevir clinical trials; that future outcomes from clinical trials of telaprevir may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at www.vrtx.com. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
For more information and to view Vertex's press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
1 Ge D, Fellay J, Thomspon AH, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009; 461:399-401
2 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.
3 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
4 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
5 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
6 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
7 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
8 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
9 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.
10 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
11 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
12 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
Source
EASL: Interim Phase 2 Data Showed Rapid Viral Response to VX-222 in Combination with Telaprevir, Pegylated-Interferon and Ribavirin Among People With Hepatitis C
First study to evaluate four-drug, 12-week treatment duration for hepatitis C
BERLIN--(press release March 31 2011) Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study (ZENITH) designed to assess the safety and tolerability of 12-week response-guided treatment regimens with its polymerase inhibitor, VX-222, and its protease inhibitor, telaprevir, in combination with pegylated-interferon and ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment. The study enrolled 106 people into one of four treatment groups. Among those who received VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin, interim data showed that 90 percent (27/30) of them had undetectable hepatitis C virus at week 12. Half (15/30) of those in the VX-222 (400 mg) treatment group were eligible to stop all treatment at week 12. People in this same treatment group who were not eligible to stop all treatment at 12 weeks were assigned to receive 24 total weeks of treatment: 12 weeks of the four-drug regimen followed by 12 weeks of pegylated-interferon and ribavirin alone. Preliminary safety results showed that the most frequently reported adverse events were mild gastrointestinal symptoms and mild fatigue. At the time of this analysis, there were no discontinuations due to gastrointestinal symptoms. Data from this study are being presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.
"Telaprevir triple therapy demonstrated significant improvements in viral cure rates and an ability to halve treatment time to 24 weeks for many people in late-stage studies," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Reducing treatment time in half again to 12 weeks would be another important advance and the early data from this study provide new information about the potential to do this with a four-drug VX-222 regimen."
Using an intent-to-treat analysis, 57 percent (17/30) of people treated with VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin had undetectable hepatitis C virus by week two. Among people who were treated with VX-222 (100 mg) in combination with telaprevir, pegylated-interferon and ribavirin, 38 percent (11/29) had undetectable hepatitis C virus by week two. To determine if patients were eligible to stop all treatment at 12 weeks in ZENITH, they had to have undetectable hepatitis C virus at weeks two and eight. Using the eligibility criteria for a 12-week total treatment duration, half (15/30) of the patients in the high-dose VX-222 combination group and 38 percent (11/29) in the low-dose combination group were eligible to stop all treatment at 12 weeks. Ninety percent (27/30) of patients in the high-dose VX-222 group had undetectable hepatitis C virus by week 12 as did 83 percent (24/29) in the low-dose VX-222 group. No viral breakthrough was observed through week 12 among patients receiving the four-drug combinations.
"The early data from this study are encouraging because they showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment," said Adrian Di Bisceglie, M.D., Chief of Hepatology at Saint Louis University School of Medicine. "Hepatitis C virus was undetectable at week 12 of treatment in 90 percent of patients who received the higher dose of VX-222, and half of those in this treatment group were eligible to stop all treatment at that time."
ZENITH is an ongoing Phase 2 study that enrolled 106 people and began with four treatment arms evaluating two-drug and four-drug combination regimens. The primary endpoint is safety and tolerability and the secondary endpoint is on-treatment antiviral activity and the proportion of people in each treatment arm who achieve a sustained viral response (SVR, defined as undetectable hepatitis C virus 24 weeks after the end of treatment). The study is designed to evaluate various combinations of VX-222, telaprevir, pegylated-interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C. In this study, VX-222, telaprevir and ribavirin are given twice daily. Arms A (n=18) and B (n=29) were designed to evaluate the all-oral, two-drug combination regimens of VX-222 (400 mg or 100 mg) and telaprevir (1,125 mg). Both of these study arms were discontinued due to a pre-defined stopping rule related to viral breakthrough. Arms C (n=29) and D (n=30) are ongoing and designed to evaluate the four-drug combination regimens of VX-222 (400 mg and 100 mg), telaprevir (1,125 mg), pegylated-interferon and ribavirin. An additional treatment arm has been added to the study to evaluate an all-oral, three-drug regimen of VX-222, telaprevir and ribavirin in people with genotype 1b chronic hepatitis C. This study arm is now open for enrollment. A sixth and final arm may be added to the trial per protocol based on data from the study.
HCV RNA was evaluated using the TaqMan assay version 2.0.
*As part of a response-guided regimen, people who have undetectable hepatitis C virus at weeks 2 and 8 are eligible to stop all treatment at week 12.
+ VX-222 (100 mg, BID), telaprevir (1,125 mg, BID), Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin).
++ VX-222 (400 mg, BID), telaprevir (1,125 mg, BID), Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin).
--------------------------------------
Preliminary Safety and Tolerability
The 12-week safety and tolerability results are preliminary and include data on all patients enrolled in the study: those enrolled in the two-drug (n=47) and four-drug (n=59) treatment arms. The most frequent adverse events observed in this study were mild gastrointestinal symptoms (including diarrhea, nausea and vomiting) and mild fatigue. No patients discontinued due to gastrointestinal symptoms.
Preliminary safety data indicate that there were six discontinuations due to adverse events among the four treatment arms through week 12. There were two serious adverse events considered by the investigator to be potentially related to study medication: acute renal failure (Arm B), which resolved after study medications were discontinued and anemia (Arm C). There was one additional severe adverse event reported of pneumonia, septic shock and renal failure; this severe adverse event was considered by the investigator to be unrelated to study medication. The three additional discontinuations included rash (n=2) and a motor vehicle accident with facial fractures (n=1).
About Telaprevir and VX-222
Vertex has two oral medicines in development for the treatment of genotype 1 chronic hepatitis C: telaprevir and VX-222. Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 chronic hepatitis C have received telaprevir in Phase 2 and Phase 3 studies. Vertex has been granted Priority Review for its applications for the approval of telaprevir by the U.S. Food and Drug Administration (FDA) and Health Canada. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA).
Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. VX-222 is currently being evaluated in combination with telaprevir, pegylated-interferon and ribavirin in a Phase 2 study. Vertex has worldwide commercial rights for VX-222.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1 Approximately 60 percent of people who undergo treatment of an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,2,3,4 or viral cure.5 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.6,7
More than 170 million people worldwide are chronically infected with hepatitis C.5 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.8 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.9 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.10,11 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9
PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.
Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) the potential importance of reducing treatment time to 12 weeks and early data from this study providing new information about the potential to do this with a four-drug VX-222 regimen; (ii) the early data being encouraging because the data showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment; (iii) the possibility that a sixth treatment arm may be added to the trial; (iv) the date of the scheduled meeting of the FDA's Antiviral Advisory Committee and (v) the FDA's target response date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that the interim on-treatment data presented in this press release may not be predictive of the final outcomes from this clinical trial, outcomes from any future clinical trials of telaprevir/VX-222 may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir/VX-222-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
About Vertex
Vertex creates new possibilities in medicine. Our team aims to discover, develop and commercialize innovative therapies so people with serious diseases can lead better lives.
Vertex scientists and our collaborators are working on new medicines to cure or significantly advance the treatment of hepatitis C, cystic fibrosis, epilepsy and other life-threatening diseases.
Founded more than 20 years ago in Cambridge, MA, we now have ongoing worldwide research programs and sites in the U.S., U.K. and Canada.
For more information and to view Vertex's press releases, please visit http://www.vrtx.com/.
(VRTX - GEN)
1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.
2 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
3 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
4 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
5 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
6 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
7 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
8 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.
9 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
10 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
11 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
Vertex Pharmaceuticals Incorporated
Media:
Dawn Kalmar, 617-444-6992
Amy Pasqua, 617-444-6992
Zachry Barber, 617-444-6992
Source
BERLIN--(press release March 31 2011) Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced interim results from an ongoing Phase 2 study (ZENITH) designed to assess the safety and tolerability of 12-week response-guided treatment regimens with its polymerase inhibitor, VX-222, and its protease inhibitor, telaprevir, in combination with pegylated-interferon and ribavirin in people with genotype 1 chronic hepatitis C who were new to treatment. The study enrolled 106 people into one of four treatment groups. Among those who received VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin, interim data showed that 90 percent (27/30) of them had undetectable hepatitis C virus at week 12. Half (15/30) of those in the VX-222 (400 mg) treatment group were eligible to stop all treatment at week 12. People in this same treatment group who were not eligible to stop all treatment at 12 weeks were assigned to receive 24 total weeks of treatment: 12 weeks of the four-drug regimen followed by 12 weeks of pegylated-interferon and ribavirin alone. Preliminary safety results showed that the most frequently reported adverse events were mild gastrointestinal symptoms and mild fatigue. At the time of this analysis, there were no discontinuations due to gastrointestinal symptoms. Data from this study are being presented today at The International Liver Congress 2011, the 46th annual meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany.
"Telaprevir triple therapy demonstrated significant improvements in viral cure rates and an ability to halve treatment time to 24 weeks for many people in late-stage studies," said Robert Kauffman, M.D., Ph.D., Senior Vice President and Chief Medical Officer for Vertex. "Reducing treatment time in half again to 12 weeks would be another important advance and the early data from this study provide new information about the potential to do this with a four-drug VX-222 regimen."
