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Adding Octreotide to Sorafenib May Benefit Patients With Advanced Hepatic Cell Carcinoma Who Have Failed Other Therapies: Presented at EASL
By Cameron Johnston
http://www.docguide.com
COPENHAGEN, Denmark -- April 25, 2009 -- The addition of octreotide to sorafenib may offer a synergistic benefit for patients with advanced hepatic cell carcinoma (HCC) who have failed or been nonresponsive to other local therapies, researchers stated here at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL).
According to the investigators, who presented their findings on April 24, the combination therapy could represent a much-needed weapon for treating this select, and difficult to treat, population.
"Octreotide has been used previously as monotherapy in patients with HCC but with little success," Liliana Montella, MD, San Giovanni di Dio Hospital, Naples, Italy, told DocGuide. "When patients fail local therapy, they have few chances of a cure, and generally, a poor prognosis."
Originally, 87 patients with HCC who had previously failed radiofrequency ablation, chemoembolisation, surgery, or chemotherapy, or a combination of these treatments were recruited for the study.
The data presented at the poster presentation covered the first 43 patients, although more than 50 have now been evaluated. The patient cohort included 28 with hepatitis C, 10 with hepatitis B, and 1 with both B and C type disease. Four had disease of unknown etiology.
Patients were treated with sorafenib 800 mg/day for 28 days continuous dosing, followed by 1 week of rest. Octreotide 40 mg was introduced on day 10 of the cycle and given every month thereafter.
The analysis showed 1 partial response (2.3%), as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria, but Dr. Montella said this would be higher if the EASL criteria were used.
There were 32 cases of stable disease (74%) and 11 cases of progressive disease (23.7%). Median time to progression was 7.0 months (95% confidence interval [CI], 3.0-10.9 months).
Overall survival, at the time of the analysis was 9.9 months (95% CI, 8.2-11.6 months), but Dr. Montella said this has now increased to more than 10 months with 95% confidence intervals ranging from 8.2-17.0 months.
The most common adverse event was diarrhoea, which occurred in 27.9% of patients (4.6% grade 3). Hand-foot syndrome occurred in 9.3% of patients, and hypertension, abdominal pain, and rectal bleeding occurred in 6.9% of patients.
"I personally think that in this select group of liver cancer patients, octreotide can be a very useful drug," concluded Dr. Montella. "We can combine these 2 drugs together to produce some very interesting results in this population of patients."
[Presentation title: Sorafenib Plus Octreotide in Advanced Hepatocellular Carcinoma: Updated Results of a Multicenter Study. Poster 785]
Presentation Date: Apr 25, 2009
SORAFENIB PLUS OCTREOTIDE IN ADVANCED HEPATOCELLULAR CARCINOMA: UPDATED RESULTS OF A MULTICENTER STUDY
S. Del Prete1, R. Addeo1, M. Caraglia2, L. Maiorino3, V. Montesarchio4, G. Cennamo1, R. Guarrasi1, V. Faiola1, L. Leo5, A. Febbraro6, B. Vincenzi7, C. Savastano8, L. Tarantino9, A. Sabia10, E. Capasso11, G. Palmieri12, A. Giorgio13, M. Bianco14, L. Montella1
1Medical Oncology, 'San Giovanni di Dio' Hospital, Frattaminore, 2Department of Biochemistry and Biophysics, Second University of Naples, 3“San Gennaro” Hospital, 4“Cotugno” Hospital, Naples, 5Piedimonte Matese, Caserta, 6Medical Oncology, Fatebenefratelli, Benevento, 7Medical Oncology Campus Biomedico, Rome, 8Medical Oncology “Ruggi d'Aragona” Hospital, Salerno, 9Hepatology and Interventional Ultrasound Unit, 'San Giovanni di Dio' Hospital, Frattaminore, 10Medical Oncology Unit, “S.Maria della Pietà”, Nola, 11Senology Unit, ASL NA3, Arzano, 12Department of Molecular and Clinical Endocrinology & Oncology, University “Federico II”, 13UO di Ecografia Interventistica IX Divisione, “Cotugno” Hospital, Naples, 14Medical Oncology, ASL NA5, Castellammare di Stabia, Italy
Background and aims: Advanced hepatocellular carcinoma (HCC) not amenable to local therapies has limited chances of cure and has a poor prognosis. Sorafenib is a multikinase inhibitor with proven activity in advanced HCC. Octreotide is already used in this setting with conflicting but usually interesting results. An original schedule with sorafenib and long-acting octreotide was tested in advanced HCC patients enrolled to evaluate safety and activity of this combination.
Methods: Patients with advanced HCC not amenable to local therapies, Child-Pugh A or B, received sorafenib at the dose of 800 mg/day continuous dosing for 28 days followed by one week of rest, and long acting octreotide at the dose of 40 mg monthly administered. Cycles were repeated until progression or unacceptable toxicity. The disease-control rate was defined as the percentage of patients who had a best-response rating of complete response, partial response, or stable disease (according to RECIST criteria) lasting for at least 28 days after the first appearance on the basis of independent radiologic review.
Results: At November 1st, 2008, 87 patients have been screened and 77 have been enrolled. At this date, 43 patients were considered evaluable (sex: 36M/7F; age range: 50-82 years; HCV: 28 pts, HBV: 10 pts, HCV+HBV:1 pt; unknown etiology: 4; Child A/B: 34/9, BCLC B/C:17/26). Sixteen patients out of 43 (37%) were naïve from other therapies, while the remaining had been previously treated with local and/or systemic treatments. We registered 1 partial response (2.3%), 32 stable diseases (74%) and 11 progressions (23.7%). Median time to progression (TTP) was 7.0 months (95% CI, 3.0-10.9 months) while the median overall survival was not yet reached. Mean overall survival was 9.9 months (95% CI, 8.2 to 11.6 months). Treatment was generally well tolerated. Grade 3/4 toxicities observed were diarrhoea and hypertension in 4.6% of treated patients, hand-foot syndrome and proctalgia in 2.3% of patients.
Conclusions: Sorafenib plus octreotide appears a feasible option in advanced HCC patients. In the attempt to improve the results obtained with sorafenib alone, this association deserves further investigations in the context of randomized studies.
Monday, April 27, 2009
THERAPEUTIC VACCINATION USING NAKED DNA
A FIRST CLINICAL TRIAL OF THERAPEUTIC VACCINATION USING NAKED DNA DELIVERED BY IN VIVO ELECTROPORATION SHOWS ANTIVIRAL EFFECTS IN PATIENTS WITH CHRONIC HEPATITIS C
EASL 2009 April 23-26, 2009 Copenhagen, Denmark
M. Matti Sallberg1, L. Frelin1, H. Diepolder2, M.-C. Jung3, I. Mathiesen4, M. Fons5, R. Hultcrantz6, T. Carlsson6, O. Weiland6
1Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden, 2Medicine, Ludvig-Maximilian University, 3ImmuSystems GmbH, Munich, Germany, 4Inovio Biomedical, Oslo, Norway, 5Inovio Biomedical, San Diego, CA, USA, 6Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
Background: Clearance of HCV infection correlates with activation of the host T cell response. We developed a T cell vaccine based on a codon-optimized HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C®, Tripep AB, Sweden) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.
