Article from The Vancouver Sun, August 29, 2011. Despite Health Canada approval, Boceprevir's price tag makes it unaffordable for most Canadians. The drug still needs two more government reviews - the Common Drug Review - a national review process managed by the Canadian Agency for Drugs and Technologies in Health (CADTH). Once the recommendation has been made, then the BC Ministry of Health determines Pharmacare coverage based on recommendations from the BC Drug Benefit Council. The earliest that Boceprevir would be available via Pharmacare is April 2012.
New Hep C drug priced out of reach of most patients
The earliest the medication could be available through BC Pharmacare is April 2012 with two more reviews to go through
By Medha, Vancouver Sun August 29, 2011
Despite approval by Health Canada, Boceprevir, a new drug that dramatically improves the effectiveness of standard hepatitis C treatments remains out of reach of most patients. Boceprevir (brand name Victrelis) is available at pharmacies at a price of $1,050 per week.
Given that the minimum recommended treatment period is 24 weeks, this means "it will remain out of reach of the majority of those who need it unless BC Pharmacare covers it," said Daryl Luster, chair of hepatitis C Global Initiatives, an advocacy group based in Vancouver.
"The drug is now available for those who are very wealthy or have private insurance, but most will require assistance from Pharmacare [to get the drug] and the process for that is long," said Dr. Eric Yoshida, head of the BC Hepatitis Program.
Approval by Health Canada is just the first step, he said. The federal agency only assesses the safety and therapeutic effect of a drug and grants permission to market the drug in Canada. Provincial governments must now decide whether to include the drug in their Pharmacare programs.
To be included in BC Pharmacare, the drug needs to go through two more reviews. First, it needs a positive recommendation from the Common Drug Review - a national review process managed by the Canadian Agency for Drugs and Technologies in Health (CADTH). As a second step, once a positive recommendation has been given, the B.C. Ministry of Health makes a Pharmacare coverage decision by considering Pharmacare policies, programs and resources and the evidence informed recommendations from the B.C. Drug Benefit Council (DBC).
The DBC's advice to the ministry is based upon a review of available clinical and pharmaco-economic evidence, clinical practice and ethical considerations, patient input, and the recommendations of the Common Drug Review, explained Brian Cotton, public affairs officer, B.C. Ministry of Health, in an email. The entire process, including the BC Pharmacare review, is expected to take at least 12 months. So the earliest Boceprevir could be available through Pharmacare in B.C. is April 2012. This may be too late.
"I hope you can get a sense of urgency for Boceprevir. It's needed now - not in April next year," said Douglas Laird, board member of the Hepatitis C Education and Prevention Society, who himself suffers from hepatitis C. "Many people infected with HCV [hepatitis C virus] are in critical condition and need the drug now."
medha@vancouversun.com
Tuesday, August 30, 2011
Thursday, August 25, 2011
LabCorp launches HCV resistance assay, GenoSure...
LabCorp Introduces HCV Resistance Testing through Monogram Biosciences with the Launch of HCV GenoSure(R) NS3/4A
BURLINGTON, N.C., Aug 25, 2011 (BUSINESS WIRE) -- Laboratory Corporation of America(R) Holdings (LabCorp(R)) (NYSE: LH) announced today the nationwide availability of a nucleic acid sequencing assay that reports NS3 and NS4A mutations and NS3 associated resistance to the recently approved hepatitis C virus (HCV) protease inhibitors, adding to LabCorp's suite of HCV testing. Identification of certain mutations may be useful to clinicians considering patient treatment decisions.
"HCV GenoSure NS3/4A represents the first in a series of HCV drug resistance assays that have been developed at Monogram Biosciences to support the clinical evaluation of HCV direct-acting antiviral (DAA) agents and their use in the management of HCV infection," commented Chris Petropoulos, PhD, LabCorp's Vice President of Monogram Research & Development. "We look forward to expanding our broad HCV assay portfolio to support the development and clinical application of additional DAA agents that target other distinct steps in the HCV replication cycle."
HCV GenoSure NS3/4A is currently available exclusively through LabCorp and its Monogram Biosciences Center of Excellence. The test is available for commercial use as well as clinical trial use. Monogram is an established leader in anti-viral drug resistance with 15 years experience in virology and infectious disease testing.
An estimated 3.2 million people in the United States and up to 170 million people worldwide are infected by HCV. Since 2002, the standard of care for HCV infection in the US has been treatment with pegylated a-interferon and ribavirin. In May 2011, the FDA approved the first two DAA agents, boceprevir (Victrelis(TM), Merck & Co) and telaprevir (Incivek(TM), Vertex Pharmaceuticals). Either agent is used in combination with pegylated a-interferon and ribavirin for the treatment of HCV genotype 1 infection. During clinical trials conducted to support regulatory approval, HCV variants containing mutations that confer reduced susceptibility to boceprevir and telaprevir emerged in patients who experienced sub-optimal treatment response.
HCV GenoSure NS3/4A analyzes the genetic sequence for the non-structural proteins NS3 and NS4A of HCV genotypes 1a and 1b that encode for an enzyme essential to viral replication. The assay detects mutations in NS3 and NS4A and specifically identifies those associated with boceprevir and telaprevir resistance.
Recommendations recently developed by the HCV Drug Resistance Advisory Group emphasize the value of resistance testing at treatment baseline and failure in support of the development and clinical evaluation of new drug candidates. In HIV, the routine use of resistance testing to guide antiviral drug treatment is established in clinical practice. In response to the recent and future availability of DAA agents, some experts anticipate that drug resistance testing will provide similar value to the clinical management of HCV infection.
About LabCorp(R)
Laboratory Corporation of America(R) Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.0 billion in 2010, over 31,000 employees worldwide, and more than 220,000 clients, LabCorp offers a broad test menu ranging from routine blood analyses to reproductive genetics to DNA sequencing. LabCorp furthers its scientific expertise and innovative clinical testing technology with its Centers of Excellence: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc., The Center for Esoteric Testing, Litholink Corporation, Genzyme Genetics(SM)*, DIANON Systems, Inc., US LABS, Monogram Biosciences, Inc., and Esoterix and its Colorado Coagulation, Endocrine Sciences, and Cytometry Associates laboratories. LabCorp conducts clinical trials testing through its Esoterix Clinical Trials Services division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our Web site at: www.labcorp.com .
*Genzyme Genetics and its logo are trademarks of Genzyme Corporation and used by Esoterix Genetic Laboratories, LLC, a wholly-owned subsidiary of LabCorp, under license. Esoterix Genetic Laboratories and LabCorp are operated independently from Genzyme Corporation.
This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2010, and subsequent SEC filings.
SOURCE: Laboratory Corporation of America(R) Holdings
BURLINGTON, N.C., Aug 25, 2011 (BUSINESS WIRE) -- Laboratory Corporation of America(R) Holdings (LabCorp(R)) (NYSE: LH) announced today the nationwide availability of a nucleic acid sequencing assay that reports NS3 and NS4A mutations and NS3 associated resistance to the recently approved hepatitis C virus (HCV) protease inhibitors, adding to LabCorp's suite of HCV testing. Identification of certain mutations may be useful to clinicians considering patient treatment decisions.
"HCV GenoSure NS3/4A represents the first in a series of HCV drug resistance assays that have been developed at Monogram Biosciences to support the clinical evaluation of HCV direct-acting antiviral (DAA) agents and their use in the management of HCV infection," commented Chris Petropoulos, PhD, LabCorp's Vice President of Monogram Research & Development. "We look forward to expanding our broad HCV assay portfolio to support the development and clinical application of additional DAA agents that target other distinct steps in the HCV replication cycle."
HCV GenoSure NS3/4A is currently available exclusively through LabCorp and its Monogram Biosciences Center of Excellence. The test is available for commercial use as well as clinical trial use. Monogram is an established leader in anti-viral drug resistance with 15 years experience in virology and infectious disease testing.
An estimated 3.2 million people in the United States and up to 170 million people worldwide are infected by HCV. Since 2002, the standard of care for HCV infection in the US has been treatment with pegylated a-interferon and ribavirin. In May 2011, the FDA approved the first two DAA agents, boceprevir (Victrelis(TM), Merck & Co) and telaprevir (Incivek(TM), Vertex Pharmaceuticals). Either agent is used in combination with pegylated a-interferon and ribavirin for the treatment of HCV genotype 1 infection. During clinical trials conducted to support regulatory approval, HCV variants containing mutations that confer reduced susceptibility to boceprevir and telaprevir emerged in patients who experienced sub-optimal treatment response.
HCV GenoSure NS3/4A analyzes the genetic sequence for the non-structural proteins NS3 and NS4A of HCV genotypes 1a and 1b that encode for an enzyme essential to viral replication. The assay detects mutations in NS3 and NS4A and specifically identifies those associated with boceprevir and telaprevir resistance.
Recommendations recently developed by the HCV Drug Resistance Advisory Group emphasize the value of resistance testing at treatment baseline and failure in support of the development and clinical evaluation of new drug candidates. In HIV, the routine use of resistance testing to guide antiviral drug treatment is established in clinical practice. In response to the recent and future availability of DAA agents, some experts anticipate that drug resistance testing will provide similar value to the clinical management of HCV infection.
About LabCorp(R)
Laboratory Corporation of America(R) Holdings, an S&P 500 company, is a pioneer in commercializing new diagnostic technologies and the first in its industry to embrace genomic testing. With annual revenues of $5.0 billion in 2010, over 31,000 employees worldwide, and more than 220,000 clients, LabCorp offers a broad test menu ranging from routine blood analyses to reproductive genetics to DNA sequencing. LabCorp furthers its scientific expertise and innovative clinical testing technology with its Centers of Excellence: The Center for Molecular Biology and Pathology, National Genetics Institute, ViroMed Laboratories, Inc., The Center for Esoteric Testing, Litholink Corporation, Genzyme Genetics(SM)*, DIANON Systems, Inc., US LABS, Monogram Biosciences, Inc., and Esoterix and its Colorado Coagulation, Endocrine Sciences, and Cytometry Associates laboratories. LabCorp conducts clinical trials testing through its Esoterix Clinical Trials Services division. LabCorp clients include physicians, government agencies, managed care organizations, hospitals, clinical labs, and pharmaceutical companies. To learn more about our organization, visit our Web site at: www.labcorp.com .