Using an intent-to-treat analysis, 57 percent (17/30) of people treated with VX-222 (400 mg) in combination with telaprevir, pegylated-interferon and ribavirin had undetectable hepatitis C virus by week two. Among people who were treated with VX-222 (100 mg) in combination with telaprevir, pegylated-interferon and ribavirin, 38 percent (11/29) had undetectable hepatitis C virus by week two. To determine if patients were eligible to stop all treatment at 12 weeks in ZENITH, they had to have undetectable hepatitis C virus at weeks two and eight. Using the eligibility criteria for a 12-week total treatment duration, half (15/30) of the patients in the high-dose VX-222 combination group and 38 percent (11/29) in the low-dose combination group were eligible to stop all treatment at 12 weeks. Ninety percent (27/30) of patients in the high-dose VX-222 group had undetectable hepatitis C virus by week 12 as did 83 percent (24/29) in the low-dose VX-222 group. No viral breakthrough was observed through week 12 among patients receiving the four-drug combinations.
"The early data from this study are encouraging because they showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment," said Adrian Di Bisceglie, M.D., Chief of Hepatology at Saint Louis University School of Medicine. "Hepatitis C virus was undetectable at week 12 of treatment in 90 percent of patients who received the higher dose of VX-222, and half of those in this treatment group were eligible to stop all treatment at that time."
ZENITH is an ongoing Phase 2 study that enrolled 106 people and began with four treatment arms evaluating two-drug and four-drug combination regimens. The primary endpoint is safety and tolerability and the secondary endpoint is on-treatment antiviral activity and the proportion of people in each treatment arm who achieve a sustained viral response (SVR, defined as undetectable hepatitis C virus 24 weeks after the end of treatment). The study is designed to evaluate various combinations of VX-222, telaprevir, pegylated-interferon and ribavirin for the treatment of genotype 1 chronic hepatitis C. In this study, VX-222, telaprevir and ribavirin are given twice daily. Arms A (n=18) and B (n=29) were designed to evaluate the all-oral, two-drug combination regimens of VX-222 (400 mg or 100 mg) and telaprevir (1,125 mg). Both of these study arms were discontinued due to a pre-defined stopping rule related to viral breakthrough. Arms C (n=29) and D (n=30) are ongoing and designed to evaluate the four-drug combination regimens of VX-222 (400 mg and 100 mg), telaprevir (1,125 mg), pegylated-interferon and ribavirin. An additional treatment arm has been added to the study to evaluate an all-oral, three-drug regimen of VX-222, telaprevir and ribavirin in people with genotype 1b chronic hepatitis C. This study arm is now open for enrollment. A sixth and final arm may be added to the trial per protocol based on data from the study.
HCV RNA was evaluated using the TaqMan assay version 2.0.
*As part of a response-guided regimen, people who have undetectable hepatitis C virus at weeks 2 and 8 are eligible to stop all treatment at week 12.
+ VX-222 (100 mg, BID), telaprevir (1,125 mg, BID), Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin).
++ VX-222 (400 mg, BID), telaprevir (1,125 mg, BID), Pegasys(R) (pegylated-interferon alfa-2a) and Copegus(R) (ribavirin).
--------------------------------------
Preliminary Safety and Tolerability
The 12-week safety and tolerability results are preliminary and include data on all patients enrolled in the study: those enrolled in the two-drug (n=47) and four-drug (n=59) treatment arms. The most frequent adverse events observed in this study were mild gastrointestinal symptoms (including diarrhea, nausea and vomiting) and mild fatigue. No patients discontinued due to gastrointestinal symptoms.
Preliminary safety data indicate that there were six discontinuations due to adverse events among the four treatment arms through week 12. There were two serious adverse events considered by the investigator to be potentially related to study medication: acute renal failure (Arm B), which resolved after study medications were discontinued and anemia (Arm C). There was one additional severe adverse event reported of pneumonia, septic shock and renal failure; this severe adverse event was considered by the investigator to be unrelated to study medication. The three additional discontinuations included rash (n=2) and a motor vehicle accident with facial fractures (n=1).
About Telaprevir and VX-222
Vertex has two oral medicines in development for the treatment of genotype 1 chronic hepatitis C: telaprevir and VX-222. Telaprevir is an investigational, oral inhibitor that acts directly on the HCV protease, an enzyme essential for viral replication. To date, more than 2,500 people with genotype 1 chronic hepatitis C have received telaprevir in Phase 2 and Phase 3 studies. Vertex has been granted Priority Review for its applications for the approval of telaprevir by the U.S. Food and Drug Administration (FDA) and Health Canada. The FDA has scheduled its Antiviral Drugs Advisory Committee to discuss the New Drug Application for telaprevir on April 28, 2011. A target response date of May 23, 2011 is set under the Prescription Drug User Fee Act (PDUFA).
Vertex is developing telaprevir in collaboration with Tibotec BVBA and Mitsubishi Tanabe Pharma. Vertex has rights to commercialize telaprevir in North America. Through its affiliate, Janssen, Tibotec has rights to commercialize telaprevir in Europe, South America, Australia, the Middle East and certain other countries. Mitsubishi Tanabe Pharma has rights to commercialize telaprevir in Japan and certain Far East countries.
VX-222 is an investigational, oral, non-nucleoside inhibitor of HCV NS5B polymerase. VX-222 is currently being evaluated in combination with telaprevir, pegylated-interferon and ribavirin in a Phase 2 study. Vertex has worldwide commercial rights for VX-222.
About Hepatitis C
Hepatitis C is a serious liver disease caused by the hepatitis C virus, which is spread through direct contact with the blood of infected people and ultimately affects the liver.1 Chronic hepatitis C can lead to serious and life-threatening liver problems, including liver damage, cirrhosis, liver failure or liver cancer.1 Though many people with hepatitis C may not experience symptoms, others may have symptoms such as fatigue, fever, jaundice and abdominal pain.1 Approximately 60 percent of people who undergo treatment of an initial 48-week regimen of pegylated-interferon and ribavirin, the currently approved medicines for genotype 1 hepatitis C, do not achieve SVR,2,3,4 or viral cure.5 If treatment is not successful and a person does not achieve a viral cure, they remain at an increased risk for progressive liver disease.6,7
More than 170 million people worldwide are chronically infected with hepatitis C.5 In the United States, nearly 4 million people have chronic hepatitis C and 75 percent of them are unaware of their infection.8 The majority of people with hepatitis C in the United States were born between 1946 and 1964, accounting for two of every three people with chronic hepatitis C.9 Hepatitis C is the leading cause of liver transplantations in the United States and is reported to contribute to 4,600 to 12,000 deaths annually.10,11 By 2029, total annual medical costs in the United States for people with hepatitis C are expected to more than double, from $30 billion in 2009 to approximately $85 billion.9
PEGASYS® and COPEGUS® are registered trademarks of Hoffmann-La Roche.
Special Note Regarding Forward-Looking Statements
This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including statements regarding (i) the potential importance of reducing treatment time to 12 weeks and early data from this study providing new information about the potential to do this with a four-drug VX-222 regimen; (ii) the early data being encouraging because the data showed patients had a very rapid decline in hepatitis C virus as early as the second week of treatment; (iii) the possibility that a sixth treatment arm may be added to the trial; (iv) the date of the scheduled meeting of the FDA's Antiviral Advisory Committee and (v) the FDA's target response date for the telaprevir NDA. While the company believes the forward-looking statements contained in this press release are accurate, there are a number of factors that could cause actual events or results to differ materially from those indicated by such forward-looking statements. Those risks and uncertainties include, among other things, that Vertex could experience unforeseen delays in obtaining approval to market telaprevir; that the interim on-treatment data presented in this press release may not be predictive of the final outcomes from this clinical trial, outcomes from any future clinical trials of telaprevir/VX-222 may not be favorable; that future scientific, clinical, competitive or other market factors may adversely affect the potential for telaprevir/VX-222-based therapy and the other risks listed under Risk Factors in Vertex's annual report and quarterly reports filed with the Securities and Exchange Commission and available through Vertex's website at http://www.vrtx.com/. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available.
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1 Centers for Disease Control and Prevention. Hepatitis C Fact Sheet: CDC Viral Hepatitis. Available at: http://www.cdc.gov/hepatitis/HCV/PDFs/HepCGeneralFactSheet.pdf. Accessed March 21, 2011.
2 Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
3 Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
4 McHutchison JG, Lawitz EJ, Shiffman ML, et al; IDEAL Study Team. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580-593.
5 Ghany MG, Strader DB, Thomas DL, Seeff, LB. Diagnosis, management and treatment of hepatitis C; An update. Hepatology. 2009;49 (4):1-40.
6 Morgan TR, Ghany MG, Kim HY, Snow KK, Lindsay K, Lok AS. Outcome of sustained virological responders and non-responders in the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial. Hepatology. 2008;50(Suppl 4):357A (Abstract 115).
7 Veldt BJ, Heathcote J, Wedmeyer H. Sustained virologic response and clinical outcomes in patients with chronic hepatitis C and advanced fibrosis. Annals of Internal Medicine. 2007; 147: 677-684.