Methods: A volume of 0,5 mL saline containing ChronVac-C® DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses adminstered using a 1,5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). Study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load < 800,000 IU/mL were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.
Results: In the 167µg group no severe side effects appeared, two mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose no severe side effects appeared, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses both had reductions in the viral load of up to 0,89log10 and 1,5 log10, respectively. In the third patient no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose no severe side effects appeared, and one developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1,2 log10 and 2,4 log10, respectively. Thus, four out of six (67%) patients in the two highest dose groups had reductions in the viral load exceeding 0,5log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
Conclusions: These data provides the first proof-of-concept for DNA-based therapeutic vaccination against chronic hepatitis C in humans using in vivo electroporation and encourage further clinical development. The data also provides further evidence for the antiviral role of the HCV-specific T cell response.
EASL 2009: Vaccination Against Chronic HCV Promises Sweeping Changes to HCV Management
Becky McCall
From Medscape Medical News
April 24, 2009 (Copenhagen, Denmark) — In vivo electroporation used in conjunction with naked DNA to deliver a T-cell vaccine has been shown to be effective as a therapeutic vaccination for hepatitis C virus (HCV) in a clinical trial for the first time. The finding was reported here at the European Association for the Study of the Liver 44th Annual Meeting.
The trial was conducted by Matti Sällberg, DDS, PhD, and colleagues from the Karolinska Institute in Stockholm, Sweden. He explained that in 50% to 80% of HCV cases, the immune system fails to eliminate the virus and the disease becomes chronic. The problem is significant: 3% of the world's population is infected with HCV, and in industrialized countries, HCV accounts for 70% of chronic hepatitis cases.
"There remains a tremendous need for new therapies in HCV. Considerable advances in therapies have been made in recent years but many treatments cause unpleasant side effects, such as depression, hyperthyroidism, and joint pain. Furthermore, these effects can be prolonged due to the need for long-term treatment in HCV," Dr. Sällberg told Medscape Gastroenterology.
Dr. Sällberg's study is the first phase 1/2a clinical trial in HCV-infected patients. The use of electroporation in combination with naked DNA has previously been used in cancer, but not infectious diseases. "With this method of vaccination, we inject part of the viral DNA into the cell, which then uses its own cell machinery to produce the vaccine. The cell effectively becomes the factory. Electrical stimulation via electroporation of the muscle cells enables [the uptake of] DNA across the cell membrane and encourages migration of antigen-presenting immune cells to the site stimulating the required immune reaction," Dr. Sällberg explained.
A volume of 0.5 mL saline containing ChronVac DNA was injected at a depth of 1 cm into the deltoid muscle. This T-cell vaccine was based on a codon-optimized HCV nonstructural 3/4A DNA gene expressed under the control of the cytomegalovirus immediate-early promoter. This was followed by two 60 ms electrical pulses administered using a 1.5 cm 4-electrode array (MedPulser DDS; Inovio, California).
Dr. Sällberg explained that it was important to deliver the DNA and to stimulate a T-cell reaction outside of the liver. "The liver is very tolerogenic and shuts down, so ideally, it is not suited to production of an immune reaction. So the immune system is educated outside the liver and these cells then migrate back into the liver to attack HCV."
Twelve treatment-naïve patients infected with HCV genotype 1 who had a viral load of less than 800,000 IU/mL were divided into 3 groups — 167 μg, 500 μg, and 1500 μg — given as 4 monthly doses of DNA. In the 167-μg-dose group, 2 patients mounted transient T-cell responses, and none had a reduced viral load. In the 500-μg-dose group, 2 patients developed better sustained HCV-specific T-cell responses and simultaneously experienced a reduction in viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient in this group, no immune response developed and no clear reduction in viral load was seen. In the 1500-μg-dose group, 1 patient developed an HCV T-cell-specific response and 2 patients showed a reduction in viral load of up to 1.2 log10 and 2.4 log10. No severe adverse effects were seen in any of the groups.
"So all in all, 67% of patients (4 out of 6 patients) in the 2 highest-dose groups showed reductions in viral load exceeding 0.5 log10. These effects lasted between 2 and more than 10 weeks. The vaccine probably kills infected cells through activation of cytotoxic T lymphocytes, either by killing or by producing cytokines, which shut off viral replication," said Dr. Sällberg.
Commenting on the study, Heiner Wedermeyer, MD, from the German Liver Foundation in Hanover, said that these results showed a very important proof of concept, with the vaccine demonstrating significant antiviral effect. "In the long term, it might be a very effective strategy to use this vaccine on top of new antiviral drugs to induce immunity in the host and prevent relapse so we can stop using antiviral drugs. It is my vision that in a few years' time, we will use 2 or 3 antivirals, combine these with a vaccine, and that's it," he explained.
The study was funded by Tripep AB, Inovio Biomedical, and the Stockholm County Council. Dr. Sällberg is a cofounder and board member of Tripep AB. Dr. Wedermeyer has disclosed no relevant financial relationships.
European Association for the Study of the Liver 44th Annual Meeting: Abstract 43. Presented April 23, 2009.
First Evidence For DNA-based Vaccination Against Chronic Hepatitis C
ScienceDaily (Apr. 24, 2009) — The first-proof-of-concept for a DNA-based therapeutic vaccination against chronic hepatitis C was announced April 23 at EASL 2009, the Annual Meeting of the European Association for the Study of the Liver in Copenhagen, Denmark.
In the first clinical trial of a therapeutic vaccination using naked DNA delivered by in vivo electroporation (EP), antiviral effects were shown in patients with hepatitis C (HCV). Researchers hope that this will encourage further clinical development. The data also provide further evidence for the antiviral role of the HCV-specific T cell response.
It is estimated that some 3% of the world's population is infected with HCV. In industrialised countries, hepatitis C accounts for 70% of chronic hepatitis cases. One of the main concerns is that HCV infection remains asymptomatic until advanced stages of the disease.
Clearance of HCV infection correlates with activation of the host T cell response. Therefore, in this study, researchers developed a T cell vaccine based on a codon-optimised HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C®) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.
Professor Matti Sallberg of Laboratory Medicine, the Karolinska Institutet, Stockholm, Sweden, who led the study, said: "In 50-80% of adult cases, the immune system fails to eliminate the HCV virus and the disease becomes chronic. Given that only about 50% of HCV infected persons are diagnosed in most developed countries and that two-thirds need to undergo antiviral treatment, this new vaccination has huge implications in terms of the future management of this widespread disease."