*Genzyme Genetics and its logo are trademarks of Genzyme Corporation and used by Esoterix Genetic Laboratories, LLC, a wholly-owned subsidiary of LabCorp, under license. Esoterix Genetic Laboratories and LabCorp are operated independently from Genzyme Corporation.
This press release contains forward-looking statements. Each of the forward-looking statements is subject to change based on various important factors, including without limitation, competitive actions in the marketplace and adverse actions of governmental and other third-party payors. Actual results could differ materially from those suggested by these forward-looking statements. Further information on potential factors that could affect LabCorp's financial results is included in the Company's Form 10-K for the year ended December 31, 2010, and subsequent SEC filings.
SOURCE: Laboratory Corporation of America(R) Holdings
Baird analyst rates Inhibitex stock "outperform" based on HCV polymerase inhibitor INX-189...
Associated Press
Ahead of the Bell: Inhibitex rates 'outperform'
By The Associated Press, 08.25.11, 09:23 AM EDT
Inhibitex has a promising potential treatment for the Hepatitis C virus, according to a Baird analyst who started coverage of the biotechnology company with an "outperform" rating.
Thomas J. Russo said in a Thursday morning research note the Alpharetta, Ga., company's molecule labeled INX-189 is a "real value driver" in an important class of treatments. INX-189 is a potential Hepatitis C treatment called a nucleotide polymerase inhibitor in mid-stage drug development. The analyst said these drugs have a "scarcity value" and that compound appears "very much in the game."
Inhibitex ( INHX - news - people ) Inc. does not have any products on the market, and most of its revenue comes from collaborations. It focuses on developing treatments for viral infections, and it also has a potential shingles treatment in late-stage testing.
Hepatitis C is the primary cause of liver transplants in the U.S. and is expected to become a much larger public health problem as aging baby boomers succumb to the disease.
Hepatitis C is an infectious disease that is spread through the blood, including by sharing needles or having sex with an infected person. The disease could also be picked up from blood transfusions before 1992, when testing of the blood supply for the virus began.
Ahead of the Bell: Inhibitex rates 'outperform'
By The Associated Press, 08.25.11, 09:23 AM EDT
Inhibitex has a promising potential treatment for the Hepatitis C virus, according to a Baird analyst who started coverage of the biotechnology company with an "outperform" rating.
Thomas J. Russo said in a Thursday morning research note the Alpharetta, Ga., company's molecule labeled INX-189 is a "real value driver" in an important class of treatments. INX-189 is a potential Hepatitis C treatment called a nucleotide polymerase inhibitor in mid-stage drug development. The analyst said these drugs have a "scarcity value" and that compound appears "very much in the game."
Inhibitex ( INHX - news - people ) Inc. does not have any products on the market, and most of its revenue comes from collaborations. It focuses on developing treatments for viral infections, and it also has a potential shingles treatment in late-stage testing.
Hepatitis C is the primary cause of liver transplants in the U.S. and is expected to become a much larger public health problem as aging baby boomers succumb to the disease.
Hepatitis C is an infectious disease that is spread through the blood, including by sharing needles or having sex with an infected person. The disease could also be picked up from blood transfusions before 1992, when testing of the blood supply for the virus began.
Wednesday, August 24, 2011
Pharmasset awarded fast track status for polymerase inhibitor PSI-938...
(Good news for Pharmasset, as the FDA awards it's polymerase inhibitor PSI-938 fast track status, which would shorten the review period from 10 months to six months. Pharmasset also announces the start of an interferon-free, dual polymerase inhibitor trial of PSI-938 in combination with it's PSI-7977 compound in the Q3 of this year)
PSI-938 Receives Fast Track Designation from the FDA for the Treatment of Chronic Hepatitis C Infection
PRINCETON, N.J., Aug. 24, 2011 /PRNewswire via COMTEX/ -- Pharmasset, Inc. /quotes/zigman/101019/quotes/nls/vrus VRUS +0.02% has received fast track designation from the U.S. Food and Drug Administration (FDA) for PSI-938 for the treatment of chronic hepatitis C virus (HCV) infection. PSI-938 is an oral guanosine nucleotide analog polymerase inhibitor of HCV.
In March 2011, Pharmasset presented data from the NUCLEAR study demonstrating that PSI-938 has potent antiviral activity and is generally safe and well tolerated, both as monotherapy and in combination with Pharmasset's lead nucleotide analog, PSI-7977. The NUCLEAR study was conducted in treatment naive subjects with genotype 1 HCV who were treated for 14 days with either PSI-938 or a combination of PSI-938 and PSI-7977 with 92% achieving HCV RNA <15IU/mL, the limit of detection, in the combination arms. Pharmasset plans to initiate QUANTUM, an interferon-free combination trial with PSI-938 and PSI-7977 in the third quarter of 2011.
Under the FDA Modernization Act of 1997, fast track designation may facilitate the development and expedite the review of a drug candidate that is intended for the treatment of a serious and life-threatening condition and demonstrates the potential to address an unmet medical need for such a condition. PSI-938 was granted the fast track designation primarily due to the need for HCV treatments with improved tolerability, safety and efficacy over the existing standard of care for both treatment-naive and treatment-experienced patients.
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 the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in four Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in three Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.
For full press release, click on the attached link.
PSI-938 Receives Fast Track Designation from the FDA for the Treatment of Chronic Hepatitis C Infection
PRINCETON, N.J., Aug. 24, 2011 /PRNewswire via COMTEX/ -- Pharmasset, Inc. /quotes/zigman/101019/quotes/nls/vrus VRUS +0.02% has received fast track designation from the U.S. Food and Drug Administration (FDA) for PSI-938 for the treatment of chronic hepatitis C virus (HCV) infection. PSI-938 is an oral guanosine nucleotide analog polymerase inhibitor of HCV.
In March 2011, Pharmasset presented data from the NUCLEAR study demonstrating that PSI-938 has potent antiviral activity and is generally safe and well tolerated, both as monotherapy and in combination with Pharmasset's lead nucleotide analog, PSI-7977. The NUCLEAR study was conducted in treatment naive subjects with genotype 1 HCV who were treated for 14 days with either PSI-938 or a combination of PSI-938 and PSI-7977 with 92% achieving HCV RNA <15IU/mL, the limit of detection, in the combination arms. Pharmasset plans to initiate QUANTUM, an interferon-free combination trial with PSI-938 and PSI-7977 in the third quarter of 2011.
Under the FDA Modernization Act of 1997, fast track designation may facilitate the development and expedite the review of a drug candidate that is intended for the treatment of a serious and life-threatening condition and demonstrates the potential to address an unmet medical need for such a condition. PSI-938 was granted the fast track designation primarily due to the need for HCV treatments with improved tolerability, safety and efficacy over the existing standard of care for both treatment-naive and treatment-experienced patients.
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 the development of oral therapeutics for the treatment of hepatitis C virus (HCV) infection. Our research and development efforts are focused on nucleoside/tide analogs, a class of compounds which act as alternative substrates for the viral polymerase, thus inhibiting viral replication. We currently have three clinical-stage product candidates advancing in trials in various populations. Our pyrimidine, PSI-7977, an unpartnered uracil nucleotide analog, is currently under study in four Phase 2b trials in patients with HCV genotypes 1 through 6, including abbreviated duration interferon and interferon-free regimens. Our purine, PSI-938, an unpartnered guanosine nucleotide analog, recently reported safety and efficacy data from 14 days of monotherapy as well as 14 days in combination with the pyrimidine, PSI-7977. An SVR-endpoint study of the purine-pyrimidine combination is anticipated to begin in the third quarter of 2011. Mericitabine (RG7128) continues in three Phase 2b trials and one interferon-free trial being conducted through a strategic collaboration with Roche.
For full press release, click on the attached link.
FDA Approves Combination Drug for Pediatric HCV Infection
FDA Approves Combination Drug for Pediatric HCV Infection
August 24, 2011 — The US Food and Drug Administration (FDA) has approved an expanded indication for peginterferon alfa-2a [40 KD] and ribavirin (Pegasys and Copegus, both made by Hoffman-LaRoche, Inc), allowing use of the combination treatment in pediatric patients aged 5 through 17 years with chronic hepatitis C (HCV) who have compensated liver disease and no prior history of interferon therapy.
The approval was based on the results of Study NV17424, which was conducted by the company in accordance with FDA postmarketing requirements for pediatric evaluation when approving the drug combination for adult use.
For the study, investigators randomly assigned 114 children to receive 48 weeks of treatment either with peginterferon alfa-2a (body surface area × 180 μg/1.73 m2 once weekly) plus ribavirin (~15 mg/kg/day in 2 divided doses) or with peginterferon alfa-2a plus placebo.
As previously demonstrated in adults, the addition of ribavirin to peginterferon alfa-2a therapy significantly improved the rate of sustained virologic response (HCV RNA < 50 IU/mL) at 24 weeks posttherapy (53% vs 20%). Treatment was particularly effective for eliciting a sustained response in patients with non–genotype 1 HCV compared with the difficult-to-treat genotype 1 (80% vs 47%).
The most important adverse event related to pediatric peginterferon alfa-2a/ribavirin therapy was growth delay relative to baseline: Weight and height for age z-scores and percentiles decreased during treatment but returned to normal for most children by 2 years posttherapy.
Other treatment-emergent effects were similar to those observed in adults and included influenza-like illness (91%), headache (62%), gastrointestinal disorders (56%), injection site reactions (45%), irritability (31%), fatigue (27%), rash (20%), pruritis (15%), and insomnia and decreased appetite (13% each). Dose modifications were required for about 35% of patients in each treatment group, most commonly because of neutropenia (peginterferon alfa-2a/ribavirin) and anemia (peginterferon alfa-2a monotherapy).
Peginterferon alfa-2a and ribavirin combination therapy is also approved by the FDA for the treatment of HCV in patients coinfected with HIV.
August 24, 2011 — The US Food and Drug Administration (FDA) has approved an expanded indication for peginterferon alfa-2a [40 KD] and ribavirin (Pegasys and Copegus, both made by Hoffman-LaRoche, Inc), allowing use of the combination treatment in pediatric patients aged 5 through 17 years with chronic hepatitis C (HCV) who have compensated liver disease and no prior history of interferon therapy.