8 Institute of Medicine of the National Academies. Hepatitis and liver cancer: a national strategy for prevention and control of hepatitis B and C. Colvin HM and Mitchell AE, ed. Available at: http://www.iom.edu/Reports/2010/Hepatitis-and-Liver-Cancer-A-National-Strategy-for-Prevention-and-Control-of-Hepatitis-B-and-C.aspx. Updated January 11, 2010. Accessed March 21, 2011.
9 Pyenson B, Fitch K, Iwasaki K. Consequences of hepatitis C virus (HCV): Costs of a baby boomer epidemic of liver disease. Available at: http://www.natap.org/2009/HCV/051809_01.htm. Updated May 2009. Accessed March 21, 2011. This report was commissioned by Vertex Pharmaceuticals, Inc.
10 Volk MI, Tocco R, Saini S, Lok, ASF. Public health impact of antiviral therapy for hepatitis C in the United States. Hepatology. 2009;50(6):1750-1755.
11 Davis GL, Alter MJ, El-Serag H, Poynard T, Jennings LW. Aging of hepatitis C virus (HCV)-infected persons in the United States: A multiple cohort model of HCV prevalence and disease progression. Gastroenterology. 2010;138:513-521.
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Source
EASL: OctoPlus' licensee Biolex presents final Phase IIb results at EASL highlighting tolerability advantages of Locteron in treatment of HCV
SOURCE: OctoPlus N.V.
Mar 31, 2011 03:22 ET
LEIDEN, NETHERLANDS--(Marketwire - March 31, 2011) -
Presentation highlights strong antiviral activity and SVR rates, significant reductions in flu-like adverse events and reduced rates of depression
Significant tolerability advantages and a 50% reduction in dosing frequency support Locteron's attractiveness for use in new triple- and quad- combination regimens
OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data highlight important tolerability advantages of Locteron versus current HCV treatments. Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments." The following information was taken directly from Biolex' press release (see www.biolex.com).
Biolex announces that final 72-week results from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. Data presented today show that Locteron achieved the SELECT-2 study objectives by demonstrating viral kinetics and response rates that were comparable with or exceeded the PEG-Intron® control while also achieving a statistically significant reduction in flu-like adverse events, reduced rates of depression, lower use of concomitant medications and a reduced rate of discontinuation due to adverse events. Locteron, the only controlled- release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.
Locteron dosing convenience and efficacy
Locteron is administered once every other week and requires half as many injections as the currently marketed interferons, each of which are injected once per week. In SELECT-2, the sustained virologic response rate (SVR) for each of the three Locteron doses studied was comparable with or exceeded the response rate for the PEG-Intron control as outlined in the table below. Click on the link below for the press release including tables.
Click here for the press release in PDF format: http://hugin.info/137076/R/1501932/437140.pdf
This announcement is distributed by Thomson Reuters on behalf of Thomson Reuters clients. The owner of this announcement warrants that:
(i) the releases contained herein are protected by copyright and other applicable laws; and
(ii) they are solely responsible for the content, accuracy and originality of the information contained therein.
Source: OctoPlus N.V. via Thomson Reuters ONE
[HUG#1501932]
For further information, please contact:
Rianne Roukema
Corporate Communications:
Telephone number: +31 (71) 524 1071
E-mail to Investor Relations: Email Contact
Source
Mar 31, 2011 03:22 ET
LEIDEN, NETHERLANDS--(Marketwire - March 31, 2011) -
Presentation highlights strong antiviral activity and SVR rates, significant reductions in flu-like adverse events and reduced rates of depression
Significant tolerability advantages and a 50% reduction in dosing frequency support Locteron's attractiveness for use in new triple- and quad- combination regimens
OctoPlus N.V. ("OctoPlus" or the "Company") (Euronext: OCTO) announces that its licensee Biolex Therapeutics will present today final results from the Locteron® Phase IIb clinical study at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. These data highlight important tolerability advantages of Locteron versus current HCV treatments. Jan Egberts, CEO of OctoPlus, comments: "These positive final results from the Phase IIb clinical study with Locteron further confirm the long term benefits of Locteron's controlled release mechanism. Our PolyActive technology has enabled the development of an interferon alpha with a significantly improved side effect profile, achieving both a 50% reduction in flu-like adverse events and substantially lower rates of depression compared to conventional interferon treatments. In combination with its reduced injection frequency, these benefits clearly position Locteron as the interferon of choice for future hepatitis C treatments." The following information was taken directly from Biolex' press release (see www.biolex.com).
Biolex announces that final 72-week results from its SELECT-2 Phase 2b trial of Locteron® for the treatment of hepatitis C are being presented today at the 46th Annual Meeting of the European Association for the Study of the Liver (EASL) in Berlin, Germany. Data presented today show that Locteron achieved the SELECT-2 study objectives by demonstrating viral kinetics and response rates that were comparable with or exceeded the PEG-Intron® control while also achieving a statistically significant reduction in flu-like adverse events, reduced rates of depression, lower use of concomitant medications and a reduced rate of discontinuation due to adverse events. Locteron, the only controlled- release interferon alpha, is designed to offer key tolerability and dosing advantages over currently marketed interferons and serve as a core component of new combination therapies as the treatment of hepatitis C evolves to triple- and quad-drug regimens.
Locteron dosing convenience and efficacy
Locteron is administered once every other week and requires half as many injections as the currently marketed interferons, each of which are injected once per week. In SELECT-2, the sustained virologic response rate (SVR) for each of the three Locteron doses studied was comparable with or exceeded the response rate for the PEG-Intron control as outlined in the table below. Click on the link below for the press release including tables.
Click here for the press release in PDF format: http://hugin.info/137076/R/1501932/437140.pdf
This announcement is distributed by Thomson Reuters on behalf of Thomson Reuters clients. The owner of this announcement warrants that:
(i) the releases contained herein are protected by copyright and other applicable laws; and
(ii) they are solely responsible for the content, accuracy and originality of the information contained therein.
Source: OctoPlus N.V. via Thomson Reuters ONE
[HUG#1501932]
For further information, please contact:
Rianne Roukema
Corporate Communications:
Telephone number: +31 (71) 524 1071
E-mail to Investor Relations: Email Contact
Source
New Drugs for Hepatitis C on the Horizon
With the promise of two new drugs to fortify the current treatment protocol, doctors see promise of a better-tailored cocktail, similar to HIV treatments, to beat back this common and often debilitating infection
By Katherine Harmon
March 30, 2011
Some 3.2 million Americans have chronic hepatitis C, an infection that can linger in the body for years before producing symptoms. It can eventually lead to serious liver scarring and cancer. And most infections in the U.S. are the disease's particularly tough breed, known as genotype 1, which has a cure rate of less than 40 percent with the best current treatment.
Two new drugs for this type, however, are now racing toward approval by the U.S. Food and Drug Administration, which could come as soon as late May. Both compounds are protease inhibitors and are expected to hit the market at about the same time.
Hepatitis C is spread through contact with blood and occasionally other bodily fluids, and 65 to 70 percent of people infected with the disease are unaware that they have it, according to John Ward, director of the Division of Viral Hepatitis at the U.S. Centers for Disease Control and Prevention. In the U.S. about one in 30 baby boomers has hepatitis C, and one in four people with HIV has the infection, he noted at a 2010 talk. The disease is responsible for some $33.3 billion in medical costs each year.
"We've been waiting for these drugs for a long time," says Darryn Potosky, a hepatologist at the University of Maryland Medical Center, who often has to tell patients they face steep odds of beating the disease.
If the new drugs come to market, patients would take one or the other in addition to the current two-drug treatment regimen. "It seems hepatitis C therapy is moving in the direction of HIV therapy, with multiple drug cocktails," Potosky says. And with that come "hopes that we can tailor treatments to patients."
Two new studies of one of the drugs, boceprevir, will be published in the March 31 issue of the New England Journal of Medicine. Both phase III trials were funded by Schering-Plough (now part of Merck), which makes the drug. There have not yet been any studies comparing boceprevir and the other new protease inhibitor, telaprevir (made by Vertex), but given the drugs' similarity, experts say they both seem promising.
In the new boceprevir trials, adding the drug to the current standard treatment (of interferon and ribavirin) effectively doubled the percentage of patients who were able to suppress the virus—an effect called sustained viral response, which is a mark of being effectively "cured."
"Patients with hepatitis C genotype 1 infection can anticipate a significant therapeutic advance," says Donald Jensen, a professor of medicine at the University of Chicago Medical Center, who wrote an editorial on the new research for the same issue of NEJM. But because these new drugs will each need to be used in combination with the existing two-drug regimes, they "will be associated with more side effects and more complexity."
Long road to safety
Doctors have long hoped for a safe and effective drug to beat hepatitis C (HCV) genotype 1—which, among strains of the disease, is "the most common and the hardest to treat at the same time," Potosky says. Some 70 to 80 percent of people infected with hepatitis C in the U.S. have this type.
With excitement building for these new drugs to arrive in the market, those who have been working on the problem have not forgotten that getting to this point "has been painstakingly slow," says Stuart Gordon of Henry Ford Hospital in Detroit, who coauthored one of the new studies.