In this study, a volume of 0.5 ml saline containing ChronVac-C® DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses administered using a 1.5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). The study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load <800,000 IU/ml were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.
In the 167µg group, no severe side effects were observed, two patients mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose, no severe side effects were observed, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses, both patients had reductions in the viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient, no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose, no severe side effects were observed, and one patient developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1.2 log10 and 2.4 log10, respectively. Thus, 67% (four out of six) of patients in the two highest dose groups had reductions in the viral load exceeding 0.5 log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
EASL 2009 April 23-26, 2009 Copenhagen, Denmark
M. Matti Sallberg1, L. Frelin1, H. Diepolder2, M.-C. Jung3, I. Mathiesen4, M. Fons5, R. Hultcrantz6, T. Carlsson6, O. Weiland6
1Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden, 2Medicine, Ludvig-Maximilian University, 3ImmuSystems GmbH, Munich, Germany, 4Inovio Biomedical, Oslo, Norway, 5Inovio Biomedical, San Diego, CA, USA, 6Medicine, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden
Background: Clearance of HCV infection correlates with activation of the host T cell response. We developed a T cell vaccine based on a codon-optimized HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C®, Tripep AB, Sweden) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.
Methods: A volume of 0,5 mL saline containing ChronVac-C® DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses adminstered using a 1,5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). Study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load < 800,000 IU/mL were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.
Results: In the 167µg group no severe side effects appeared, two mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose no severe side effects appeared, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses both had reductions in the viral load of up to 0,89log10 and 1,5 log10, respectively. In the third patient no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose no severe side effects appeared, and one developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1,2 log10 and 2,4 log10, respectively. Thus, four out of six (67%) patients in the two highest dose groups had reductions in the viral load exceeding 0,5log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
Conclusions: These data provides the first proof-of-concept for DNA-based therapeutic vaccination against chronic hepatitis C in humans using in vivo electroporation and encourage further clinical development. The data also provides further evidence for the antiviral role of the HCV-specific T cell response.
EASL 2009: Vaccination Against Chronic HCV Promises Sweeping Changes to HCV Management
Becky McCall
From Medscape Medical News
April 24, 2009 (Copenhagen, Denmark) — In vivo electroporation used in conjunction with naked DNA to deliver a T-cell vaccine has been shown to be effective as a therapeutic vaccination for hepatitis C virus (HCV) in a clinical trial for the first time. The finding was reported here at the European Association for the Study of the Liver 44th Annual Meeting.
The trial was conducted by Matti Sällberg, DDS, PhD, and colleagues from the Karolinska Institute in Stockholm, Sweden. He explained that in 50% to 80% of HCV cases, the immune system fails to eliminate the virus and the disease becomes chronic. The problem is significant: 3% of the world's population is infected with HCV, and in industrialized countries, HCV accounts for 70% of chronic hepatitis cases.
"There remains a tremendous need for new therapies in HCV. Considerable advances in therapies have been made in recent years but many treatments cause unpleasant side effects, such as depression, hyperthyroidism, and joint pain. Furthermore, these effects can be prolonged due to the need for long-term treatment in HCV," Dr. Sällberg told Medscape Gastroenterology.
Dr. Sällberg's study is the first phase 1/2a clinical trial in HCV-infected patients. The use of electroporation in combination with naked DNA has previously been used in cancer, but not infectious diseases. "With this method of vaccination, we inject part of the viral DNA into the cell, which then uses its own cell machinery to produce the vaccine. The cell effectively becomes the factory. Electrical stimulation via electroporation of the muscle cells enables [the uptake of] DNA across the cell membrane and encourages migration of antigen-presenting immune cells to the site stimulating the required immune reaction," Dr. Sällberg explained.
A volume of 0.5 mL saline containing ChronVac DNA was injected at a depth of 1 cm into the deltoid muscle. This T-cell vaccine was based on a codon-optimized HCV nonstructural 3/4A DNA gene expressed under the control of the cytomegalovirus immediate-early promoter. This was followed by two 60 ms electrical pulses administered using a 1.5 cm 4-electrode array (MedPulser DDS; Inovio, California).
Dr. Sällberg explained that it was important to deliver the DNA and to stimulate a T-cell reaction outside of the liver. "The liver is very tolerogenic and shuts down, so ideally, it is not suited to production of an immune reaction. So the immune system is educated outside the liver and these cells then migrate back into the liver to attack HCV."
Twelve treatment-naïve patients infected with HCV genotype 1 who had a viral load of less than 800,000 IU/mL were divided into 3 groups — 167 μg, 500 μg, and 1500 μg — given as 4 monthly doses of DNA. In the 167-μg-dose group, 2 patients mounted transient T-cell responses, and none had a reduced viral load. In the 500-μg-dose group, 2 patients developed better sustained HCV-specific T-cell responses and simultaneously experienced a reduction in viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient in this group, no immune response developed and no clear reduction in viral load was seen. In the 1500-μg-dose group, 1 patient developed an HCV T-cell-specific response and 2 patients showed a reduction in viral load of up to 1.2 log10 and 2.4 log10. No severe adverse effects were seen in any of the groups.
"So all in all, 67% of patients (4 out of 6 patients) in the 2 highest-dose groups showed reductions in viral load exceeding 0.5 log10. These effects lasted between 2 and more than 10 weeks. The vaccine probably kills infected cells through activation of cytotoxic T lymphocytes, either by killing or by producing cytokines, which shut off viral replication," said Dr. Sällberg.
Commenting on the study, Heiner Wedermeyer, MD, from the German Liver Foundation in Hanover, said that these results showed a very important proof of concept, with the vaccine demonstrating significant antiviral effect. "In the long term, it might be a very effective strategy to use this vaccine on top of new antiviral drugs to induce immunity in the host and prevent relapse so we can stop using antiviral drugs. It is my vision that in a few years' time, we will use 2 or 3 antivirals, combine these with a vaccine, and that's it," he explained.
The study was funded by Tripep AB, Inovio Biomedical, and the Stockholm County Council. Dr. Sällberg is a cofounder and board member of Tripep AB. Dr. Wedermeyer has disclosed no relevant financial relationships.
European Association for the Study of the Liver 44th Annual Meeting: Abstract 43. Presented April 23, 2009.
First Evidence For DNA-based Vaccination Against Chronic Hepatitis C
ScienceDaily (Apr. 24, 2009) — The first-proof-of-concept for a DNA-based therapeutic vaccination against chronic hepatitis C was announced April 23 at EASL 2009, the Annual Meeting of the European Association for the Study of the Liver in Copenhagen, Denmark.