The approval was based on the results of Study NV17424, which was conducted by the company in accordance with FDA postmarketing requirements for pediatric evaluation when approving the drug combination for adult use.
For the study, investigators randomly assigned 114 children to receive 48 weeks of treatment either with peginterferon alfa-2a (body surface area × 180 μg/1.73 m2 once weekly) plus ribavirin (~15 mg/kg/day in 2 divided doses) or with peginterferon alfa-2a plus placebo.
As previously demonstrated in adults, the addition of ribavirin to peginterferon alfa-2a therapy significantly improved the rate of sustained virologic response (HCV RNA < 50 IU/mL) at 24 weeks posttherapy (53% vs 20%). Treatment was particularly effective for eliciting a sustained response in patients with non–genotype 1 HCV compared with the difficult-to-treat genotype 1 (80% vs 47%).
The most important adverse event related to pediatric peginterferon alfa-2a/ribavirin therapy was growth delay relative to baseline: Weight and height for age z-scores and percentiles decreased during treatment but returned to normal for most children by 2 years posttherapy.
Other treatment-emergent effects were similar to those observed in adults and included influenza-like illness (91%), headache (62%), gastrointestinal disorders (56%), injection site reactions (45%), irritability (31%), fatigue (27%), rash (20%), pruritis (15%), and insomnia and decreased appetite (13% each). Dose modifications were required for about 35% of patients in each treatment group, most commonly because of neutropenia (peginterferon alfa-2a/ribavirin) and anemia (peginterferon alfa-2a monotherapy).
Peginterferon alfa-2a and ribavirin combination therapy is also approved by the FDA for the treatment of HCV in patients coinfected with HIV.
Tuesday, August 23, 2011
Zacks Equity Research on Telaprevir approval in Canada...
Analyst Blog
Vertex's Incivek Approved in Canada
By: Zacks Equity Research
August 23, 2011 |
Vertex Pharmaceuticals Inc. (VRTX - Snapshot Report) recently announced that the Canadian regulatory body has approved Incivek (telaprevir), for treating patients with genotype 1 chronic hepatitis C (HCV) with compensated liver disease, including cirrhosis (scarring of the liver). We note that even though the liver is damaged in patients with compensated liver disease it still functions.
The drug is to be used in combination with pegylated-interferon and ribavirin for the treatment of HCV in both treatment-naïve and treatment-failed patients.
We note that Incivek was approved in the US in May 2011 for the treatment of HCV. Further, during the second quarter of 2011, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Incivek in the European Union (EU) as a treatment for HCV. Partner Johnson & Johnson (JNJ - Analyst Report) anticipates a response from the European regulatory body in the third quarter of 2011. Following the approval, Incivek will be marketed in the EU and certain other territories under the brand name Incivo.
Vertex Pharma has exclusive US commercialization rights to Incivek and has joined hands with Johnson & Johnson and Mitsubishi Tanabe Pharma for the commercialization of the drug outside the US. While Johnson & Johnson is responsible for the commercialization of Incivek outside North America and the Far East, Mitsubishi Pharma will market it in certain areas of the Far East including Japan.
Mitsubishi Tanabe filed for the regulatory approval of Incivek in Japan in January 2011.
The drug which faces competition from Merck & Co. Inc.’s (MRK - Analyst Report) Victrelis, recorded sales of $74.5 million during the second quarter of 2011 (first quarter of the drug’s launch), and helped limit the loss of Vertex Pharma at 82 cents.
Riding on the strong sales of Incivek, total revenue during the second quarter soared 262% to $114.4 million, surpassing the Zacks Consensus Estimate of $54 million. (Read our full coverage on the earnings report at: Incivek Limits Vertex's Losses)
Our View
We currently have a Neutral recommendation on Vertex Pharma. The stock carries a Zacks #3 Rank (Hold rating) in the short-run. We are pleased with the Canadian approval of Incivek as it’s the only marketed drug at Vertex Pharma and, we believe that Incivek will help the company post positive earnings.
Vertex's Incivek Approved in Canada
By: Zacks Equity Research
August 23, 2011 |
Vertex Pharmaceuticals Inc. (VRTX - Snapshot Report) recently announced that the Canadian regulatory body has approved Incivek (telaprevir), for treating patients with genotype 1 chronic hepatitis C (HCV) with compensated liver disease, including cirrhosis (scarring of the liver). We note that even though the liver is damaged in patients with compensated liver disease it still functions.
The drug is to be used in combination with pegylated-interferon and ribavirin for the treatment of HCV in both treatment-naïve and treatment-failed patients.
We note that Incivek was approved in the US in May 2011 for the treatment of HCV. Further, during the second quarter of 2011, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the approval of Incivek in the European Union (EU) as a treatment for HCV. Partner Johnson & Johnson (JNJ - Analyst Report) anticipates a response from the European regulatory body in the third quarter of 2011. Following the approval, Incivek will be marketed in the EU and certain other territories under the brand name Incivo.
Vertex Pharma has exclusive US commercialization rights to Incivek and has joined hands with Johnson & Johnson and Mitsubishi Tanabe Pharma for the commercialization of the drug outside the US. While Johnson & Johnson is responsible for the commercialization of Incivek outside North America and the Far East, Mitsubishi Pharma will market it in certain areas of the Far East including Japan.
Mitsubishi Tanabe filed for the regulatory approval of Incivek in Japan in January 2011.
The drug which faces competition from Merck & Co. Inc.’s (MRK - Analyst Report) Victrelis, recorded sales of $74.5 million during the second quarter of 2011 (first quarter of the drug’s launch), and helped limit the loss of Vertex Pharma at 82 cents.
Riding on the strong sales of Incivek, total revenue during the second quarter soared 262% to $114.4 million, surpassing the Zacks Consensus Estimate of $54 million. (Read our full coverage on the earnings report at: Incivek Limits Vertex's Losses)
Our View
We currently have a Neutral recommendation on Vertex Pharma. The stock carries a Zacks #3 Rank (Hold rating) in the short-run. We are pleased with the Canadian approval of Incivek as it’s the only marketed drug at Vertex Pharma and, we believe that Incivek will help the company post positive earnings.
Monday, August 15, 2011
Selection of hepatitis C virus resistant to ribavirin...
(Data published in Virology Journal 2011, 8:402 suggests that ribavirin-resistant variants of HCV virus are possible, with relative replicative fitness equal to that of wild-type virus. This data, while in vitro, may give some pause to the idea of interferon-free regimens to treat HCV)
Given the side effects associated with intravenous injections of interferon, an interferon-free regimen for the treatment of HCV infections is highly desirable. Recently published clinical studies show that interferon-free combination therapies containing ribavirin are efficacious, suggesting that an interferon-free therapy could be adopted in the near future.
Therefore, understanding HCV resistance to ribavirin could be of major importance. In an approach to understand the effect of ribavirin on HCV replication and HCV resistance, we have selected a ribavirin resistant mutant of HCV in vitro.
Methods: We serially passed the J6/JFH1 strain of HCV in Huh7D cells (a Huh7 cell derivative more permissive to HCV replication) in the presence of different concentrations of ribavirin.
Virus replication was assessed by detection of HCV antigens by immunfluorscence of infected cells and titration of recovered virus present in the supernatant. cDNAs from virus RNA grown in 0 or 250 uM concentrations of ribavirin were synthesized by RT-PCR, and sequenced.
Results: A concentration of 125 uM of ribavirin did not have a dramatic effect on HCV replication, while 500 uM of ribavirin lead to viral extinction.
Concentrations of 250 uM of ribavirin dramatically reduced virus replication which was sustained over six passages. At passage seven viral resurgence began and over two passages the level of virus reached that of the wild type virus grown without ribavirin.
Virus recovered from these cultures were more resistant to 250 uM ribavirin than wild type virus, and showed no difference in replication relative to wild type virus when grown in the absence of ribavirin. The ribavirin resistant virus accumulated multiple synonymous and non-synonymous mutations that are presently being analyzed for their relationship to ribavirin resistance.
Conclusions: It is possible to select a ribavirin resistant mutant of HCV that can replicate to levels similar to wild type virus grown without ribavirin.
Analysis of the mutations responsible for the ribavirin resistance may aid in understanding the mechanism of action of ribavirin.
Author: Dino Feigelstock,Kathleen Mihalik,Stephen Feinstone
Credits/Source: Virology Journal 2011, 8:402
Given the side effects associated with intravenous injections of interferon, an interferon-free regimen for the treatment of HCV infections is highly desirable. Recently published clinical studies show that interferon-free combination therapies containing ribavirin are efficacious, suggesting that an interferon-free therapy could be adopted in the near future.
Therefore, understanding HCV resistance to ribavirin could be of major importance. In an approach to understand the effect of ribavirin on HCV replication and HCV resistance, we have selected a ribavirin resistant mutant of HCV in vitro.
Methods: We serially passed the J6/JFH1 strain of HCV in Huh7D cells (a Huh7 cell derivative more permissive to HCV replication) in the presence of different concentrations of ribavirin.
Virus replication was assessed by detection of HCV antigens by immunfluorscence of infected cells and titration of recovered virus present in the supernatant. cDNAs from virus RNA grown in 0 or 250 uM concentrations of ribavirin were synthesized by RT-PCR, and sequenced.
Results: A concentration of 125 uM of ribavirin did not have a dramatic effect on HCV replication, while 500 uM of ribavirin lead to viral extinction.
Concentrations of 250 uM of ribavirin dramatically reduced virus replication which was sustained over six passages. At passage seven viral resurgence began and over two passages the level of virus reached that of the wild type virus grown without ribavirin.
Virus recovered from these cultures were more resistant to 250 uM ribavirin than wild type virus, and showed no difference in replication relative to wild type virus when grown in the absence of ribavirin. The ribavirin resistant virus accumulated multiple synonymous and non-synonymous mutations that are presently being analyzed for their relationship to ribavirin resistance.
Conclusions: It is possible to select a ribavirin resistant mutant of HCV that can replicate to levels similar to wild type virus grown without ribavirin.
Analysis of the mutations responsible for the ribavirin resistance may aid in understanding the mechanism of action of ribavirin.