Just finding the right compounds was challenging, he notes. An early protease-inhibitor contender, made by Boehringer Ingelheim, was found to be too toxic, and "many of the HCV polymerase inhibitors had to stop their development because of unacceptable side effects," Gordon notes.
And because the new treatment regime must be shown to be better than the current standard of care, which is a 48-week course, "the sheer time involved in conducting these large trials" made for slow going. But a payoff might be near.
One new trial, of 1,097 patients with hepatitis C genotype 1 who had never been treated, found that after 24 or 44 weeks of adding boceprevir to their drug regimen some two-thirds of non-black patients showed they were effectively suppressing the virus. The drug combo was not as effective for black patients, who are less likely to have a gene alteration that is linked to responsiveness to one of the drugs. But adding boceprevir still boosted response rates in these patients from 23 percent to more than half in the 44-week treatment group.
In the other trial, 403 patients with the disease who had not responded to traditional treatment—either showing no improvement or relapsing—were studied. Adding boceprevir to the standard treatment for 32 or 44 weeks resulted in sustained viral response rates in 59 and 66 percent of patients, respectively, compared with 38 percent in the control group.
The studies were both somewhat unusual in that they started patients out with a month-long lead-in period in which patients received the two drugs already available—before boceprevir was introduced to some groups. This "allowed some prediction capability of both subsequent response as well as risk of developing resistant variants," Jensen explains.
Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."
Potosky notes that the extent of resistance will only become clear with time—and as more people take the new drugs. And just as they monitor HIV patients for telltale resistance patterns, doctors should be able to detect early signs of resistance in people being treated for hepatitis C as well.
Adding boceprevir also increased the amount of side effects patients experienced. More than 40 percent of subjects taking this third drug required treatment for anemia in one of the studies, and in the other, severe anemia led doctors to decrease dosage in some 20 percent of subjects. Even though some of these cases were serious, few patients dropped out of treatment.
With boceprevir and telaprevir likely in the home stretch to reach potentially millions of hepatitis C patients in the U.S., doctors and researchers are now turning their focus to the many challenges that remain.
Aside from keeping resistance low and dialing down side effects, the next steps are to try to simplify the treatment regimen. "Everyone wants to get rid of interferon and ribavirin because both have toxicity that make them often difficult to tolerate," Gordon notes. Interferon also currently is usually administered via injection, so moving to an all-oral, once-a-day dosing would make treatment better and more consistent.
Gordon also looks forward to finding ways to help special populations of patients, including those who have HIV, end-stage liver disease or renal disease, as well as children, "who are currently not eligible for our current therapies."
Source
By Katherine Harmon
March 30, 2011
Some 3.2 million Americans have chronic hepatitis C, an infection that can linger in the body for years before producing symptoms. It can eventually lead to serious liver scarring and cancer. And most infections in the U.S. are the disease's particularly tough breed, known as genotype 1, which has a cure rate of less than 40 percent with the best current treatment.
Two new drugs for this type, however, are now racing toward approval by the U.S. Food and Drug Administration, which could come as soon as late May. Both compounds are protease inhibitors and are expected to hit the market at about the same time.
Hepatitis C is spread through contact with blood and occasionally other bodily fluids, and 65 to 70 percent of people infected with the disease are unaware that they have it, according to John Ward, director of the Division of Viral Hepatitis at the U.S. Centers for Disease Control and Prevention. In the U.S. about one in 30 baby boomers has hepatitis C, and one in four people with HIV has the infection, he noted at a 2010 talk. The disease is responsible for some $33.3 billion in medical costs each year.
"We've been waiting for these drugs for a long time," says Darryn Potosky, a hepatologist at the University of Maryland Medical Center, who often has to tell patients they face steep odds of beating the disease.
If the new drugs come to market, patients would take one or the other in addition to the current two-drug treatment regimen. "It seems hepatitis C therapy is moving in the direction of HIV therapy, with multiple drug cocktails," Potosky says. And with that come "hopes that we can tailor treatments to patients."
Two new studies of one of the drugs, boceprevir, will be published in the March 31 issue of the New England Journal of Medicine. Both phase III trials were funded by Schering-Plough (now part of Merck), which makes the drug. There have not yet been any studies comparing boceprevir and the other new protease inhibitor, telaprevir (made by Vertex), but given the drugs' similarity, experts say they both seem promising.
In the new boceprevir trials, adding the drug to the current standard treatment (of interferon and ribavirin) effectively doubled the percentage of patients who were able to suppress the virus—an effect called sustained viral response, which is a mark of being effectively "cured."
"Patients with hepatitis C genotype 1 infection can anticipate a significant therapeutic advance," says Donald Jensen, a professor of medicine at the University of Chicago Medical Center, who wrote an editorial on the new research for the same issue of NEJM. But because these new drugs will each need to be used in combination with the existing two-drug regimes, they "will be associated with more side effects and more complexity."
Long road to safety
Doctors have long hoped for a safe and effective drug to beat hepatitis C (HCV) genotype 1—which, among strains of the disease, is "the most common and the hardest to treat at the same time," Potosky says. Some 70 to 80 percent of people infected with hepatitis C in the U.S. have this type.
With excitement building for these new drugs to arrive in the market, those who have been working on the problem have not forgotten that getting to this point "has been painstakingly slow," says Stuart Gordon of Henry Ford Hospital in Detroit, who coauthored one of the new studies.
Just finding the right compounds was challenging, he notes. An early protease-inhibitor contender, made by Boehringer Ingelheim, was found to be too toxic, and "many of the HCV polymerase inhibitors had to stop their development because of unacceptable side effects," Gordon notes.
And because the new treatment regime must be shown to be better than the current standard of care, which is a 48-week course, "the sheer time involved in conducting these large trials" made for slow going. But a payoff might be near.
One new trial, of 1,097 patients with hepatitis C genotype 1 who had never been treated, found that after 24 or 44 weeks of adding boceprevir to their drug regimen some two-thirds of non-black patients showed they were effectively suppressing the virus. The drug combo was not as effective for black patients, who are less likely to have a gene alteration that is linked to responsiveness to one of the drugs. But adding boceprevir still boosted response rates in these patients from 23 percent to more than half in the 44-week treatment group.
In the other trial, 403 patients with the disease who had not responded to traditional treatment—either showing no improvement or relapsing—were studied. Adding boceprevir to the standard treatment for 32 or 44 weeks resulted in sustained viral response rates in 59 and 66 percent of patients, respectively, compared with 38 percent in the control group.
The studies were both somewhat unusual in that they started patients out with a month-long lead-in period in which patients received the two drugs already available—before boceprevir was introduced to some groups. This "allowed some prediction capability of both subsequent response as well as risk of developing resistant variants," Jensen explains.
Early studies showed that although a protease inhibitor given on its own was very effective initially, it often led to resistant strains of the virus in a matter of days, Gordon says. Even with interferon and ribavirin, resistance "remains a concern," he says. To keep it to a minimum, "clinicians must follow such patients very closely during therapy because if the viral level starts to rise after initially declining, then the protease inhibitor must be stopped to prevent the development of even more resistant strains."
Potosky notes that the extent of resistance will only become clear with time—and as more people take the new drugs. And just as they monitor HIV patients for telltale resistance patterns, doctors should be able to detect early signs of resistance in people being treated for hepatitis C as well.
Adding boceprevir also increased the amount of side effects patients experienced. More than 40 percent of subjects taking this third drug required treatment for anemia in one of the studies, and in the other, severe anemia led doctors to decrease dosage in some 20 percent of subjects. Even though some of these cases were serious, few patients dropped out of treatment.
With boceprevir and telaprevir likely in the home stretch to reach potentially millions of hepatitis C patients in the U.S., doctors and researchers are now turning their focus to the many challenges that remain.
Aside from keeping resistance low and dialing down side effects, the next steps are to try to simplify the treatment regimen. "Everyone wants to get rid of interferon and ribavirin because both have toxicity that make them often difficult to tolerate," Gordon notes. Interferon also currently is usually administered via injection, so moving to an all-oral, once-a-day dosing would make treatment better and more consistent.
Gordon also looks forward to finding ways to help special populations of patients, including those who have HIV, end-stage liver disease or renal disease, as well as children, "who are currently not eligible for our current therapies."
Source
Boceprevir for Previously Treated Chronic HCV Genotype 1 Infection
Bruce R. Bacon, M.D., Stuart C. Gordon, M.D., Eric Lawitz, M.D., Patrick Marcellin, M.D., John M. Vierling, M.D., Stefan Zeuzem, M.D., Fred Poordad, M.D., Zachary D. Goodman, M.D., Ph.D., Heather L. Sings, Ph.D., Navdeep Boparai, M.S., Margaret Burroughs, M.D., Clifford A. Brass, M.D., Ph.D., Janice K. Albrecht, Ph.D., and Rafael Esteban, M.D. for the HCV RESPOND-2 Investigators
N Engl J Med 2011; 364:1207-1217 March 31, 2011
Background
In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.
Methods
To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.
Results
A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.
Conclusions
The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.)