In the first clinical trial of a therapeutic vaccination using naked DNA delivered by in vivo electroporation (EP), antiviral effects were shown in patients with hepatitis C (HCV). Researchers hope that this will encourage further clinical development. The data also provide further evidence for the antiviral role of the HCV-specific T cell response.
It is estimated that some 3% of the world's population is infected with HCV. In industrialised countries, hepatitis C accounts for 70% of chronic hepatitis cases. One of the main concerns is that HCV infection remains asymptomatic until advanced stages of the disease.
Clearance of HCV infection correlates with activation of the host T cell response. Therefore, in this study, researchers developed a T cell vaccine based on a codon-optimised HCV non-structural (NS) 3/4A DNA-gene expressed under the control of the cytomegalovirus immediate-early promoter (ChronVac-C®) delivered by in vivo electroporation (EP). A first phase I/IIa clinical trial in HCV infected patients is currently ongoing.
Professor Matti Sallberg of Laboratory Medicine, the Karolinska Institutet, Stockholm, Sweden, who led the study, said: "In 50-80% of adult cases, the immune system fails to eliminate the HCV virus and the disease becomes chronic. Given that only about 50% of HCV infected persons are diagnosed in most developed countries and that two-thirds need to undergo antiviral treatment, this new vaccination has huge implications in terms of the future management of this widespread disease."
In this study, a volume of 0.5 ml saline containing ChronVac-C® DNA was injected at 1 cm depth in the deltoid muscle. This was followed by two 60ms electrical pulses administered using a 1.5 cm four-electrode array (Medpulser DDS; Inovio, CA, US). The study aims were safety, immunogenicity, and effects on the viral load. Twelve treatment naive patients infected with HCV genotype 1 and a viral load <800,000 IU/ml were divided in four groups of 167 µg, 500 µg, and 1,500 µg given as four monthly doses of DNA.
In the 167µg group, no severe side effects were observed, two patients mounted transient T cell responses, and none had a reduced viral load. In the 500µg dose, no severe side effects were observed, and two developed better sustained HCV-specific T cell responses. Simultaneous with these responses, both patients had reductions in the viral load of up to 0.89 log10 and 1.5 log10, respectively. In the third patient, no immune response developed and no clear reductions in the viral load were seen. In the 1,500µg dose, no severe side effects were observed, and one patient developed HCV-specific T cell response. Two patients had reductions in the viral load of up to 1.2 log10 and 2.4 log10, respectively. Thus, 67% (four out of six) of patients in the two highest dose groups had reductions in the viral load exceeding 0.5 log10 lasting for two to >10 weeks. Of these, three had activations of the HCV-specific T cell responses at the time of the reductions in the viral load.
Saturday, April 25, 2009
Ground-Breaking Combination of All-Oral Agents Demonstrates Potential as Hepatitis C Treatment Regimen
Ground-Breaking Combination of All-Oral Agents Demonstrates Potential as Hepatitis C Treatment Regimen
- Combination of R7227, protease inhibitor, and R7128, nucleoside polymerase inhibitor, shows significant potency in reducing viral load in patients with hepatitis C -
NUTLEY, N.J., BRISBANE, C.A. and PRINCETON, N.J. (April 25, 2009) – Roche, InterMune, Inc. (Nasdaq: ITMN) and Pharmasset (Nasdaq: VRUS) today announced the first results from their innovative, interferon-free regimen of direct acting antiviral (DAA) combination therapy for the treatment of patients chronically infected with the hepatitis C virus (HCV).[i] The study combined two oral DAAs, R7227 (also known as ITMN-191) and R7128, for the first time in patients. There were no serious adverse events reported during the 14 days of dosing, and the reductions in levels of HCV RNA were significant.
“First-In-Man Demonstration Of Potent Antiviral Activity with a Nucleoside Polymerase (R7128) and Protease (R7227/ITMN-191) Inhibitor Combination in HCV: Safety, Pharmacokinetics, and Virologic Results from INFORM-1,” Abstract #1046: to be presented at 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22 – 26, 2009.
Results of the INFORM-1 study were presented today during the late-breaker session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen. The trial, conducted in centers in New Zealand and Australia, is the first to investigate the combination of two oral antiviral medicines in the absence of interferon and ribavirin. The results demonstrated for the first time that the combination of an oral protease inhibitor and an oral nucleoside polymerase inhibitor resulted in significant HCV viral load reduction in patients with HCV. Roche is developing R7227, a protease inhibitor, with InterMune, and R7128, a nucleoside polymerase inhibitor, with Pharmasset. Further studies will test the activity and safety of the combination of R7227 and R7128 with and without interferon and/or ribavirin. The current standard of care for HCV is a combination of pegylated interferon plus ribavirin, which delivers overall sustained virologic response rates (SVR) of 50-60 percent.
“These are exciting times in our fight against hepatitis C, and the investigation of the innovative oral treatment regimen in INFORM-1, if validated in further study, may radically change future treatment strategies in our patients with chronic HCV infection,” said Edward Gane, M.D., Associate Professor, University of Auckland and Director, Auckland Clinical Studies Limited. “The initial results from this study of the R7227/R7128 combination raise hopes of the possibility for an interferon-free treatment regimen, as well as the potential for a shorter, more potent interferon-based regimen.”
INFORM-1 Results in Brief
INFORM-1 is a randomized, double-blind, ascending dose Phase I trial which has enrolled a total of 57 patients.
Patients receiving the combination of R7227 and R7128 for 14 days – without pegylated interferon or ribavirin – experienced a median reduction in viral levels of -4.8 to -5.2 log10 IU/mL in the highest doses tested. The addition of R7128 to R7227 resulted in sustained viral load reductions over the dosing period, with aproximately 63 percent of patients experiencing a decrease in viral levels below the quantification limit of the diagnostic assay (less than 40 IU/mL). Furthermore, 25 percent of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) after 14 days.
In the early low-dose groups, after only three days of dosing, the mean reduction in viral load levels was 0.6 log10 IU/mL greater with combination treatment (-2.9), compared to the performance of the individual compounds when administered as a single agent (-0.46 and -1.84 for R7128 and R7227, respectively). This suggests an additive effect for the combination.
No treatment-related serious adverse events (SAEs), no dose reductions and no discontinuations were reported in the study. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
Next Steps in the Development Program
The companies are now exploring twice-daily dosing of R7227 and higher total daily doses (600 mg twice-daily and 900 mg twice-daily) than those explored in the first patient cohorts of INFORM-1. The companies also plan to explore the innovative DAA combination therapy in “treatment-experienced” patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.
Other Clinical Studies with R7227 and R7128
In addition to clinical studies of combination DAA regimens such as those studied in INFORM-1, R7227 and R7128 each are proceeding rapidly in development in combination with Roche’s PEGASYS® (peginterferon alfa-2a) and COPEGUS® (ribavirin). A Phase IIb study with R7128 has now begun, while a Phase IIb study with R7227 is slated to begin in the summer.