Author: Dino Feigelstock,Kathleen Mihalik,Stephen Feinstone
Credits/Source: Virology Journal 2011, 8:402
Thursday, August 11, 2011
FDA approves Gilead's once-daily HIV pill, Complera
(The FDA approves Complera - a once daily combination of Truvada and Edurant - for the treatment of HIV in treatment naive subjects. New drug combinations that allow for less pill burden are always welcome and help increase adherence. However when it comes to HIV, providers are always looking for options down the line if the patient happens to become resistant to therapy. Two things to take note of in the press release:
1. "The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz."
2. "More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz."
This essentially means that a patient becoming resistant to either the Truvada or Edurant portion of the regimen would potentially have less options for sequential therapy down the line compared to the efavirenz-containing regimen used in the control arm of the Complera studies.
The rilpivirine-portion of the drug also appears to be heavily effected by gastric PH and potential for drug-drug interactions involving CYP3A which may lower rilpivirine to sub-therapeutic levels and potentially be a mechanism of resistance )
U.S. Food and Drug Administration Approves Gilead Sciences’ Complera™, a New Complete Once-Daily, Single-Tablet Regimen for HIV-1 Infection in Treatment-Naïve Adults
- Complera Combines the Most-Prescribed HIV Product in the United States with the Newest Antiretroviral Agent Approved by the FDA -
- Approval Marks Gilead's Second Successful Collaboration to Develop a Complete Single-Tablet Regimen for HIV/AIDS -
FOSTER CITY, Calif., Aug 10, 2011 (BUSINESS WIRE) --
Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Complera(TM) (emtricitabine/rilpivirine/tenofovir disoproxil fumarate), a complete single-tablet regimen for the treatment of HIV-1 infection in treatment-naïve adults. Complera combines three antiretroviral medications in one daily tablet - Gilead's Truvada(R), which is a fixed-dose combination of the two nucleoside reverse transcriptase inhibitors emtricitabine and tenofovir disoproxil fumarate, and Tibotec Pharmaceuticals' non-nucleoside reverse transcriptase inhibitor, rilpivirine (marketed as Edurant(TM) in the United States by Janssen Therapeutics, Division of Janssen Products, LP). Truvada and rilpivirine were approved by the FDA in August 2004 and May 2011, respectively, for use as part of HIV combination therapy.
"In the 30 years since the first AIDS cases were reported, we've made incredible strides in the treatment of this disease," said Tony Mills, MD, Director of Medical Research, Anthony Mills MD, Inc. and a participating investigator in ongoing Complera studies. "The concept of a single-tablet regimen has become a goal in HIV drug development, and the standard of care in medical practice in the United States. However, no one therapy is appropriate for all patients. Given its efficacy, safety and convenience, the availability of Complera represents an exciting milestone in addressing the individual needs of patients new to HIV therapy."
The approval of Complera is supported by 48-week data from two Phase 3 double-blind, active controlled, randomized studies (ECHO and THRIVE) conducted by Tibotec that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naïve HIV-1 infected adults. Both arms of the study were administered with a background regimen, in which the majority of patients in the rilpivirine arm received Truvada. A bioequivalence study, conducted by Gilead, demonstrated that the co-formulated single-tablet regimen achieved the same levels of medication in the blood as emtricitabine plus rilpivirine plus tenofovir disoproxil fumarate.
"Complera is the second complete single-tablet regimen that Gilead has introduced, and it represents a collaboration between two organizations that share a vision of simplifying HIV therapy for patients," said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. "Tremendous progress has been made in the field of HIV, but we recognize new therapies are still needed, and we continue to work to advance options that address the needs of patients."
Complera is the second complete antiretroviral treatment regimen for HIV-1 available to treatment-naïve patients in a single once-daily pill. The first, Atripla(R) (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), is marketed by Gilead and Bristol-Myers Squibb. Complera does not cure HIV-1 infection or help prevent the transmission of HIV to others. Complera has Boxed Warnings including lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for additional important safety information. The following points should be considered when initiating therapy with Complera:
More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.
Complera is not recommended for patients less than 18 years of age.
Gilead first entered into a license and collaboration agreement with Tibotec for the development and commercialization of Complera in July 2009. Under the terms of the agreement, Gilead will assume the lead role in the manufacturing, registration, distribution and commercialization of Complera in the United States, Canada, Brazil, the European Union, Australia and New Zealand. Tibotec will be responsible for the commercialization of rilpivirine as a stand-alone product and will hold rights to co-detail Complera in these territories. A marketing application for the emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen is currently pending in the European Union.
The companies also have finalized an agreement for the development and commercialization of the single-tablet regimen for the rest of world, including the developing world. Gilead will be responsible for the registration, distribution and commercialization of the single-tablet regimen in certain European countries, Latin America and the Caribbean. Tibotec will be responsible for all countries outside of the Gilead territories, the most significant of which include Asia Pacific, including Japan, the Middle East, Eastern Europe and all of Africa.
Important Product Safety Information About Complera, Including Boxed Warnings
BOXED WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Complera, in combination with other antiretrovirals.
Complera is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Complera have not been established in patients coinfected with HBV and HIV-1.Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Complera.Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Complera.If appropriate, initiation of anti-hepatitis B therapy may be warranted.
CONTRAINDICATIONS
Complera should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs:
the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
the antimycobacterials rifabutin, rifampin, rifapentine
proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
the glucocorticoid systemic dexamethasone (more than a single dose)
St John's wort (Hypericum perforatum)
WARNINGS AND PRECAUTIONS
New onset or worsening renal impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir disoproxil fumarate. Assess creatinine clearance (CrCl) before initiating treatment with Complera. Monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera(R) (adefovir dipivoxil). Avoid administering Complera with concurrent or recent use of nephrotoxic drugs. Patients with CrCl below 50 mL per minute should not receive Complera.
Drug Interactions
Complera should be used with caution when given with drugs that may reduce the exposure of rilpivirine.
Complera should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N = 1,368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N = 686) or efavirenz (N = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Complera, and if so, to determine whether the risks of continued therapy outweigh the benefits.
Decreases in bone mineral density
Bone mineral density (BMD) monitoring should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir disoproxil fumarate.
Co-administration with other products
Complera should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir disoproxil fumarate (Emtriva, Edurant, Viread, Truvada, Atripla), with medicinal products containing lamivudine (Epivir, Epivir-HBV, Epzicom, Combivir, Trizivir), or with adefovir dipivoxil (Hepsera).
Fat redistribution
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy.
Immune reconstitution syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Complera. Further evaluation and treatment may be necessary.
ADVERSE REACTIONS
The most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) were insomnia and headache.
The most common adverse drug reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater-than or equal to 10%) were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.
DRUG INTERACTIONS
Complera should not be used with drugs where significant decreases in rilpivirine plasma concentrations may occur (See CONTRAINDICATIONS).
Complera is a complete regimen for the treatment of HIV-1 infection; therefore Complera should not be administered with other antiretroviral medications for the treatment of HIV-1 infection.
Drugs inducing or inhibiting CYP3A enzymes: Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
Drugs increasing gastric PH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
Drugs affecting renal function: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Complera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir.
QT prolonging drugs: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.
DOSAGE AND ADMINISTRATION
Adults: The recommended dose of Complera is one tablet taken orally once daily with a meal.
Renal Impairment: Because Complera is a fixed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute).
Important Safety Product Information About Truvada, Including Boxed Warnings
Truvada, a combination of Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate [DF]), is indicated in combination with other antiretroviral agents (such as non nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection.
The following points should be considered when initiating therapy with Truvada for the treatment of HIV-1 infection:
It is not recommended that Truvada be used as a component of a triple nucleoside regimen.
Truvada should not be coadministered with Atripla (efavirenz/emtricitabine/tenofovir DF), Emtriva, Viread, or lamivudine-containing products.
In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including Viread, a component of Truvada, in combination with other antiretrovirals.
Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
WARNINGS AND PRECAUTIONS
New Onset or Worsening Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF.
Assess CrCl before initiating treatment with Truvada. Routinely monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera (adefovir dipivoxil).
Dosing interval adjustment of Truvada and close monitoring of renal function are recommended in all patients with CrCl 30-49 mL/min. No safety or efficacy data are available in patients with renal impairment who received Truvada using these dosing guidelines, so the potential benefit of Truvada therapy should be assessed against the potential risk of renal toxicity. Truvada should not be administered in patients with CrCl <30 mL/min or patients requiring hemodialysis. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. Coadministration With Other Products Since Truvada contains emtricitabine and tenofovir DF, Truvada should not be coadministered with Atripla, Emtriva or Viread. Due to similarities between emtricitabine and lamivudine, Truvada should not be coadministered with other drugs containing lamivudine, including Combivir (zidovudine/lamivudine) Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). Truvada should not be administered with Hepsera. Bone Mineral Density Decreases in bone mineral density (BMD): BMD monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or who are at risk for osteopenia. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Truvada, which may necessitate further evaluation and treatment. Early Virologic Failure Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients on regimens containing only 3 nucleoside reverse transcriptase inhibitors (NRTIs). Monitor carefully and consider treatment modification. ADVERSE REACTIONS The most common (incidence greater-than or equal to 10%, any severity) and/or treatment-emergent (Grade 2-4, occurring in greater-than or equal to 5% of subjects) adverse reactions occurring in subjects treated with efavirenz, emtricitabine and tenofovir DF in Study 934 through 144 weeks include diarrhea, nausea, fatigue, sinusitis, upper respiratory tract infections, nasopharyngitis, headache, dizziness, depression, insomnia, abnormal dreams and rash. DRUG INTERACTIONS Didanosine (ddI): tenofovir disoproxil fumarate increases ddI concentrations. Use with caution and monitor for evidence of ddI toxicity (eg, pancreatitis, neuropathy) when coadministered. The ddI dose should be reduced to 250 mg for patients weighing >60 kg. Data are not available to recommend a dose adjustment of ddI for patients weighing <60 kg. Coadministration of didanosine buffered tablet formulation with Truvada should be under fasted conditions.
Atazanavir (ATV): coadministration decreases ATV concentrations and increases tenofovir concentrations. ATV 300 mg should be boosted with ritonavir 100 mg only and taken with food when administered with Truvada. Monitor for evidence of tenofovir-associated adverse reactions and discontinue Truvada if appropriate. ATV without ritonavir should not be coadministered with Truvada.