Results
Baseline Characteristics
A total of 640 patients were evaluated for enrollment in the study; 403 were enrolled and underwent randomization and treatment (Figure S1 in the Supplementary Appendix). The baseline demographic characteristics were balanced among the three treatment groups (Table 1Table 1Baseline Characteristics of the Patients, According to Treatment Group.), with the exception of high viral load (group 2 vs. group 1, P=0.04). The mean age was 52.7 years, 12% of patients were black, and the mean body weight was 84.9 kg. Approximately 88% of patients had a high viral load (an HCV RNA level >800,000 IU per milliliter) at baseline. The prevalence of infection with HCV genotypes 1a and 1b was similar (47% and 44%, respectively). A total of 19% of patients had a Metavir fibrosis score of 3 or 4. The majority of patients (64%) had had a relapse after previous HCV therapy.
Efficacy
In the primary-analysis population, rates of sustained virologic response were significantly higher among patients receiving boceprevir than among those treated with peginterferon-ribavirin alone (Figure 2Figure 2Patients with a Sustained Virologic Response, According to Treatment Group and Analysis.), with overall rates of sustained virologic response of 21%, 59%, and 66% in groups 1, 2, and 3, respectively (P<0.001). This increase seen with boceprevir was due largely to end-of-treatment rates of response (i.e., an undetectable HCV RNA level) that were greater in group 2 (70%) and group 3 (77%) than in group 1 (31%), as well as a decreased rate of relapse in group 2 (in 17 of 111 patients [15%]) and group 3 (in 14 of 121 patients [12%]) as compared with group 1 (in 8 of 25 patients [32%]). Viral breakthrough and incomplete virologic response were infrequent during the treatment period (with either occurring in 1 of 80 patients [1%] in group 1, in 9 of 162 patients [6%] in group 2, and in 7 of 161 patients [4%] in group 3).
The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%. A total of 102 patients (15%, 28%, and 27% in groups 1, 2, and 3, respectively) had a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4-week lead-in period (Figure 2). In this subgroup, a sustained virologic response was achieved in none of the patients in group 1 and in 33% and 34% in groups 2 and 3, respectively. Among patients who had a good response to interferon (a decrease in HCV RNA level of 1 log10 IU per milliliter or more at treatment week 4), the rates of sustained virologic response were 25%, 73%, and 79% in group 1, group 2, and group 3, respectively.
An assessment for amino acid variants associated with reduced susceptibility to boceprevir was performed for 114 patients in group 2 or group 3 in whom a sustained virologic response did not occur. Postbaseline data were available for 98 of the 114 patients (86%), with variants detected in 43 of these 98 patients (44%). The rate of amino acid variants associated with reduced susceptibility to boceprevir was higher among patients with a poor response to interferon (13 of 46 [28%] in group 2 and 15 of 44 [34%] in group 3) than among patients with a good response to interferon (10 of 110 [9%] in group 2 and 7 of 112 [6%] in group 3).
In group 2, the duration of total therapy was based on a prespecified decision at treatment week 8, at which time patients with an undetectable HCV RNA level were eligible for a shorter period of therapy. The proportion of patients with an undetectable HCV RNA level at week 8 in the boceprevir groups (74 of 162 patients [46%] in group 2 and 84 of 161 patients [52%] in group 3) was approximately six times the proportion in group 1 (7 of 80 [9%]). Early response (i.e., an undetectable HCV RNA level at week 8) was associated with high rate of sustained virologic response in all three groups (7 of 7 patients [100%] in group 1; 64 of 74 patients [86%] in group 2; and 74 of 84 patients [88%] in group 3).
An evaluation of treatment effect according to subgroups of baseline characteristics showed that the numerical odds of a sustained virologic response was greater, across all subgroups, with either response-guided triple therapy (group 2) or 44-week triple therapy (group 3) than with the standard of care (group 1) (Figure 3Figure 3Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup.).
Although there was a sustained virologic response in 12 more patients in group 3 than in group 2, the rates in each group did not differ significantly (odds ratio of a sustained virologic response in group 3 vs. group 2, 1.4; 95% confidence interval, 0.9 to 2.2). A similarly small difference was seen between these two groups during the period in which the therapy was identical (week 0 through treatment week 36), with 9 to 14 more patients having an undetectable HCV RNA level during treatment weeks 8 to 36 in group 3 than in group 2 (Figure S2 in the Supplementary Appendix). In post hoc exploratory analyses, we observed that this difference appeared to be driven by patients with cirrhosis at baseline: the percentage of patients with cirrhosis who had an undetectable HCV RNA level at week 8 was 18% (3 of 17 patients) in group 2, versus 73% (16 of 22 patients) in group 3, despite identical treatment through this time point (Figure S2 in the Supplementary Appendix). This suggests an underlying difference in responsiveness that is not fully accounted for by treatment-group randomization. In contrast, among patients without cirrhosis at baseline, the percentage with an undetectable HCV RNA level at week 8 was 50% (66 of 132 patients) in group 2 and 49% (63 of 128) in group 3. The odds of a sustained virologic response were similar between group 3 and group 2 for most baseline factors except for body weight under 75 kg, elevated alanine aminotransferase level, and cirrhosis, for which there was a greater odds of a sustained virologic response in group 3 (Figure S3 in the Supplementary Appendix). In contrast, the odds of a sustained virologic response were not different for those with advanced fibrosis (a Metavir fibrosis score of 3 or 4), which is often preferentially used owing to the variability of biopsy readings.
Multivariable stepwise logistic-regression analysis served to identify five baseline factors that were significantly associated with achievement of a sustained virologic response: assignment to either boceprevir group rather than the control group (odds ratios for group 2 and group 3 vs. group 1, 7.3 and 10.7, respectively; P<0.001 for both comparisons), previous relapse (odds ratio vs. previous nonresponse, 3.1; P<0.001), low viral load at baseline (odds ratio vs. high load, 2.5; P=0.02), and absence of cirrhosis (odds ratio vs. presence, 2.1; P=0.04) (Table S1 in the Supplementary Appendix). When the decline in viral load (i.e., decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at week 4 (was added to the model, the week 4 response was a stronger predictor of sustained virologic response than historical response (odds ratio, 5.2; P<0.001).
Safety
The study included a stopping rule whereby patients in whom an undetectable HCV RNA level was not achieved by treatment week 12 discontinued all therapy. The low rate of an undetectable HCV RNA level by treatment week 12 in group 1 resulted in 61% of patients discontinuing treatment for this reason, as compared with 22% and 18% of patients in group 2 and group 3, respectively (Figure S1 in the Supplementary Appendix). Thus, the median duration of treatment was 2.4 to 3.2 times longer in the boceprevir groups than in the control group (Table 2Table 2Adverse Events, According to Treatment Group.).
In the boceprevir groups as compared with the control group, a greater proportion of patients reported serious adverse events and there were more discontinuations and dose modifications owing to adverse events. There was a higher incidence of anemia in the groups receiving boceprevir (43 to 46%) than in the control group (20%). Consistent with the increased incidence of anemia, the proportion of patients with hemoglobin levels of 6.5 to less than 9.5 g per deciliter was higher in groups 2 and 3 than in group 1; however, discontinuation owing to anemia was infrequent (occurring in 0% of patients group 1 and group 2 and in 3% [5 of 161 patients] in group 3). Erythropoietin was administered to 21%, 41%, and 46% of patients in groups 1, 2, and 3, respectively. Of the 403 patients, 17 received a transfusion for the management of anemia; 16 of these patients also received erythropoietin. Adverse events, dose modifications, and study-drug discontinuation in the 49 patients with cirrhosis are summarized in Table S3 in the Supplementary Appendix.
The most common adverse events observed in all treatment groups were flulike symptoms that are typically reported in association with peginterferon-ribavirin therapy (Table S5 in the Supplementary Appendix). Dysgeusia, rash, and dry skin were reported more commonly in the boceprevir groups than in the control group.
Discussion
Our data show that the addition of boceprevir to peginterferon-ribavirin therapy leads to high rates of sustained virologic response among patients in whom prior treatment had failed. Furthermore, patients who had previously had a relapse after receiving the standard of care had rates of sustained virologic response of up to 75%, with rates of 40 to 52% in the subgroup of patients with a previous nonresponse. Patients with undetectable HCV RNA levels at treatment week 8 were shown to have a rate of sustained virologic response that was similar whether boceprevir was taken for 32 weeks or 44 weeks; thus, an early response identified patients who could benefit from shorter treatment. There were no identified groups of patients with a previous treatment failure for whom the standard of care was more efficacious than was triple therapy. We observed high rates of a sustained virologic response among black patients and patients with advanced liver disease, who usually have a poor response,17,18 representing a clinically significant improvement over the standard of care.19
Rates of anemia were higher among patients receiving boceprevir-containing regimens than among those receiving control therapy, and many patients required erythropoietin treatment. Discontinuation for anemia was infrequent (affecting 3% of patients in group 3 only). Consistent with the increased incidence of anemia, a higher proportion of boceprevir recipients, as compared with controls, had a neutrophil count of 500 to less than 750 per cubic millimeter or underwent a red-cell transfusion.