The Foundation and Future of HCV Treatment
Combination therapy of pegylated interferon and ribavirin is the current standard of care for HCV. PEGASYS is the leading treatment for HCV, and also is the pegylated interferon therapy of choice for most HCV antiviral agents in development – including those developed through collaborations with Roche, as well as those developed by other companies. The collaborations with InterMune and Pharmasset position Roche as a leader in developing innovative treatments for HCV.
Dial-In and Webcast Details
InterMune and Pharmasset will host a live webcast of a discussion of the INFORM-1 results from the EASL conference today, Saturday, April 25, 2009, at 7:00 p.m. CEST (1:00 p.m. EDT). Participating in the discussion will be Dr. Ed Gane, principal investigator in the INFORM-1 trial. Members of management from Roche, InterMune and Pharmasset will also be available to answer questions. A live webcast and slide presentation will be available through the Investor Relations pages of both InterMune and Pharmasset at www.intermune.com or www.pharmasset.com, respectively. Alternatively, interested parties may access the discussion and ask questions by dialing 888-799-0528 (U.S. & Canada) or 973-200-3372 (international), conference ID # 95452531. A webcast replay will be available approximately three hours after the call and will be archived at www.intermune.com and at www.pharmasset.com.
The teleconference replay will be available for 10 business days following the call and can be accessed by dialing 800-642-1687 (U.S. and Canada) or 706-645-9291 (international), and entering conference ID # 95452531.
The companies recommend logging on at least 15 minutes prior to the start of the webcast to ensure adequate time for any software downloads that may be required.
About R7227 (ITMN-191)
R7227 is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log10 reductions in levels of HCV levels in chronic HCV patients, when administered for 14 days as monotherapy and when combined with PEGASYS and COPEGUS. R7227 was safe and well-tolerated in these studies.
About R7128
R7128, a cytidine nucleoside analog inhibitor of HCV RNA polymerase, is being developed for the treatment of chronic HCV infection. R7128 has shown potent in vivo activity against all of the most common HCV genotypes (1, 2 and 3). R7128 was safe and well-tolerated when given with PEGASYS and COPEGUS for up to 28 days.
About PEGASYS
PEGASYS, in combination with COPEGUS (ribavirin), is indicated for the treatment of adults with chronic HCV who have compensated liver disease and have not previously been treated with interferon alpha. Efficacy has been demonstrated in patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). In addition, PEGASYS in combination with COPEGUS is the first and only FDA-approved regimen for the treatment of chronic HCV in patients coinfected with HCV and HIV. PEGASYS is the only pegylated interferon indicated for the treatment of adult patients with chronic hepatitis B (HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation).
PEGASYS is dosed at 180mcg as a subcutaneous injection taken once a week. COPEGUS is available as a 200mg tablet, and is administered orally two times a day as a split dose. Roche has backed PEGASYS with the most extensive clinical research program ever undertaken in HCV, with major studies initiated to advance treatment for HCV patients with unmet needs, including patients co-infected with HIV and HCV, African Americans, patients with cirrhosis, and patients who have failed to respond to previous therapy.
Important Safety Information About PEGASYS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).
Alpha interferons, including PEGASYS® (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS®, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients’ clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score >/=6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and causal relationship between interferon alfa-based therapies and these events is difficult to establish.
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65 percent), headache (43 percent), pyrexia (41 percent), myalgia (40 percent), irritability/anxiety/nervousness (33 percent), insomnia (30 percent), alopecia (28 percent), neutropenia (27 percent), nausea/vomiting (25 percent), rigors (25 percent), anorexia (24 percent), injection site reaction (23 percent), arthralgia (22 percent), depression (20 percent), pruritus (19 percent) and dermatitis (16 percent).
Serious adverse events in hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world’s leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. For additional information about the U.S. pharmaceuticals business, visit our website http://www.rocheusa.com. Product and treatment information for U.S. healthcare professionals is available at www.RocheExchange.com.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase III program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF and a research program focused on pirfenidone analog ITMN-520. The hepatology portfolio includes the HCV protease inhibitor compound R7227 (ITMN-191), a second-generation HCV protease inhibitor research program, and a research program evaluating a new target in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Pharmasset is currently developing three product candidates. R7128, an oral treatment for chronic HCV infection, has completed a 4-week clinical trial in combination with PEGASYS plus COPEGUS through a strategic collaboration with Roche, and is initiating a Phase IIb trial. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase II clinical trial. PSI-7851, an unpartnered second generation HCV nucleotide analogue recently entered Phase I studies. Additional information is available on the Internet at http://www.pharmasset.com
Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect the companies’ judgments and involve risks and uncertainties as of the date of this release, including without limitation the statements related to anticipated product development timelines. All forward-looking statements and other information included in this press release are based on information available to the companies as of the date hereof, and the companies assume no obligation to update any such forward-looking statements or information. Actual results could differ materially from those described in the forward-looking statements.
Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in the companies’ most recent annual reports on Form 10-K filed with the SEC and in other periodic reports filed with the SEC. The risks and other factors discussed above should be considered only in connection with the fully
discussed risks and other factors discussed in detail in the respective Forms 10-K and in the companies’ other periodic reports filed with the SEC, all of which are available via their respective web sites at www.intermune.com and www.pharmasset.com.
All trademarks used or mentioned in this release are protected by law.
- About INFORM-1: www.clinicaltrials.gov
- Combination of R7227, protease inhibitor, and R7128, nucleoside polymerase inhibitor, shows significant potency in reducing viral load in patients with hepatitis C -
NUTLEY, N.J., BRISBANE, C.A. and PRINCETON, N.J. (April 25, 2009) – Roche, InterMune, Inc. (Nasdaq: ITMN) and Pharmasset (Nasdaq: VRUS) today announced the first results from their innovative, interferon-free regimen of direct acting antiviral (DAA) combination therapy for the treatment of patients chronically infected with the hepatitis C virus (HCV).[i] The study combined two oral DAAs, R7227 (also known as ITMN-191) and R7128, for the first time in patients. There were no serious adverse events reported during the 14 days of dosing, and the reductions in levels of HCV RNA were significant.
“First-In-Man Demonstration Of Potent Antiviral Activity with a Nucleoside Polymerase (R7128) and Protease (R7227/ITMN-191) Inhibitor Combination in HCV: Safety, Pharmacokinetics, and Virologic Results from INFORM-1,” Abstract #1046: to be presented at 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen, Denmark, April 22 – 26, 2009.