Lopinavir/ritonavir (LPV/r): coadministration increases tenofovir concentrations. Patients receiving LPV/r and Truvada should be monitored for tenofovir-associated adverse reactions and discontinue Truvada if appropriate.
DOSAGE AND ADMINISTRATION
Recommended dose: one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food in adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb.).
Renal dosing guidelines
Creatinine clearance
(mL/min)a
greater-than or equal to 50 30-49
<30
(including patients
requiring hemodialysis)
Recommended
dosing
Every 24 hours Every 48 hours
Truvada should not be
administered
aCalculated using ideal (lean) body weight.
The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment; clinical response to treatment and renal function should be closely monitored in these patients.
Please see full Prescribing Information for Complera and Truvada (including BOXED WARNINGS).
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.
Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that physicians may not see advantages of Complera over other therapies and may therefore be reluctant to prescribe the product, and payers may be reluctant to approve or provide reimbursement for the product. In addition, pending marketing applications such as those in the European Union may not be approved or approval may be delayed, and marketing approval, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2011, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
U.S. full prescribing information for Complera is available at www.Gilead.com.
U.S. full prescribing information for Truvada is available at www.Truvada.com.
U.S. full prescribing information for Atripla is available at www.Atripla.com.
Complera, Truvada, Viread, Emtriva and Hepsera are trademarks or registered trademarks of Gilead Sciences, Inc. or its related companies.
Edurant is a trademark of Tibotec Pharmaceuticals.
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
SOURCE: Gilead Sciences, Inc.
Gilead Sciences, Inc.
Susan Hubbard, 650-522-5715 (Investors)
Erin Rau, 650-522-5635 (Media)
1. "The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz."
2. "More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz."
This essentially means that a patient becoming resistant to either the Truvada or Edurant portion of the regimen would potentially have less options for sequential therapy down the line compared to the efavirenz-containing regimen used in the control arm of the Complera studies.
The rilpivirine-portion of the drug also appears to be heavily effected by gastric PH and potential for drug-drug interactions involving CYP3A which may lower rilpivirine to sub-therapeutic levels and potentially be a mechanism of resistance )
U.S. Food and Drug Administration Approves Gilead Sciences’ Complera™, a New Complete Once-Daily, Single-Tablet Regimen for HIV-1 Infection in Treatment-Naïve Adults
- Complera Combines the Most-Prescribed HIV Product in the United States with the Newest Antiretroviral Agent Approved by the FDA -
- Approval Marks Gilead's Second Successful Collaboration to Develop a Complete Single-Tablet Regimen for HIV/AIDS -
FOSTER CITY, Calif., Aug 10, 2011 (BUSINESS WIRE) --
Gilead Sciences, Inc. (Nasdaq:GILD) today announced that the U.S. Food and Drug Administration (FDA) has approved Complera(TM) (emtricitabine/rilpivirine/tenofovir disoproxil fumarate), a complete single-tablet regimen for the treatment of HIV-1 infection in treatment-naïve adults. Complera combines three antiretroviral medications in one daily tablet - Gilead's Truvada(R), which is a fixed-dose combination of the two nucleoside reverse transcriptase inhibitors emtricitabine and tenofovir disoproxil fumarate, and Tibotec Pharmaceuticals' non-nucleoside reverse transcriptase inhibitor, rilpivirine (marketed as Edurant(TM) in the United States by Janssen Therapeutics, Division of Janssen Products, LP). Truvada and rilpivirine were approved by the FDA in August 2004 and May 2011, respectively, for use as part of HIV combination therapy.
"In the 30 years since the first AIDS cases were reported, we've made incredible strides in the treatment of this disease," said Tony Mills, MD, Director of Medical Research, Anthony Mills MD, Inc. and a participating investigator in ongoing Complera studies. "The concept of a single-tablet regimen has become a goal in HIV drug development, and the standard of care in medical practice in the United States. However, no one therapy is appropriate for all patients. Given its efficacy, safety and convenience, the availability of Complera represents an exciting milestone in addressing the individual needs of patients new to HIV therapy."
The approval of Complera is supported by 48-week data from two Phase 3 double-blind, active controlled, randomized studies (ECHO and THRIVE) conducted by Tibotec that evaluated the safety and efficacy of rilpivirine compared to efavirenz among treatment-naïve HIV-1 infected adults. Both arms of the study were administered with a background regimen, in which the majority of patients in the rilpivirine arm received Truvada. A bioequivalence study, conducted by Gilead, demonstrated that the co-formulated single-tablet regimen achieved the same levels of medication in the blood as emtricitabine plus rilpivirine plus tenofovir disoproxil fumarate.
"Complera is the second complete single-tablet regimen that Gilead has introduced, and it represents a collaboration between two organizations that share a vision of simplifying HIV therapy for patients," said John C. Martin, PhD, Chairman and Chief Executive Officer, Gilead Sciences. "Tremendous progress has been made in the field of HIV, but we recognize new therapies are still needed, and we continue to work to advance options that address the needs of patients."
Complera is the second complete antiretroviral treatment regimen for HIV-1 available to treatment-naïve patients in a single once-daily pill. The first, Atripla(R) (efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg), is marketed by Gilead and Bristol-Myers Squibb. Complera does not cure HIV-1 infection or help prevent the transmission of HIV to others. Complera has Boxed Warnings including lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for additional important safety information. The following points should be considered when initiating therapy with Complera:
More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.
The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.
More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.
Complera is not recommended for patients less than 18 years of age.
Gilead first entered into a license and collaboration agreement with Tibotec for the development and commercialization of Complera in July 2009. Under the terms of the agreement, Gilead will assume the lead role in the manufacturing, registration, distribution and commercialization of Complera in the United States, Canada, Brazil, the European Union, Australia and New Zealand. Tibotec will be responsible for the commercialization of rilpivirine as a stand-alone product and will hold rights to co-detail Complera in these territories. A marketing application for the emtricitabine/rilpivirine/tenofovir disoproxil fumarate single-tablet regimen is currently pending in the European Union.
The companies also have finalized an agreement for the development and commercialization of the single-tablet regimen for the rest of world, including the developing world. Gilead will be responsible for the registration, distribution and commercialization of the single-tablet regimen in certain European countries, Latin America and the Caribbean. Tibotec will be responsible for all countries outside of the Gilead territories, the most significant of which include Asia Pacific, including Japan, the Middle East, Eastern Europe and all of Africa.
Important Product Safety Information About Complera, Including Boxed Warnings
BOXED WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Complera, in combination with other antiretrovirals.
Complera is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Complera have not been established in patients coinfected with HBV and HIV-1.Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Complera.Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Complera.If appropriate, initiation of anti-hepatitis B therapy may be warranted.
CONTRAINDICATIONS
Complera should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs:
the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
the antimycobacterials rifabutin, rifampin, rifapentine
proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
the glucocorticoid systemic dexamethasone (more than a single dose)
St John's wort (Hypericum perforatum)
WARNINGS AND PRECAUTIONS
New onset or worsening renal impairment
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir disoproxil fumarate. Assess creatinine clearance (CrCl) before initiating treatment with Complera. Monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera(R) (adefovir dipivoxil). Avoid administering Complera with concurrent or recent use of nephrotoxic drugs. Patients with CrCl below 50 mL per minute should not receive Complera.
Drug Interactions
Complera should be used with caution when given with drugs that may reduce the exposure of rilpivirine.
Complera should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.
Depressive Disorders
The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N = 1,368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N = 686) or efavirenz (N = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Complera, and if so, to determine whether the risks of continued therapy outweigh the benefits.
Decreases in bone mineral density
Bone mineral density (BMD) monitoring should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir disoproxil fumarate.
Co-administration with other products
Complera should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir disoproxil fumarate (Emtriva, Edurant, Viread, Truvada, Atripla), with medicinal products containing lamivudine (Epivir, Epivir-HBV, Epzicom, Combivir, Trizivir), or with adefovir dipivoxil (Hepsera).
Fat redistribution
Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy.
Immune reconstitution syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Complera. Further evaluation and treatment may be necessary.
ADVERSE REACTIONS
The most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) were insomnia and headache.
The most common adverse drug reactions to emtricitabine and tenofovir disoproxil fumarate (incidence greater-than or equal to 10%) were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.
DRUG INTERACTIONS
Complera should not be used with drugs where significant decreases in rilpivirine plasma concentrations may occur (See CONTRAINDICATIONS).
Complera is a complete regimen for the treatment of HIV-1 infection; therefore Complera should not be administered with other antiretroviral medications for the treatment of HIV-1 infection.
Drugs inducing or inhibiting CYP3A enzymes: Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
Drugs increasing gastric PH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
Drugs affecting renal function: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Complera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir.
QT prolonging drugs: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.
DOSAGE AND ADMINISTRATION
Adults: The recommended dose of Complera is one tablet taken orally once daily with a meal.
Renal Impairment: Because Complera is a fixed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute).
Important Safety Product Information About Truvada, Including Boxed Warnings
Truvada, a combination of Emtriva (emtricitabine) and Viread (tenofovir disoproxil fumarate [DF]), is indicated in combination with other antiretroviral agents (such as non nucleoside reverse transcriptase inhibitors or protease inhibitors) for the treatment of HIV-1 infection.
The following points should be considered when initiating therapy with Truvada for the treatment of HIV-1 infection:
It is not recommended that Truvada be used as a component of a triple nucleoside regimen.
Truvada should not be coadministered with Atripla (efavirenz/emtricitabine/tenofovir DF), Emtriva, Viread, or lamivudine-containing products.
In treatment-experienced patients, the use of Truvada should be guided by laboratory testing and treatment history.
WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including Viread, a component of Truvada, in combination with other antiretrovirals.
Truvada is not approved for the treatment of chronic hepatitis B virus (HBV) infection, and the safety and efficacy of Truvada have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Truvada. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Truvada. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
WARNINGS AND PRECAUTIONS
New Onset or Worsening Renal Impairment
Emtricitabine and tenofovir are principally eliminated by the kidney. Renal impairment, including acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF.
Assess CrCl before initiating treatment with Truvada. Routinely monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera (adefovir dipivoxil).