This study included a 4-week lead-in period during which peginterferon-ribavirin was administered, which allowed for the assessment of the patient's interferon responsiveness immediately before the addition of boceprevir. We have previously shown that a decline in viral load of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy is significantly correlated to a decline of less than 2 log10 IU per milliliter after 12 weeks of treatment.20 We identified 102 patients with a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at week 4. This is an important recognition of the changes that can evolve over time in patients who had previously been treated and are awaiting retreatment. Possible explanations for such changes include an increase in body weight, development of glucose intolerance, an increase in hepatic steatosis, and progression of fibrosis, all of which could have resulted in diminished responsiveness to peginterferon-ribavirin. Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33 to 34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone.
In summary, the results of our phase 3 trial show that boceprevir, when added to peginterferon alfa-2b and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients.
The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or other institutions listed as authors' affiliations.
Sponsored by Schering-Plough (now part of Merck).
Methods
Study Oversight
The study protocol is available with the full text of this article at NEJM.org. The trial (HCV RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2]) was funded by Schering-Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with the external academic investigators and members of the external data and safety monitoring board. The academic authors had agreements with the sponsor concerning the confidentiality of the data. The academic authors collected the data, which was then analyzed by the sponsor. The sponsor held the data and made them available to the academic authors. The first draft of the manuscript was written by one academic author and three industry authors. All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol.
Study Patients
From August through November 2008, we screened 640 patients with HCV genotype 1 infection at 80 sites in North America and Europe. Eligibility criteria included demonstrated responsiveness to interferon (minimum duration of therapy, 12 weeks). We defined patients as having either nonresponse (i.e., a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 but with a detectable HCV RNA level during the therapy period) or relapse (i.e., an undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virologic response [i.e., with a detectable HCV RNA level during the follow-up period]).
Exclusion criteria included hepatitis B or infection with the human immunodeficiency virus, any other cause of clinically significant liver disease, decompensated liver disease, uncontrolled diabetes mellitus, a severe psychiatric disorder, and active substance abuse. Liver-biopsy specimens were assessed for Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment of boceprevir or placebo. Possible Metavir fibrosis scores are as follows: a score of 0 indicates no fibrosis, 1 indicates portal fibrosis without septa, 2 indicates portal fibrosis with few septa, 3 indicates numerous septa without cirrhosis, and 4 indicates cirrhosis.
Study Design
The primary objective was to compare two treatment regimens containing boceprevir in combination with open-label peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) to treatment with peginterferon-ribavirin plus placebo in previously treated adults with chronic HCV genotype 1 infection. Our study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided written informed consent before randomization.
Patients were randomly assigned, in a 1:2:2 ratio with the use of an interactive voice-response system, to one of three treatment groups, with stratification according to previous response to therapy (nonresponse or relapse) and HCV subgenotype (1a or 1b) as determined by means of sequencing of the HCV 5' noncoding region (Trugene).13 Patients with HCV genotype 1 infection whose HCV subtype could not be classified were randomly assigned to one of the treatment groups. The HCV genotype 1 subtype was also determined by means of sequencing of the nonstructural 5B (NS5B) region (Virco).
The study design is illustrated in Figure 1Figure 1Study Design.. For purposes of the study doses, peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly, and ribavirin was administered at a divided daily dose of 600 to 1400 mg per day on the basis of body weight. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and with an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir. The study was double-blinded regarding the administration of boceprevir.
During the 4-week lead-in period, all patients received peginterferon plus ribavirin. Subsequent treatment varied according to group. Group 1 (the control group) received peginterferon-ribavirin plus boceprevir-matched placebo for 44 weeks. Group 2 received a response-guided therapy regimen consisting of boceprevir plus peginterferon-ribavirin, for 32 weeks; according to the week 12 stopping rule, patients with an undetectable HCV RNA level at weeks 8 and 12 completed therapy at week 36, whereas those with a detectable HCV RNA level at week 8 (but an undetectable level at week 12) received peginterferon-ribavirin plus placebo for an additional 12 weeks. Group 3 received boceprevir and peginterferon-ribavirin for 44 weeks.
The stopping rule applied in all groups was that failure to achieve an undetectable HCV RNA level at week 12 resulted in discontinuation of all treatment and advancement to follow-up.
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study.13 Measurement was performed at the screening visit, at baseline, every 2 weeks through week 12, and then at weeks 16, 20, 24, 30, 36, 42, and 48, as well as at weeks 4, 12, and 24 of the follow-up period.
Safety
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening adverse events were managed by means of dose reduction. The recommended guidelines for a two-step dose reduction of peginterferon and for a three-step dose reduction of ribavirin were similar to those previously described (as is summarized in the Supplementary Appendix, available at NEJM.org).7,14-16
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Statistical Analysis
Analyses regarding the primary objective included data from all patients who received at least one dose of any study medication. The key secondary objective was to compare the two boceprevir regimens with the peginterferon-ribavirin regimen in patients who completed the lead-in period and received at least one dose of placebo or boceprevir. Specifically, comparisons for the primary and key secondary objectives were made between group 3 and group 1 and between group 2 and group 1.
The primary efficacy end point was a sustained virologic response, defined as an undetectable plasma HCV RNA level at week 24 of the follow-up period. Secondary and other efficacy analyses were performed to calculate the proportion of patients with an early response (i.e., an undetectable HCV RNA level at week 8) in whom a sustained virologic response was achieved, as well as the proportion of patients with a relapse.
The primary statistical comparison was carried out with the use of a two-sided Cochran-Mantel-Haenszel chi-square test with adjustment for the baseline stratification factors. The study had a statistical power of 90% to detect an absolute improvement in the rate of sustained virologic response by 21 percentage points over the rate in group 1 (assuming response rates of 22% in the control group and 43% in the boceprevir groups) with the use of a two-sided chi-square test and an alpha value of 0.05.
To control for type I error in the primary analysis, a step-down approach was used. Group 3 was first compared against group 1. If the P value for the comparison was less than 0.05, the next comparison - of group 2 and group 1 - was carried out. A similar step-down approach was prespecified to control for the type I error regarding the key secondary objective. To account for multiplicity between the primary and key secondary analyses, the key secondary analyses were conducted only if the significance of the primary comparisons was established. P values calculated for sustained virologic response are provided for only the two prespecified primary and key secondary comparisons.
Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined according to prespecified baseline characteristics. Multivariable logistic-regression analyses involving treatment regimen and prespecified baseline characteristics were performed to evaluate sustained virologic responses. A stepwise procedure was used to identify independent predictors of sustained virologic response (with P=0.05 as the threshold level for variables to be entered into the model and retained in the final model). In addition, we fit a stepwise logistic-regression model of the response (decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at treatment week 4 and baseline characteristics.
Source
N Engl J Med 2011; 364:1207-1217 March 31, 2011
Background
In patients with chronic infection with hepatitis C virus (HCV) genotype 1 who do not have a sustained response to therapy with peginterferon-ribavirin, outcomes after retreatment are suboptimal. Boceprevir, a protease inhibitor that binds to the HCV nonstructural 3 (NS3) active site, has been suggested as an additional treatment.
Methods
To assess the effect of the combination of boceprevir and peginterferon-ribavirin for retreatment of patients with chronic HCV genotype 1 infection, we randomly assigned patients (in a 1:2:2 ratio) to one of three groups. In all three groups, peginterferon alfa-2b and ribavirin were administered for 4 weeks (the lead-in period). Subsequently, group 1 (control group) received placebo plus peginterferon-ribavirin for 44 weeks; group 2 received boceprevir plus peginterferon-ribavirin for 32 weeks, and patients with a detectable HCV RNA level at week 8 received placebo plus peginterferon-ribavirin for an additional 12 weeks; and group 3 received boceprevir plus peginterferon-ribavirin for 44 weeks.
Results
A total of 403 patients were treated. The rate of sustained virologic response was significantly higher in the two boceprevir groups (group 2, 59%; group 3, 66%) than in the control group (21%, P<0.001). Among patients with an undetectable HCV RNA level at week 8, the rate of sustained virologic response was 86% after 32 weeks of triple therapy and 88% after 44 weeks of triple therapy. Among the 102 patients with a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at treatment week 4, the rates of sustained virologic response were 0%, 33%, and 34% in groups 1, 2, and 3, respectively. Anemia was significantly more common in the boceprevir groups than in the control group, and erythropoietin was administered in 41 to 46% of boceprevir-treated patients and 21% of controls.
Conclusions
The addition of boceprevir to peginterferon-ribavirin resulted in significantly higher rates of sustained virologic response in previously treated patients with chronic HCV genotype 1 infection, as compared with peginterferon-ribavirin alone. (Funded by Schering-Plough [now Merck]; HCV RESPOND-2 ClinicalTrials.gov number, NCT00708500.)
Results
Baseline Characteristics
A total of 640 patients were evaluated for enrollment in the study; 403 were enrolled and underwent randomization and treatment (Figure S1 in the Supplementary Appendix). The baseline demographic characteristics were balanced among the three treatment groups (Table 1Table 1Baseline Characteristics of the Patients, According to Treatment Group.), with the exception of high viral load (group 2 vs. group 1, P=0.04). The mean age was 52.7 years, 12% of patients were black, and the mean body weight was 84.9 kg. Approximately 88% of patients had a high viral load (an HCV RNA level >800,000 IU per milliliter) at baseline. The prevalence of infection with HCV genotypes 1a and 1b was similar (47% and 44%, respectively). A total of 19% of patients had a Metavir fibrosis score of 3 or 4. The majority of patients (64%) had had a relapse after previous HCV therapy.