Results of the INFORM-1 study were presented today during the late-breaker session at the 44th Annual Meeting of the European Association for the Study of the Liver (EASL) in Copenhagen. The trial, conducted in centers in New Zealand and Australia, is the first to investigate the combination of two oral antiviral medicines in the absence of interferon and ribavirin. The results demonstrated for the first time that the combination of an oral protease inhibitor and an oral nucleoside polymerase inhibitor resulted in significant HCV viral load reduction in patients with HCV. Roche is developing R7227, a protease inhibitor, with InterMune, and R7128, a nucleoside polymerase inhibitor, with Pharmasset. Further studies will test the activity and safety of the combination of R7227 and R7128 with and without interferon and/or ribavirin. The current standard of care for HCV is a combination of pegylated interferon plus ribavirin, which delivers overall sustained virologic response rates (SVR) of 50-60 percent.
“These are exciting times in our fight against hepatitis C, and the investigation of the innovative oral treatment regimen in INFORM-1, if validated in further study, may radically change future treatment strategies in our patients with chronic HCV infection,” said Edward Gane, M.D., Associate Professor, University of Auckland and Director, Auckland Clinical Studies Limited. “The initial results from this study of the R7227/R7128 combination raise hopes of the possibility for an interferon-free treatment regimen, as well as the potential for a shorter, more potent interferon-based regimen.”
INFORM-1 Results in Brief
INFORM-1 is a randomized, double-blind, ascending dose Phase I trial which has enrolled a total of 57 patients.
Patients receiving the combination of R7227 and R7128 for 14 days – without pegylated interferon or ribavirin – experienced a median reduction in viral levels of -4.8 to -5.2 log10 IU/mL in the highest doses tested. The addition of R7128 to R7227 resulted in sustained viral load reductions over the dosing period, with aproximately 63 percent of patients experiencing a decrease in viral levels below the quantification limit of the diagnostic assay (less than 40 IU/mL). Furthermore, 25 percent of patients in the highest dosage groups were below the limit of detection of the virus in their blood (less than 15 IU/mL) after 14 days.
In the early low-dose groups, after only three days of dosing, the mean reduction in viral load levels was 0.6 log10 IU/mL greater with combination treatment (-2.9), compared to the performance of the individual compounds when administered as a single agent (-0.46 and -1.84 for R7128 and R7227, respectively). This suggests an additive effect for the combination.
No treatment-related serious adverse events (SAEs), no dose reductions and no discontinuations were reported in the study. Pharmacokinetic analysis confirmed that there were no drug-drug interactions between the compounds.
Next Steps in the Development Program
The companies are now exploring twice-daily dosing of R7227 and higher total daily doses (600 mg twice-daily and 900 mg twice-daily) than those explored in the first patient cohorts of INFORM-1. The companies also plan to explore the innovative DAA combination therapy in “treatment-experienced” patients with HCV, or those who did not achieve SVR with a previous interferon-based treatment.
Other Clinical Studies with R7227 and R7128
In addition to clinical studies of combination DAA regimens such as those studied in INFORM-1, R7227 and R7128 each are proceeding rapidly in development in combination with Roche’s PEGASYS® (peginterferon alfa-2a) and COPEGUS® (ribavirin). A Phase IIb study with R7128 has now begun, while a Phase IIb study with R7227 is slated to begin in the summer.
The Foundation and Future of HCV Treatment
Combination therapy of pegylated interferon and ribavirin is the current standard of care for HCV. PEGASYS is the leading treatment for HCV, and also is the pegylated interferon therapy of choice for most HCV antiviral agents in development – including those developed through collaborations with Roche, as well as those developed by other companies. The collaborations with InterMune and Pharmasset position Roche as a leader in developing innovative treatments for HCV.
Dial-In and Webcast Details
InterMune and Pharmasset will host a live webcast of a discussion of the INFORM-1 results from the EASL conference today, Saturday, April 25, 2009, at 7:00 p.m. CEST (1:00 p.m. EDT). Participating in the discussion will be Dr. Ed Gane, principal investigator in the INFORM-1 trial. Members of management from Roche, InterMune and Pharmasset will also be available to answer questions. A live webcast and slide presentation will be available through the Investor Relations pages of both InterMune and Pharmasset at www.intermune.com or www.pharmasset.com, respectively. Alternatively, interested parties may access the discussion and ask questions by dialing 888-799-0528 (U.S. & Canada) or 973-200-3372 (international), conference ID # 95452531. A webcast replay will be available approximately three hours after the call and will be archived at www.intermune.com and at www.pharmasset.com.
The teleconference replay will be available for 10 business days following the call and can be accessed by dialing 800-642-1687 (U.S. and Canada) or 706-645-9291 (international), and entering conference ID # 95452531.
The companies recommend logging on at least 15 minutes prior to the start of the webcast to ensure adequate time for any software downloads that may be required.
About R7227 (ITMN-191)
R7227 is a potent, macrocyclic inhibitor of HCV NS3/4A protease activity, and has produced multi-log10 reductions in levels of HCV levels in chronic HCV patients, when administered for 14 days as monotherapy and when combined with PEGASYS and COPEGUS. R7227 was safe and well-tolerated in these studies.
About R7128
R7128, a cytidine nucleoside analog inhibitor of HCV RNA polymerase, is being developed for the treatment of chronic HCV infection. R7128 has shown potent in vivo activity against all of the most common HCV genotypes (1, 2 and 3). R7128 was safe and well-tolerated when given with PEGASYS and COPEGUS for up to 28 days.
About PEGASYS
PEGASYS, in combination with COPEGUS (ribavirin), is indicated for the treatment of adults with chronic HCV who have compensated liver disease and have not previously been treated with interferon alpha. Efficacy has been demonstrated in patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A) and patients with HIV disease that are clinically stable (e.g., antiretroviral therapy not required or receiving stable antiretroviral therapy). In addition, PEGASYS in combination with COPEGUS is the first and only FDA-approved regimen for the treatment of chronic HCV in patients coinfected with HCV and HIV. PEGASYS is the only pegylated interferon indicated for the treatment of adult patients with chronic hepatitis B (HBeAg positive and HBeAg negative chronic hepatitis B who have compensated liver disease and evidence of viral replication and liver inflammation).
PEGASYS is dosed at 180mcg as a subcutaneous injection taken once a week. COPEGUS is available as a 200mg tablet, and is administered orally two times a day as a split dose. Roche has backed PEGASYS with the most extensive clinical research program ever undertaken in HCV, with major studies initiated to advance treatment for HCV patients with unmet needs, including patients co-infected with HIV and HCV, African Americans, patients with cirrhosis, and patients who have failed to respond to previous therapy.
Important Safety Information About PEGASYS
PEGASYS, alone or in combination with COPEGUS, is indicated for the treatment of adults with chronic hepatitis C virus infection who have compensated liver disease and have not been previously treated with interferon alpha. Patients in whom efficacy was demonstrated included patients with compensated liver disease and histological evidence of cirrhosis (Child-Pugh class A).