Dosing interval adjustment of Truvada and close monitoring of renal function are recommended in all patients with CrCl 30-49 mL/min. No safety or efficacy data are available in patients with renal impairment who received Truvada using these dosing guidelines, so the potential benefit of Truvada therapy should be assessed against the potential risk of renal toxicity. Truvada should not be administered in patients with CrCl <30 mL/min or patients requiring hemodialysis. Avoid administering Truvada with concurrent or recent use of nephrotoxic drugs. Coadministration With Other Products Since Truvada contains emtricitabine and tenofovir DF, Truvada should not be coadministered with Atripla, Emtriva or Viread. Due to similarities between emtricitabine and lamivudine, Truvada should not be coadministered with other drugs containing lamivudine, including Combivir (zidovudine/lamivudine) Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine). Truvada should not be administered with Hepsera. Bone Mineral Density Decreases in bone mineral density (BMD): BMD monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or who are at risk for osteopenia. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of Viread. Fat Redistribution Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. Immune Reconstitution Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including Truvada, which may necessitate further evaluation and treatment. Early Virologic Failure Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients on regimens containing only 3 nucleoside reverse transcriptase inhibitors (NRTIs). Monitor carefully and consider treatment modification. ADVERSE REACTIONS The most common (incidence greater-than or equal to 10%, any severity) and/or treatment-emergent (Grade 2-4, occurring in greater-than or equal to 5% of subjects) adverse reactions occurring in subjects treated with efavirenz, emtricitabine and tenofovir DF in Study 934 through 144 weeks include diarrhea, nausea, fatigue, sinusitis, upper respiratory tract infections, nasopharyngitis, headache, dizziness, depression, insomnia, abnormal dreams and rash. DRUG INTERACTIONS Didanosine (ddI): tenofovir disoproxil fumarate increases ddI concentrations. Use with caution and monitor for evidence of ddI toxicity (eg, pancreatitis, neuropathy) when coadministered. The ddI dose should be reduced to 250 mg for patients weighing >60 kg. Data are not available to recommend a dose adjustment of ddI for patients weighing <60 kg. Coadministration of didanosine buffered tablet formulation with Truvada should be under fasted conditions.
Atazanavir (ATV): coadministration decreases ATV concentrations and increases tenofovir concentrations. ATV 300 mg should be boosted with ritonavir 100 mg only and taken with food when administered with Truvada. Monitor for evidence of tenofovir-associated adverse reactions and discontinue Truvada if appropriate. ATV without ritonavir should not be coadministered with Truvada.
Lopinavir/ritonavir (LPV/r): coadministration increases tenofovir concentrations. Patients receiving LPV/r and Truvada should be monitored for tenofovir-associated adverse reactions and discontinue Truvada if appropriate.
DOSAGE AND ADMINISTRATION
Recommended dose: one tablet (containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate) once daily taken orally with or without food in adults and pediatric patients 12 years of age and older with body weight greater than or equal to 35 kg (greater than or equal to 77 lb.).
Renal dosing guidelines
Creatinine clearance
(mL/min)a
greater-than or equal to 50 30-49
<30
(including patients
requiring hemodialysis)
Recommended
dosing
Every 24 hours Every 48 hours
Truvada should not be
administered
aCalculated using ideal (lean) body weight.
The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate renal impairment; clinical response to treatment and renal function should be closely monitored in these patients.
Please see full Prescribing Information for Complera and Truvada (including BOXED WARNINGS).
About Gilead Sciences
Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company's mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.
Forward-Looking Statement
This press release includes forward-looking statements, within the meaning of the Private Securities Litigation Reform Act of 1995, that are subject to risks, uncertainties and other factors, including the risk that physicians may not see advantages of Complera over other therapies and may therefore be reluctant to prescribe the product, and payers may be reluctant to approve or provide reimbursement for the product. In addition, pending marketing applications such as those in the European Union may not be approved or approval may be delayed, and marketing approval, if granted, may have significant limitations on its use. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead's Quarterly Report on Form 10-Q for the quarter ended June 30, 2011, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.
U.S. full prescribing information for Complera is available at www.Gilead.com.
U.S. full prescribing information for Truvada is available at www.Truvada.com.
U.S. full prescribing information for Atripla is available at www.Atripla.com.
Complera, Truvada, Viread, Emtriva and Hepsera are trademarks or registered trademarks of Gilead Sciences, Inc. or its related companies.
Edurant is a trademark of Tibotec Pharmaceuticals.
Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.
For more information on Gilead Sciences, please visit the company's website at www.gilead.com or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.
SOURCE: Gilead Sciences, Inc.
Gilead Sciences, Inc.
Susan Hubbard, 650-522-5715 (Investors)
Erin Rau, 650-522-5635 (Media)
Tuesday, August 9, 2011
Emmet B. Keeffe, MD, RIP
It is with a sad heart to learn that Dr. Keeffe passed away Monday evening. He was one of the true giants of HCV research and an all-around true gentleman. He will be greatly missed.
Monday, August 8, 2011
HCV Resistance: Similarities and Differences With HIV CME on Clinical Care Options
A great new CME with Stuart Ray, MD from Johns Hopkins University reviewing the similarities and differences in HCV resistance compared to HIV. Highly recommended. Free, but registration to Clinical Care Options required. Link here
Wednesday, August 3, 2011
Epixis HCV vaccine looks effective even with mutated HCV variants in murine studies...
From Reuters.... French scientists have developed an experimental preventative vaccine that has shown to activate a robust immune response. The vaccine was shown to prevent infection with several mutated variants of the HCV virus in murine studies.
By Ben Hirschler
LONDON | Wed Aug 3, 2011 5:27pm EDT
LONDON (Reuters) - French scientists have developed a novel hepatitis C vaccine that may offer the first effective way to prevent an infection that can cause chronic liver disease and cancer.
There is currently no available vaccine for hepatitis C, though some companies are developing so-called "therapeutic vaccines," which are designed to help patients who are already infected.
The latest experimental shot has been tested successfully on mice and monkeys, but not humans, and has been shown to activate a broad response from immune system proteins called neutralizing antibodies.
The antibodies fought off multiple variants of the hepatitis C virus in tests, suggesting the new vaccine should be effective even after the virus mutates, the researchers reported on Wednesday.
Neutralizing antibodies play a central role in most existing vaccines against other diseases, but harnessing them in hepatitis C has previously proved elusive. Work to date on therapeutic vaccines has focused on another immune system mechanism known as T-cells.
"For a preventative vaccine, neutralizing antibodies are absolutely essential, and for a therapeutic product they would also be a big advantage," David Klatzmann, a member of the research team, told Reuters.
About 130 million to 170 million people worldwide are chronically infected with hepatitis C virus, and more than 350,000 die from hepatitis C-related liver diseases each year, according to the World Health Organization.
Unlike hepatitis A or B, most people with hepatitis C develop chronic disease because their bodies are unable to get rid of the virus. The condition is spread by exposure to infected blood.
Interferon and ribavirin-based therapy has been the mainstay of treatment, although recently Vertex and Merck have both launched promising new medicines that are tipped to become multibillion-dollar-a-year sellers.
Commercial interest in hepatitis C vaccines has been more muted. French biotech company Transgene and Austria's Intercell are both testing therapeutic versions, but the main markets for a preventative shot would be in the developing world, which is less attractive for Big Pharma.
Commercial rights to the new vaccine are held by French start-up Epixis, which is being acquired by an undisclosed U.S. biotech company.
Epixis CEO Charlotte Dalba said she hoped that initial human trials of the vaccine could start in 2012, provided funding was in place.
The experimental vaccine uses virus-like particles, which resemble viruses but are non-infectious because they don't contain any viral genetic material. Details of its development were published in the journal Science Translational Medicine.
In an accompanying commentary, Ranjit Ray of Saint Louis University said the work to date on mice and macaque monkeys showed significant progress, though "many questions still remain."
SOURCE: bit.ly/qX39WK Science Translational Medicine, August 3, 2011.
By Ben Hirschler
LONDON | Wed Aug 3, 2011 5:27pm EDT
LONDON (Reuters) - French scientists have developed a novel hepatitis C vaccine that may offer the first effective way to prevent an infection that can cause chronic liver disease and cancer.
There is currently no available vaccine for hepatitis C, though some companies are developing so-called "therapeutic vaccines," which are designed to help patients who are already infected.
The latest experimental shot has been tested successfully on mice and monkeys, but not humans, and has been shown to activate a broad response from immune system proteins called neutralizing antibodies.
The antibodies fought off multiple variants of the hepatitis C virus in tests, suggesting the new vaccine should be effective even after the virus mutates, the researchers reported on Wednesday.
Neutralizing antibodies play a central role in most existing vaccines against other diseases, but harnessing them in hepatitis C has previously proved elusive. Work to date on therapeutic vaccines has focused on another immune system mechanism known as T-cells.
"For a preventative vaccine, neutralizing antibodies are absolutely essential, and for a therapeutic product they would also be a big advantage," David Klatzmann, a member of the research team, told Reuters.
About 130 million to 170 million people worldwide are chronically infected with hepatitis C virus, and more than 350,000 die from hepatitis C-related liver diseases each year, according to the World Health Organization.
Unlike hepatitis A or B, most people with hepatitis C develop chronic disease because their bodies are unable to get rid of the virus. The condition is spread by exposure to infected blood.
Interferon and ribavirin-based therapy has been the mainstay of treatment, although recently Vertex and Merck have both launched promising new medicines that are tipped to become multibillion-dollar-a-year sellers.
Commercial interest in hepatitis C vaccines has been more muted. French biotech company Transgene and Austria's Intercell are both testing therapeutic versions, but the main markets for a preventative shot would be in the developing world, which is less attractive for Big Pharma.
Commercial rights to the new vaccine are held by French start-up Epixis, which is being acquired by an undisclosed U.S. biotech company.
Epixis CEO Charlotte Dalba said she hoped that initial human trials of the vaccine could start in 2012, provided funding was in place.
The experimental vaccine uses virus-like particles, which resemble viruses but are non-infectious because they don't contain any viral genetic material. Details of its development were published in the journal Science Translational Medicine.
In an accompanying commentary, Ranjit Ray of Saint Louis University said the work to date on mice and macaque monkeys showed significant progress, though "many questions still remain."
SOURCE: bit.ly/qX39WK Science Translational Medicine, August 3, 2011.