Efficacy
In the primary-analysis population, rates of sustained virologic response were significantly higher among patients receiving boceprevir than among those treated with peginterferon-ribavirin alone (Figure 2Figure 2Patients with a Sustained Virologic Response, According to Treatment Group and Analysis.), with overall rates of sustained virologic response of 21%, 59%, and 66% in groups 1, 2, and 3, respectively (P<0.001). This increase seen with boceprevir was due largely to end-of-treatment rates of response (i.e., an undetectable HCV RNA level) that were greater in group 2 (70%) and group 3 (77%) than in group 1 (31%), as well as a decreased rate of relapse in group 2 (in 17 of 111 patients [15%]) and group 3 (in 14 of 121 patients [12%]) as compared with group 1 (in 8 of 25 patients [32%]). Viral breakthrough and incomplete virologic response were infrequent during the treatment period (with either occurring in 1 of 80 patients [1%] in group 1, in 9 of 162 patients [6%] in group 2, and in 7 of 161 patients [4%] in group 3).
The rates of sustained virologic response among patients with prior relapse were 29% in group 1, versus 69% and 75% in group 2 and group 3, respectively; among patients with prior nonresponse, the corresponding rates were 7% versus 40% and 52%. A total of 102 patients (15%, 28%, and 27% in groups 1, 2, and 3, respectively) had a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter after the 4-week lead-in period (Figure 2). In this subgroup, a sustained virologic response was achieved in none of the patients in group 1 and in 33% and 34% in groups 2 and 3, respectively. Among patients who had a good response to interferon (a decrease in HCV RNA level of 1 log10 IU per milliliter or more at treatment week 4), the rates of sustained virologic response were 25%, 73%, and 79% in group 1, group 2, and group 3, respectively.
An assessment for amino acid variants associated with reduced susceptibility to boceprevir was performed for 114 patients in group 2 or group 3 in whom a sustained virologic response did not occur. Postbaseline data were available for 98 of the 114 patients (86%), with variants detected in 43 of these 98 patients (44%). The rate of amino acid variants associated with reduced susceptibility to boceprevir was higher among patients with a poor response to interferon (13 of 46 [28%] in group 2 and 15 of 44 [34%] in group 3) than among patients with a good response to interferon (10 of 110 [9%] in group 2 and 7 of 112 [6%] in group 3).
In group 2, the duration of total therapy was based on a prespecified decision at treatment week 8, at which time patients with an undetectable HCV RNA level were eligible for a shorter period of therapy. The proportion of patients with an undetectable HCV RNA level at week 8 in the boceprevir groups (74 of 162 patients [46%] in group 2 and 84 of 161 patients [52%] in group 3) was approximately six times the proportion in group 1 (7 of 80 [9%]). Early response (i.e., an undetectable HCV RNA level at week 8) was associated with high rate of sustained virologic response in all three groups (7 of 7 patients [100%] in group 1; 64 of 74 patients [86%] in group 2; and 74 of 84 patients [88%] in group 3).
An evaluation of treatment effect according to subgroups of baseline characteristics showed that the numerical odds of a sustained virologic response was greater, across all subgroups, with either response-guided triple therapy (group 2) or 44-week triple therapy (group 3) than with the standard of care (group 1) (Figure 3Figure 3Odds Ratios for a Sustained Virologic Response in Group 2 versus Group 1 and Group 3 versus Group 1, According to Subgroup.).
Although there was a sustained virologic response in 12 more patients in group 3 than in group 2, the rates in each group did not differ significantly (odds ratio of a sustained virologic response in group 3 vs. group 2, 1.4; 95% confidence interval, 0.9 to 2.2). A similarly small difference was seen between these two groups during the period in which the therapy was identical (week 0 through treatment week 36), with 9 to 14 more patients having an undetectable HCV RNA level during treatment weeks 8 to 36 in group 3 than in group 2 (Figure S2 in the Supplementary Appendix). In post hoc exploratory analyses, we observed that this difference appeared to be driven by patients with cirrhosis at baseline: the percentage of patients with cirrhosis who had an undetectable HCV RNA level at week 8 was 18% (3 of 17 patients) in group 2, versus 73% (16 of 22 patients) in group 3, despite identical treatment through this time point (Figure S2 in the Supplementary Appendix). This suggests an underlying difference in responsiveness that is not fully accounted for by treatment-group randomization. In contrast, among patients without cirrhosis at baseline, the percentage with an undetectable HCV RNA level at week 8 was 50% (66 of 132 patients) in group 2 and 49% (63 of 128) in group 3. The odds of a sustained virologic response were similar between group 3 and group 2 for most baseline factors except for body weight under 75 kg, elevated alanine aminotransferase level, and cirrhosis, for which there was a greater odds of a sustained virologic response in group 3 (Figure S3 in the Supplementary Appendix). In contrast, the odds of a sustained virologic response were not different for those with advanced fibrosis (a Metavir fibrosis score of 3 or 4), which is often preferentially used owing to the variability of biopsy readings.
Multivariable stepwise logistic-regression analysis served to identify five baseline factors that were significantly associated with achievement of a sustained virologic response: assignment to either boceprevir group rather than the control group (odds ratios for group 2 and group 3 vs. group 1, 7.3 and 10.7, respectively; P<0.001 for both comparisons), previous relapse (odds ratio vs. previous nonresponse, 3.1; P<0.001), low viral load at baseline (odds ratio vs. high load, 2.5; P=0.02), and absence of cirrhosis (odds ratio vs. presence, 2.1; P=0.04) (Table S1 in the Supplementary Appendix). When the decline in viral load (i.e., decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at week 4 (was added to the model, the week 4 response was a stronger predictor of sustained virologic response than historical response (odds ratio, 5.2; P<0.001).
Safety
The study included a stopping rule whereby patients in whom an undetectable HCV RNA level was not achieved by treatment week 12 discontinued all therapy. The low rate of an undetectable HCV RNA level by treatment week 12 in group 1 resulted in 61% of patients discontinuing treatment for this reason, as compared with 22% and 18% of patients in group 2 and group 3, respectively (Figure S1 in the Supplementary Appendix). Thus, the median duration of treatment was 2.4 to 3.2 times longer in the boceprevir groups than in the control group (Table 2Table 2Adverse Events, According to Treatment Group.).
In the boceprevir groups as compared with the control group, a greater proportion of patients reported serious adverse events and there were more discontinuations and dose modifications owing to adverse events. There was a higher incidence of anemia in the groups receiving boceprevir (43 to 46%) than in the control group (20%). Consistent with the increased incidence of anemia, the proportion of patients with hemoglobin levels of 6.5 to less than 9.5 g per deciliter was higher in groups 2 and 3 than in group 1; however, discontinuation owing to anemia was infrequent (occurring in 0% of patients group 1 and group 2 and in 3% [5 of 161 patients] in group 3). Erythropoietin was administered to 21%, 41%, and 46% of patients in groups 1, 2, and 3, respectively. Of the 403 patients, 17 received a transfusion for the management of anemia; 16 of these patients also received erythropoietin. Adverse events, dose modifications, and study-drug discontinuation in the 49 patients with cirrhosis are summarized in Table S3 in the Supplementary Appendix.
The most common adverse events observed in all treatment groups were flulike symptoms that are typically reported in association with peginterferon-ribavirin therapy (Table S5 in the Supplementary Appendix). Dysgeusia, rash, and dry skin were reported more commonly in the boceprevir groups than in the control group.
Discussion
Our data show that the addition of boceprevir to peginterferon-ribavirin therapy leads to high rates of sustained virologic response among patients in whom prior treatment had failed. Furthermore, patients who had previously had a relapse after receiving the standard of care had rates of sustained virologic response of up to 75%, with rates of 40 to 52% in the subgroup of patients with a previous nonresponse. Patients with undetectable HCV RNA levels at treatment week 8 were shown to have a rate of sustained virologic response that was similar whether boceprevir was taken for 32 weeks or 44 weeks; thus, an early response identified patients who could benefit from shorter treatment. There were no identified groups of patients with a previous treatment failure for whom the standard of care was more efficacious than was triple therapy. We observed high rates of a sustained virologic response among black patients and patients with advanced liver disease, who usually have a poor response,17,18 representing a clinically significant improvement over the standard of care.19
Rates of anemia were higher among patients receiving boceprevir-containing regimens than among those receiving control therapy, and many patients required erythropoietin treatment. Discontinuation for anemia was infrequent (affecting 3% of patients in group 3 only). Consistent with the increased incidence of anemia, a higher proportion of boceprevir recipients, as compared with controls, had a neutrophil count of 500 to less than 750 per cubic millimeter or underwent a red-cell transfusion.