Alpha interferons, including PEGASYS® (Peginterferon alfa-2a), may cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Therapy should be withdrawn in patients with persistently severe or worsening signs or symptoms of these conditions. In many, but not all cases, these disorders resolve after stopping PEGASYS therapy (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
Use with Ribavirin. Ribavirin, including COPEGUS®, may cause birth defects and/or death of the fetus. Extreme care must be taken to avoid pregnancy in female patients and in female partners of male patients. Ribavirin causes hemolytic anemia. The anemia associated with ribavirin therapy may result in a worsening of cardiac disease. Ribavirin is genotoxic and mutagenic and should be considered a potential carcinogen (see CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in complete product information).
PEGASYS is contraindicated in patients with hypersensitivity to PEGASYS or any of its components, autoimmune hepatitis, and hepatic decompensation (Child-Pugh score greater than 6; class B and C) in cirrhotic CHC monoinfected patients before or during treatment. PEGASYS is also contraindicated in hepatic decompensation with Child-Pugh score greater than or equal to 6 in cirrhotic CHC patients coinfected with HIV before or during treatment. PEGASYS is also contraindicated in neonates and infants because it contains benzyl alcohol. Benzyl alcohol is associated with an increased incidence of neurological and other complications in neonates and infants, which are sometimes fatal. PEGASYS and COPEGUS therapy is additionally contraindicated in patients with a hypersensitivity to COPEGUS or any of its components, in women who are pregnant, men whose female partners are pregnant, and patients with hemoglobinopathies (eg, thalassemia major, sickle-cell anemia).
COPEGUS THERAPY SHOULD NOT BE STARTED UNLESS A REPORT OF A NEGATIVE PREGNANCY TEST HAS BEEN OBTAINED IMMEDIATELY PRIOR TO INITIATION OF THERAPY. Women of childbearing potential and men must use two forms of effective contraception during treatment and during the 6 months after treatment has concluded. Routine monthly pregnancy tests must be performed during this time. If pregnancy should occur during treatment or during 6 months post-therapy, the patient must be advised of the significant teratogenic risk of COPEGUS therapy to the fetus. Healthcare providers and patients are strongly encouraged to immediately report any pregnancy in a patient or partner of a patient during treatment or during 6 months after treatment cessation to the Ribavirin Pregnancy Registry at 1-800-593-2214.
Chronic hepatitis C (CHC) patients with cirrhosis may be at risk of hepatic decompensation and death when treated with alpha interferons, including PEGASYS. During treatment, patients’ clinical status and hepatic function should be closely monitored, and PEGASYS treatment should be immediately discontinued if decompensation (Child-Pugh score >/=6) is observed. Ischemic and hemorrhagic cerebrovascular events have been observed in patients treated with interferon alfa-based therapies, including PEGASYS. Events occurred in patients with few or no reported risk factors for stroke, including patients less than 45 years of age. Because these are spontaneous reports, estimates of frequency cannot be made and causal relationship between interferon alfa-based therapies and these events is difficult to establish.
The most common adverse events reported for PEGASYS and COPEGUS combination therapy observed in clinical trials were fatigue/asthenia (65 percent), headache (43 percent), pyrexia (41 percent), myalgia (40 percent), irritability/anxiety/nervousness (33 percent), insomnia (30 percent), alopecia (28 percent), neutropenia (27 percent), nausea/vomiting (25 percent), rigors (25 percent), anorexia (24 percent), injection site reaction (23 percent), arthralgia (22 percent), depression (20 percent), pruritus (19 percent) and dermatitis (16 percent).
Serious adverse events in hepatitis C trials included neuropsychiatric disorders (homicidal ideation, suicidal ideation, suicide attempt, suicide, psychotic disorder and hallucinations), serious and severe bacterial infections (sepsis), bone marrow toxicity (cytopenia and rarely, aplastic anemia), cardiovascular disorders (hypertension, supraventricular arrhythmias and myocardial infarction), hypersensitivity (including anaphylaxis), endocrine disorders (including thyroid disorders and diabetes mellitus), autoimmune disorders (including idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, psoriasis, lupus, rheumatoid arthritis and interstitial nephritis), pulmonary disorders (dyspnea, pneumonia, bronchiolitis obliterans, interstitial pneumonitis and sarcoidosis), colitis (ulcerative and hemorrhagic/ischemic colitis), pancreatitis, and ophthalmologic disorders (decrease or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema).
Adverse reactions reported during post-approval use of PEGASYS therapy, with and without ribavirin, include hearing impairment, hearing loss, serious skin reactions, including erythema multiforme major, and infections (bacterial, viral and fungal).
About Roche
Hoffmann-La Roche Inc. (Roche), based in Nutley, N.J., is the U.S. pharmaceuticals headquarters of the Roche Group, one of the world’s leading research-oriented healthcare groups with core businesses in pharmaceuticals and diagnostics. For more than 100 years in the U.S., Roche has been committed to developing innovative products and services that address prevention, diagnosis and treatment of diseases, thus enhancing people's health and quality of life. For additional information about the U.S. pharmaceuticals business, visit our website http://www.rocheusa.com. Product and treatment information for U.S. healthcare professionals is available at www.RocheExchange.com.
About InterMune
InterMune is a biotechnology company focused on the research, development and commercialization of innovative therapies in pulmonology and hepatology. InterMune has a pipeline portfolio addressing idiopathic pulmonary fibrosis (IPF) and hepatitis C virus (HCV) infections. The pulmonology portfolio includes the Phase III program, CAPACITY, which is evaluating pirfenidone as a possible therapeutic candidate for the treatment of patients with IPF and a research program focused on pirfenidone analog ITMN-520. The hepatology portfolio includes the HCV protease inhibitor compound R7227 (ITMN-191), a second-generation HCV protease inhibitor research program, and a research program evaluating a new target in hepatology. For additional information about InterMune and its R&D pipeline, please visit www.intermune.com.
About Pharmasset
Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Pharmasset is currently developing three product candidates. R7128, an oral treatment for chronic HCV infection, has completed a 4-week clinical trial in combination with PEGASYS plus COPEGUS through a strategic collaboration with Roche, and is initiating a Phase IIb trial. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase II clinical trial. PSI-7851, an unpartnered second generation HCV nucleotide analogue recently entered Phase I studies. Additional information is available on the Internet at http://www.pharmasset.com
Forward-Looking Statements
This news release contains forward-looking statements within the meaning of section 21E of the Securities Exchange Act of 1934, as amended, that reflect the companies’ judgments and involve risks and uncertainties as of the date of this release, including without limitation the statements related to anticipated product development timelines. All forward-looking statements and other information included in this press release are based on information available to the companies as of the date hereof, and the companies assume no obligation to update any such forward-looking statements or information. Actual results could differ materially from those described in the forward-looking statements.