Hedge Fund Manager waives indictment in Albuferon 'Money for data' scam...
From today's Financial Times - the dirty part of Wall Street as a hedge fund portfolio manager who traded money for data from a French doctor involved in the clinical trials of HGS's Albuferon, waives indictment and plans to plead guilty.
Ex-FrontPoint manager waives indictment
By Kara Scannell in New York
Joseph “Chip” Skowron, a former hedge fund portfolio manager charged with allegedly trading on secret information he obtained from a French doctor, has agreed to waive an indictment, according to court documents, indicating an intention to plead guilty.
Mr Skowron of FrontPoint Partners was charged with securities fraud and obstruction of justice in April for allegedly trading shares of Human Genome Sciences after learning negative news about the clinical drug trial of Albuferon, a drug used in the treatment of hepatitis C.
More
On this story
* Regulator rebuffs plea on SAC Capital probes
* SEC settles over social media fundraising
* Fund manager latest to fall in inside trade push
* Senator presses regulator over SAC
* In depth Hedge funds
The doctor who served on the steering committee for the trial, Yves Benhamou, received envelopes stuffed with cash in exchange for the information, prosecutors say. He pleaded guilty in April to tipping off Mr Skowron. By trading, prosecutors allege, Mr Skowron avoided more than $30m in losses.
Prosecutors said in court documents that they would file a criminal information document following Mr Skowron’s agreement to waive an indictment, a move that is often taken when a defendant intends to plead guilty. Mr Skowron’s attorney could not be reached for comment.
The investigation, which first became known in November following the arrest of Mr Benhamou, proved too much for FrontPoint. The firm eliminated its healthcare investment team and assured investors it was not a target of the investigation. Nevertheless, investors eventually withdrew money and the fund has since wound down most of its operations. FrontPoint has not been accused of any wrongdoing.
Mr Skowron first met Mr Benhamou through his position as a consultant for Guidepoint Global, an expert network firm. Prosecutors said Mr Skowron convinced Mr Benhamou to provide him with secret information about the clinical trial.
Mr Skowron paid Mr Benhamou €5,000 in cash in a hotel room in Barcelona as a “present”, saying he was happy with their relationship, according to court filings.
According to prosecutors, Mr Skowron instructed Mr Benhamou to lie to FrontPoint’s lawyers about what they discussed during the calls after being notified that the Securities and Exchange Commission opened an investigation into the trading. Mr Skowron gave Mr Benhamou $10,000 in cash during a meeting in a hotel bar in Milan to keep quiet about the trades, prosecutors allege.
Ex-FrontPoint manager waives indictment
By Kara Scannell in New York
Joseph “Chip” Skowron, a former hedge fund portfolio manager charged with allegedly trading on secret information he obtained from a French doctor, has agreed to waive an indictment, according to court documents, indicating an intention to plead guilty.
Mr Skowron of FrontPoint Partners was charged with securities fraud and obstruction of justice in April for allegedly trading shares of Human Genome Sciences after learning negative news about the clinical drug trial of Albuferon, a drug used in the treatment of hepatitis C.
More
On this story
* Regulator rebuffs plea on SAC Capital probes
* SEC settles over social media fundraising
* Fund manager latest to fall in inside trade push
* Senator presses regulator over SAC
* In depth Hedge funds
The doctor who served on the steering committee for the trial, Yves Benhamou, received envelopes stuffed with cash in exchange for the information, prosecutors say. He pleaded guilty in April to tipping off Mr Skowron. By trading, prosecutors allege, Mr Skowron avoided more than $30m in losses.
Prosecutors said in court documents that they would file a criminal information document following Mr Skowron’s agreement to waive an indictment, a move that is often taken when a defendant intends to plead guilty. Mr Skowron’s attorney could not be reached for comment.
The investigation, which first became known in November following the arrest of Mr Benhamou, proved too much for FrontPoint. The firm eliminated its healthcare investment team and assured investors it was not a target of the investigation. Nevertheless, investors eventually withdrew money and the fund has since wound down most of its operations. FrontPoint has not been accused of any wrongdoing.
Mr Skowron first met Mr Benhamou through his position as a consultant for Guidepoint Global, an expert network firm. Prosecutors said Mr Skowron convinced Mr Benhamou to provide him with secret information about the clinical trial.
Mr Skowron paid Mr Benhamou €5,000 in cash in a hotel room in Barcelona as a “present”, saying he was happy with their relationship, according to court filings.
According to prosecutors, Mr Skowron instructed Mr Benhamou to lie to FrontPoint’s lawyers about what they discussed during the calls after being notified that the Securities and Exchange Commission opened an investigation into the trading. Mr Skowron gave Mr Benhamou $10,000 in cash during a meeting in a hotel bar in Milan to keep quiet about the trades, prosecutors allege.
Health Canada clears Boceprevir for treatment of chronic genotype 1 Hepatitis C....
From the Montreal Gazette dated August 3rd - Health Canada approves Victrelis for the treatment of chronic genotype 1 HCV. Telaprevir is still under review.
VANCOUVER — A new drug, recently approved by Health Canada, brings a cure closer for the 250,000 hepatitis C sufferers across Canada.
Boceprevir — brand name victrelis — when added to current standard therapy has been shown to have higher cure rates in studies published early this year by the New England Journal of Medicine.
A similar drug, telaprevir, is under 'priority review' at Health Canada.
"Given the prevalence of the disease, this is a significant development" said Dr. Alnoor Ramji, clinical assistant professor at the University of British Columbia. "The new medicine is part of a new generation of drugs that offer patients a greater hope for a cure."
The approval is just what Abbotsford resident Chris Robinson, 51, has been waiting for since he was diagnosed with cirrhosis caused by chronic hepatitis C infection last year.
"I asked the doctor, what this drug will do and he said, 'It will cure you'," said Robinson.
Robinson's doctors have withheld treatment to date, as the advanced nature of his condition made current treatments risky.
Unlike current treatments that work by boosting the immune system, this new type of drug works directly against the virus by inhibiting an enzyme that the virus needs in order to replicate, said Ramji — who was also involved in the clinical trials of boceprevir in Canada.
"When added to the current cocktail of drugs, the new drugs take the effectiveness rate to 67 per cent from the current rate of about 40 per cent," said Ramji.
The other advantage, he said, is that these treatments have the potential to shorten the treatment period — from 48 weeks to about 28 weeks — depending on the response of the patient, reducing the impact of serious side-effects.
Hepatitis C is a virus that is transmitted through the blood. It infects the liver, causing it to become inflamed and preventing it from working properly. It is often the cause of severe liver disease including cirrhosis and liver cancer.
Fever, fatigue, reduced appetite, stomach pain, dark urine, jaundice (yellowing of skin or eyes), nausea and vomiting, aching muscles and joints, poor concentration, anxiety and depression are some of the symptoms.
There is no vaccine against hepatitis C and it can be acquired in numerous ways, including sharing razors, toothbrushes and scissors with an infected person. Injection drug use — current or past — is the cause of approximately 60 per cent of infections in Canada.
Read more: http://www.vancouversun.com/health/Health+Canada+clears+promising+drug/5196650/story.html#ixzz1U0hMXxdL
VANCOUVER — A new drug, recently approved by Health Canada, brings a cure closer for the 250,000 hepatitis C sufferers across Canada.
Boceprevir — brand name victrelis — when added to current standard therapy has been shown to have higher cure rates in studies published early this year by the New England Journal of Medicine.
A similar drug, telaprevir, is under 'priority review' at Health Canada.
"Given the prevalence of the disease, this is a significant development" said Dr. Alnoor Ramji, clinical assistant professor at the University of British Columbia. "The new medicine is part of a new generation of drugs that offer patients a greater hope for a cure."
The approval is just what Abbotsford resident Chris Robinson, 51, has been waiting for since he was diagnosed with cirrhosis caused by chronic hepatitis C infection last year.
"I asked the doctor, what this drug will do and he said, 'It will cure you'," said Robinson.
Robinson's doctors have withheld treatment to date, as the advanced nature of his condition made current treatments risky.
Unlike current treatments that work by boosting the immune system, this new type of drug works directly against the virus by inhibiting an enzyme that the virus needs in order to replicate, said Ramji — who was also involved in the clinical trials of boceprevir in Canada.
"When added to the current cocktail of drugs, the new drugs take the effectiveness rate to 67 per cent from the current rate of about 40 per cent," said Ramji.
The other advantage, he said, is that these treatments have the potential to shorten the treatment period — from 48 weeks to about 28 weeks — depending on the response of the patient, reducing the impact of serious side-effects.
Hepatitis C is a virus that is transmitted through the blood. It infects the liver, causing it to become inflamed and preventing it from working properly. It is often the cause of severe liver disease including cirrhosis and liver cancer.
Fever, fatigue, reduced appetite, stomach pain, dark urine, jaundice (yellowing of skin or eyes), nausea and vomiting, aching muscles and joints, poor concentration, anxiety and depression are some of the symptoms.
There is no vaccine against hepatitis C and it can be acquired in numerous ways, including sharing razors, toothbrushes and scissors with an infected person. Injection drug use — current or past — is the cause of approximately 60 per cent of infections in Canada.
Read more: http://www.vancouversun.com/health/Health+Canada+clears+promising+drug/5196650/story.html#ixzz1U0hMXxdL
VANCOUVER — A new drug, recently approved by Health Canada, brings a cure closer for the 250,000 hepatitis C sufferers across Canada.
Boceprevir — brand name victrelis — when added to current standard therapy has been shown to have higher cure rates in studies published early this year by the New England Journal of Medicine.
A similar drug, telaprevir, is under 'priority review' at Health Canada.
"Given the prevalence of the disease, this is a significant development" said Dr. Alnoor Ramji, clinical assistant professor at the University of British Columbia. "The new medicine is part of a new generation of drugs that offer patients a greater hope for a cure."
The approval is just what Abbotsford resident Chris Robinson, 51, has been waiting for since he was diagnosed with cirrhosis caused by chronic hepatitis C infection last year.
"I asked the doctor, what this drug will do and he said, 'It will cure you'," said Robinson.
Robinson's doctors have withheld treatment to date, as the advanced nature of his condition made current treatments risky.