This study included a 4-week lead-in period during which peginterferon-ribavirin was administered, which allowed for the assessment of the patient's interferon responsiveness immediately before the addition of boceprevir. We have previously shown that a decline in viral load of less than 1 log10 IU per milliliter after 4 weeks of peginterferon-ribavirin therapy is significantly correlated to a decline of less than 2 log10 IU per milliliter after 12 weeks of treatment.20 We identified 102 patients with a poor response to interferon, defined as a decrease in the HCV RNA level of less than 1 log10 IU per milliliter at week 4. This is an important recognition of the changes that can evolve over time in patients who had previously been treated and are awaiting retreatment. Possible explanations for such changes include an increase in body weight, development of glucose intolerance, an increase in hepatic steatosis, and progression of fibrosis, all of which could have resulted in diminished responsiveness to peginterferon-ribavirin. Notably, a sustained virologic response was achieved, after boceprevir was added to the standard of care, in 33 to 34% of the patients with a poor response to interferon, as compared with 0% in the patients retreated with peginterferon-ribavirin alone.
In summary, the results of our phase 3 trial show that boceprevir, when added to peginterferon alfa-2b and ribavirin, leads to high rates of sustained virologic response in difficult-to-treat patients.
The opinions expressed in this report represent the consensus of the authors and do not necessarily reflect the formal position of Merck or other institutions listed as authors' affiliations.
Sponsored by Schering-Plough (now part of Merck).
Methods
Study Oversight
The study protocol is available with the full text of this article at NEJM.org. The trial (HCV RESPOND-2 [Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol 2]) was funded by Schering-Plough (now part of Merck) and was designed, managed, and analyzed by Merck in conjunction with the external academic investigators and members of the external data and safety monitoring board. The academic authors had agreements with the sponsor concerning the confidentiality of the data. The academic authors collected the data, which was then analyzed by the sponsor. The sponsor held the data and made them available to the academic authors. The first draft of the manuscript was written by one academic author and three industry authors. All authors were involved in the collection, analysis, or interpretation of the data; revision of the manuscript; and the decision to submit the manuscript for publication. All authors vouch for the completeness and accuracy of the data and analyses as well as the fidelity of the study to the protocol.
Study Patients
From August through November 2008, we screened 640 patients with HCV genotype 1 infection at 80 sites in North America and Europe. Eligibility criteria included demonstrated responsiveness to interferon (minimum duration of therapy, 12 weeks). We defined patients as having either nonresponse (i.e., a decrease in the HCV RNA level of at least 2 log10 IU per milliliter by week 12 but with a detectable HCV RNA level during the therapy period) or relapse (i.e., an undetectable HCV RNA level at the end of treatment, without subsequent attainment of a sustained virologic response [i.e., with a detectable HCV RNA level during the follow-up period]).
Exclusion criteria included hepatitis B or infection with the human immunodeficiency virus, any other cause of clinically significant liver disease, decompensated liver disease, uncontrolled diabetes mellitus, a severe psychiatric disorder, and active substance abuse. Liver-biopsy specimens were assessed for Metavir fibrosis scores and steatosis scores by a single academic author who is a pathologist and was unaware of the assignment of boceprevir or placebo. Possible Metavir fibrosis scores are as follows: a score of 0 indicates no fibrosis, 1 indicates portal fibrosis without septa, 2 indicates portal fibrosis with few septa, 3 indicates numerous septa without cirrhosis, and 4 indicates cirrhosis.
Study Design
The primary objective was to compare two treatment regimens containing boceprevir in combination with open-label peginterferon alfa-2b and ribavirin (PegIntron and Rebetol, respectively; Merck) to treatment with peginterferon-ribavirin plus placebo in previously treated adults with chronic HCV genotype 1 infection. Our study was conducted in accordance with the principles of Good Clinical Practice and was approved by the appropriate institutional review boards and regulatory agencies. All patients provided written informed consent before randomization.
Patients were randomly assigned, in a 1:2:2 ratio with the use of an interactive voice-response system, to one of three treatment groups, with stratification according to previous response to therapy (nonresponse or relapse) and HCV subgenotype (1a or 1b) as determined by means of sequencing of the HCV 5' noncoding region (Trugene).13 Patients with HCV genotype 1 infection whose HCV subtype could not be classified were randomly assigned to one of the treatment groups. The HCV genotype 1 subtype was also determined by means of sequencing of the nonstructural 5B (NS5B) region (Virco).
The study design is illustrated in Figure 1Figure 1Study Design.. For purposes of the study doses, peginterferon alfa-2b was administered subcutaneously at a dose of 1.5 μg per kilogram of body weight once weekly, and ribavirin was administered at a divided daily dose of 600 to 1400 mg per day on the basis of body weight. Treatment with boceprevir consisted of oral administration at a dose of 800 mg three times daily (to be taken with food and with an interval of 7 to 9 hours between doses) in four capsules of 200 mg each. Placebo was matched to boceprevir. The study was double-blinded regarding the administration of boceprevir.
During the 4-week lead-in period, all patients received peginterferon plus ribavirin. Subsequent treatment varied according to group. Group 1 (the control group) received peginterferon-ribavirin plus boceprevir-matched placebo for 44 weeks. Group 2 received a response-guided therapy regimen consisting of boceprevir plus peginterferon-ribavirin, for 32 weeks; according to the week 12 stopping rule, patients with an undetectable HCV RNA level at weeks 8 and 12 completed therapy at week 36, whereas those with a detectable HCV RNA level at week 8 (but an undetectable level at week 12) received peginterferon-ribavirin plus placebo for an additional 12 weeks. Group 3 received boceprevir and peginterferon-ribavirin for 44 weeks.
The stopping rule applied in all groups was that failure to achieve an undetectable HCV RNA level at week 12 resulted in discontinuation of all treatment and advancement to follow-up.
Plasma HCV RNA levels were measured with the use of the TaqMan 2.0 assay (Roche Diagnostics), which has lower limits of quantification and detection of 25 and 9.3 IU per milliliter, respectively; the lower limit of detection was used for decision making at various points throughout the study.13 Measurement was performed at the screening visit, at baseline, every 2 weeks through week 12, and then at weeks 16, 20, 24, 30, 36, 42, and 48, as well as at weeks 4, 12, and 24 of the follow-up period.
Safety
Adverse events were graded by investigators according to a modified World Health Organization grading system. Non-life-threatening adverse events were managed by means of dose reduction. The recommended guidelines for a two-step dose reduction of peginterferon and for a three-step dose reduction of ribavirin were similar to those previously described (as is summarized in the Supplementary Appendix, available at NEJM.org).7,14-16
Viral breakthrough was defined as achievement of an undetectable HCV RNA level and subsequent occurrence of an HCV RNA level greater than 1000 IU per milliliter. Incomplete virologic response and rebound was defined as an increase of 1 log10 IU per milliliter in the HCV RNA level from the nadir, with an HCV RNA level greater than 1000 IU per milliliter (if both samples being compared were collected the same number of days after the last peginterferon injection). In cases in which the timing between the peginterferon injection and the HCV RNA sample collection was different for the two samples, an increase of 2 log10 IU per milliliter was required to meet this criterion. If a patient had virologic breakthrough or an incomplete virologic response and rebound while receiving therapy, boceprevir treatment could be discontinued, but peginterferon-ribavirin could be continued for up to 48 weeks with appropriate clinical follow-up.
Statistical Analysis
Analyses regarding the primary objective included data from all patients who received at least one dose of any study medication. The key secondary objective was to compare the two boceprevir regimens with the peginterferon-ribavirin regimen in patients who completed the lead-in period and received at least one dose of placebo or boceprevir. Specifically, comparisons for the primary and key secondary objectives were made between group 3 and group 1 and between group 2 and group 1.
The primary efficacy end point was a sustained virologic response, defined as an undetectable plasma HCV RNA level at week 24 of the follow-up period. Secondary and other efficacy analyses were performed to calculate the proportion of patients with an early response (i.e., an undetectable HCV RNA level at week 8) in whom a sustained virologic response was achieved, as well as the proportion of patients with a relapse.
The primary statistical comparison was carried out with the use of a two-sided Cochran-Mantel-Haenszel chi-square test with adjustment for the baseline stratification factors. The study had a statistical power of 90% to detect an absolute improvement in the rate of sustained virologic response by 21 percentage points over the rate in group 1 (assuming response rates of 22% in the control group and 43% in the boceprevir groups) with the use of a two-sided chi-square test and an alpha value of 0.05.
To control for type I error in the primary analysis, a step-down approach was used. Group 3 was first compared against group 1. If the P value for the comparison was less than 0.05, the next comparison - of group 2 and group 1 - was carried out. A similar step-down approach was prespecified to control for the type I error regarding the key secondary objective. To account for multiplicity between the primary and key secondary analyses, the key secondary analyses were conducted only if the significance of the primary comparisons was established. P values calculated for sustained virologic response are provided for only the two prespecified primary and key secondary comparisons.
Summary statistics are reported for each of the three treatment regimens for subgroups of patients defined according to prespecified baseline characteristics. Multivariable logistic-regression analyses involving treatment regimen and prespecified baseline characteristics were performed to evaluate sustained virologic responses. A stepwise procedure was used to identify independent predictors of sustained virologic response (with P=0.05 as the threshold level for variables to be entered into the model and retained in the final model). In addition, we fit a stepwise logistic-regression model of the response (decrease from baseline in the HCV RNA level of ≥1.0 log10 IU per milliliter vs. <1.0 log10 IU per milliliter) at treatment week 4 and baseline characteristics.
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