Factors that could cause or contribute to such differences include, but are not limited to, those discussed in detail under the heading "Risk Factors" in the companies’ most recent annual reports on Form 10-K filed with the SEC and in other periodic reports filed with the SEC. The risks and other factors discussed above should be considered only in connection with the fully
discussed risks and other factors discussed in detail in the respective Forms 10-K and in the companies’ other periodic reports filed with the SEC, all of which are available via their respective web sites at www.intermune.com and www.pharmasset.com.
All trademarks used or mentioned in this release are protected by law.
- About INFORM-1: www.clinicaltrials.gov
Artificial Liver Extends Lives
March 7, 2009
www.thedenverchannel.com
A New Solution
A new out of body artificial liver is addressing the problem by essentially doing what dialysis does for Kidneys. A patient's plasma passes through the dialysis membrane in the machine. The plasma then filters through human liver cells. "That plasma then bathes these liver cells, and the liver cells perform their function and return purified and detoxified plasma to the patient, Dr. Brown said.
For More Information
Please Contact
New York Presbyterian Hospital
Research Office
212 305 3839
www.thedenverchannel.com
A New Solution
A new out of body artificial liver is addressing the problem by essentially doing what dialysis does for Kidneys. A patient's plasma passes through the dialysis membrane in the machine. The plasma then filters through human liver cells. "That plasma then bathes these liver cells, and the liver cells perform their function and return purified and detoxified plasma to the patient, Dr. Brown said.
For More Information
Please Contact
New York Presbyterian Hospital
Research Office
212 305 3839
Responders and liver disease progression
HEPNews
The Hepatitis Education Project Newsletter
Liver Disease with Undetectable HCV RNA
People infected with HCV as indicated by antibodies in the blood who have an undetectable viral load are usually considered to have inactive disease, and undetectable HCV Rna six months after completion of treatment is regarded as cured. But a study in the December 2008 Hepatology suggests hidden HCV may still cause liver disease progression. M. Hoare and colleagues studied 172 HCV antibody positive but HCV RNA negative individuals who underwent liver biopsies between 1992 and 2000. After 102 were excluded for having other possible causes of liver damage the remaining 70 participants were analyzed after a median of seven years of follow-up. Within this group, 5.7% became HCV RNA positive during follow-up but the rest had continued undetectable viral load. Only five participants had normal liver biopsies: 82% had some fibrosis, with 24% having moderate to advanced fibrosis [Ishak stage 2-3]. HCV RNA negative individuals had fewer CD4 T-cells and more CD8 T-cells than uninfected control subjects, but the same number of patients with detectable viral load. These findings suggest that HCv antibody positive people with undectable HCV RNA have an ongoing immune response in the liver, supporting the view that the virus may persist in the liver in a majority of these cases.
The Hepatitis Education Project Newsletter
Liver Disease with Undetectable HCV RNA
People infected with HCV as indicated by antibodies in the blood who have an undetectable viral load are usually considered to have inactive disease, and undetectable HCV Rna six months after completion of treatment is regarded as cured. But a study in the December 2008 Hepatology suggests hidden HCV may still cause liver disease progression. M. Hoare and colleagues studied 172 HCV antibody positive but HCV RNA negative individuals who underwent liver biopsies between 1992 and 2000. After 102 were excluded for having other possible causes of liver damage the remaining 70 participants were analyzed after a median of seven years of follow-up. Within this group, 5.7% became HCV RNA positive during follow-up but the rest had continued undetectable viral load. Only five participants had normal liver biopsies: 82% had some fibrosis, with 24% having moderate to advanced fibrosis [Ishak stage 2-3]. HCV RNA negative individuals had fewer CD4 T-cells and more CD8 T-cells than uninfected control subjects, but the same number of patients with detectable viral load. These findings suggest that HCv antibody positive people with undectable HCV RNA have an ongoing immune response in the liver, supporting the view that the virus may persist in the liver in a majority of these cases.
Hep C infection and the Brain
From HEPNews the Hepatitis Education Project Newsletter
http://www.hepeducation.org
Hepatitis C virus infection and the brain
There is growing evidence that hepatitis C virus [HCV]-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy, fatigue persists in about one third of the patients, Many patients, in addition report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning abilities as characteristic for HCv-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebal serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilization compatible with alterations of thec dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in the lymphoid tissue, Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain probably in microglia and to infect brain cells, especially astrocytes. Microglia are tiny cells found in the spinal cord and brain. Theit activation ia a common sign of neuor-inflammatory disorder such as encephalitis or stroke, and though they're not well understood, it is known they can perform either protective or harmful functions. Astrocytes are neuron-generating cells.
Sources
Metabolic Brain Disorders Jan 7, 2009
PMID 191301196 by Weissenborn K. Trye AB, Heeren M, Worthman H, Pflugrad H, Berding G. Bokemeyer M, Tillman HL, Goldbecker A, department of Neurology, Hannover Medical School, 30623, Hannover, Germany
Email Karin@mh-hannover.de
Now I understand better why I still have chronic fatigue after three years of treatment and of being a non-responder
Scott
http://www.hepeducation.org
Hepatitis C virus infection and the brain
There is growing evidence that hepatitis C virus [HCV]-infection may affect the brain. About half of the HCV-infected patients complain of chronic fatigue irrespective of their stage of liver disease or virus replication rate. Even after successful antiviral therapy, fatigue persists in about one third of the patients, Many patients, in addition report of deficits in attention, concentration and memory, some also of depression. Psychometric testing revealed deficits in attention and verbal learning abilities as characteristic for HCv-afflicted patients with normal liver function. Magnetic resonance spectroscopic studies showed alterations of the cerebral choline, N-acetyl-aspartate, and creatine content in the basal ganglia, white matter and frontal cortex, respectively. Recently, pathologic cerebal serotonin and dopamine transporter binding and regional alterations of the cerebral glucose utilization compatible with alterations of thec dopaminergic attentional system were observed. Several studies detected HCV in brain samples or cerebro-spinal fluid. Interestingly, viral sequences in the brain often differed from those in the liver, but were closely related to those found in the lymphoid tissue, Therefore, the Trojan horse hypothesis emerged: HCV-infected mononuclear blood cells enter the brain, enabling the virus to reside within the brain probably in microglia and to infect brain cells, especially astrocytes. Microglia are tiny cells found in the spinal cord and brain. Theit activation ia a common sign of neuor-inflammatory disorder such as encephalitis or stroke, and though they're not well understood, it is known they can perform either protective or harmful functions. Astrocytes are neuron-generating cells.
Sources
Metabolic Brain Disorders Jan 7, 2009
PMID 191301196 by Weissenborn K. Trye AB, Heeren M, Worthman H, Pflugrad H, Berding G. Bokemeyer M, Tillman HL, Goldbecker A, department of Neurology, Hannover Medical School, 30623, Hannover, Germany
Email Karin@mh-hannover.de
Now I understand better why I still have chronic fatigue after three years of treatment and of being a non-responder
Scott
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