Unlike current treatments that work by boosting the immune system, this new type of drug works directly against the virus by inhibiting an enzyme that the virus needs in order to replicate, said Ramji — who was also involved in the clinical trials of boceprevir in Canada.
"When added to the current cocktail of drugs, the new drugs take the effectiveness rate to 67 per cent from the current rate of about 40 per cent," said Ramji.
The other advantage, he said, is that these treatments have the potential to shorten the treatment period — from 48 weeks to about 28 weeks — depending on the response of the patient, reducing the impact of serious side-effects.
Hepatitis C is a virus that is transmitted through the blood. It infects the liver, causing it to become inflamed and preventing it from working properly. It is often the cause of severe liver disease including cirrhosis and liver cancer.
Fever, fatigue, reduced appetite, stomach pain, dark urine, jaundice (yellowing of skin or eyes), nausea and vomiting, aching muscles and joints, poor concentration, anxiety and depression are some of the symptoms.
There is no vaccine against hepatitis C and it can be acquired in numerous ways, including sharing razors, toothbrushes and scissors with an infected person. Injection drug use — current or past — is the cause of approximately 60 per cent of infections in Canada.
Read more: http://www.vancouversun.com/health/Health+Canada+clears+promising+drug/5196650/story.html#ixzz1U0hMXxdL
VANCOUVER — A new drug, recently approved by Health Canada, brings a cure closer for the 250,000 hepatitis C sufferers across Canada.
Boceprevir — brand name victrelis — when added to current standard therapy has been shown to have higher cure rates in studies published early this year by the New England Journal of Medicine.
A similar drug, telaprevir, is under 'priority review' at Health Canada.
"Given the prevalence of the disease, this is a significant development" said Dr. Alnoor Ramji, clinical assistant professor at the University of British Columbia. "The new medicine is part of a new generation of drugs that offer patients a greater hope for a cure."
The approval is just what Abbotsford resident Chris Robinson, 51, has been waiting for since he was diagnosed with cirrhosis caused by chronic hepatitis C infection last year.
"I asked the doctor, what this drug will do and he said, 'It will cure you'," said Robinson.
Robinson's doctors have withheld treatment to date, as the advanced nature of his condition made current treatments risky.
Unlike current treatments that work by boosting the immune system, this new type of drug works directly against the virus by inhibiting an enzyme that the virus needs in order to replicate, said Ramji — who was also involved in the clinical trials of boceprevir in Canada.
"When added to the current cocktail of drugs, the new drugs take the effectiveness rate to 67 per cent from the current rate of about 40 per cent," said Ramji.
The other advantage, he said, is that these treatments have the potential to shorten the treatment period — from 48 weeks to about 28 weeks — depending on the response of the patient, reducing the impact of serious side-effects.
Hepatitis C is a virus that is transmitted through the blood. It infects the liver, causing it to become inflamed and preventing it from working properly. It is often the cause of severe liver disease including cirrhosis and liver cancer.
Fever, fatigue, reduced appetite, stomach pain, dark urine, jaundice (yellowing of skin or eyes), nausea and vomiting, aching muscles and joints, poor concentration, anxiety and depression are some of the symptoms.
There is no vaccine against hepatitis C and it can be acquired in numerous ways, including sharing razors, toothbrushes and scissors with an infected person. Injection drug use — current or past — is the cause of approximately 60 per cent of infections in Canada.
Read more: http://www.vancouversun.com/health/Health+Canada+clears+promising+drug/5196650/story.html#ixzz1U0hMXxdL
Victrelis goes live today in the UK....
MSD launches hepatitis C drug Victrelis in UK
MSD (known as Merck in the US and Canada), today launched Victrelis (boceprevir) in the UK. The drug is a new treatment for chronic hepatitis C genotype 1 in adults with compensated liver disease who have yet to undergo treatment or have failed previous therapy.
Victrelis is the first licensed treatment for hepatitis C which is direct acting, targeting the virus itself. The launch follows an accelerated assessment by the European Medicines Agency (EMA), due to its "major public-health need."
In comparison to current therapies, Victrelis works through inhibiting a key viral enzyme, affecting the virus' ability to replicate.
Victrelis is to be used in combination with the current standard treatment to tackle genotype 1 of the virus, the most prominent strand in the UK, affecting 40-50 per cent of patients.
In clinical trials of those who had previously failed treatment, the addition of Victrelis to standard therapy almost tripled the number of patients clearing the virus.
MSD (known as Merck in the US and Canada), today launched Victrelis (boceprevir) in the UK. The drug is a new treatment for chronic hepatitis C genotype 1 in adults with compensated liver disease who have yet to undergo treatment or have failed previous therapy.
Victrelis is the first licensed treatment for hepatitis C which is direct acting, targeting the virus itself. The launch follows an accelerated assessment by the European Medicines Agency (EMA), due to its "major public-health need."
In comparison to current therapies, Victrelis works through inhibiting a key viral enzyme, affecting the virus' ability to replicate.
Victrelis is to be used in combination with the current standard treatment to tackle genotype 1 of the virus, the most prominent strand in the UK, affecting 40-50 per cent of patients.
In clinical trials of those who had previously failed treatment, the addition of Victrelis to standard therapy almost tripled the number of patients clearing the virus.
Tuesday, August 2, 2011
More information on the impact of genotype 1a and 1b on resistance and response to Boceprevir...
(More info on the impact of genotype 1a vs 1b in regards to Boceprevir response and resistance from Liz Highwayman published in AIDSMAP.com. Merck researchers gathered data gathered from SPRINT-2 (Tx naive) and RESPOND-2 (prior non-responders) trials.and compared frequencies of boceprevir resistance-associated variants (mutations) among people with HCV genotype 1a and 1b. The researchers found that resistance-associated variants were more common among people with genotype 1a, consistent with the higher likelihood of treatment failure. It appears that it takes only a single mutation for wild-type HCV genotype 1a to become resistant to boceprevir, whereas two mutations are required for genotype 1b, giving a "biological rationale" for differences in response rates. )
Boceprevir response and resistance differs according to HCV genotype 1 subtype
Hepatitis C treatment
Liz Highleyman
Content provided by hivandhepatitis.com
Published: 28 July 2011
People with hepatitis C virus (HCV) genotype 1b respond better to boceprevir and are less likely to develop drug resistance than those with genotype 1a, according to study findings reported last week at the International AIDS Society Conference (IAS 2011) in Rome.
The advent of direct-acting antiviral agents has led to a paradigm shift in treatment for chronic hepatitis C. The first two drugs out of the pipeline – the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek) – are used with pegylated interferon plus ribavirin standard therapy, but all-oral combinations are currently under study. As with HIV treatment, using these new agents in suboptimal regimens can lead to resistance.
Boceprevir, which was approved by the European Commission last week, improved sustained virological response or cure rates when taken with pegylated interferon/ribavirin in the pivotal Phase 3 SPRINT-2 and RESPOND-2 trials. SPRINT-2 included 1097 previously untreated patients with HCV genotype 1 and RESPOND-2 included 403 people who did not respond or relapsed after a prior attempt at standard therapy.
It is well known that HCV genotype 1 is the most difficult to treat, but these trials also revealed differences between subtypes within this genotype. Genotype 1a is predominant in Northern Europe and North America, whilst genotype 1b is more common in Southern and Eastern Europe and Japan.
Daria Hazuda from Merck and colleagues compared frequencies of boceprevir resistance-associated variants (mutations) among people with HCV genotype 1a and 1b in SPRINT-2 and RESPOND-2.
These studies, conducted mainly in Western Europe and the US, enroled HCV mono-infected patients with compensated liver disease. Individuals co-infected with HIV or hepatitis B were excluded. A majority of patients in both studies were men; SPRINT-2 included 14% people of African descent, a group that responds poorly to interferon-based therapy.
In both trials participants received a four-week "lead-in" of pegylated interferon plus ribavirin before adding either boceprevir or placebo. Some participants continued treatment for the standard duration of 48 weeks, whilst others used response-guided therapy based on early HCV viral load reduction.
Hazuda's team collected plasma samples at baseline and again near the time of virological failure if patients did not achieve sustained virological response. The NS3/4a region of the HCV genome was sequenced and major resistance-associated variants were identified.
Among treatment-naive participants in SPRINT-2, sustained response rates were slightly but consistently higher for people with HCV genotype 1b. In the 48-week triple therapy group, rates were 73% for genotype 1b vs 62% for 1b, compared to 41% and 35%, respectively, using standard therapy alone. A similar pattern was observed in RESPOND-2, with sustained response rates of 71% for genotype 1b and 64% for 1a with triple therapy, compared to 18% and 24%, respectively, with pegylated interferon/ribavirin alone.
The researchers found that resistance-associated variants were more common among people with genotype 1a, consistent with the higher likelihood of treatment failure.
In SPRINT-2, 19% of all genotype 1a patients had these mutations compared to 10% of people with genotype 1b. In RESPOND-2 the corresponding rates were 16% and 11%, respectively. Looking only at people who did not achieve sustained response in SPRINT-2, 58% of genotype 1a patients and 48% of genotype 1b patients developed resistance mutations. In RESPOND-2, the rates were 48% and 41%, respectively.
The V36M and R155K resistance-associated variants were detected more often in people with HCV genotype 1a, whilst T54A/S, A156S, and V170A were predominant in patients with genotype 1b.
Hazuda explained that for certain positions in the genome it takes only a single mutation for wild-type HCV genotype 1a to become resistant to boceprevir, whereas two mutations are required for genotype 1b, giving a "biological rationale" for differences in response rates.
She further noted that people with poor response during the interferon lead-in phase defined as less than a 1 log drop in HCV RNA by week 4 of treatment were more likely to develop resistance mutations than those with good early response (69% vs 31%, respectively).
Boceprevir response and resistance differs according to HCV genotype 1 subtype
Hepatitis C treatment
Liz Highleyman
Content provided by hivandhepatitis.com
Published: 28 July 2011
People with hepatitis C virus (HCV) genotype 1b respond better to boceprevir and are less likely to develop drug resistance than those with genotype 1a, according to study findings reported last week at the International AIDS Society Conference (IAS 2011) in Rome.
The advent of direct-acting antiviral agents has led to a paradigm shift in treatment for chronic hepatitis C. The first two drugs out of the pipeline – the HCV protease inhibitors boceprevir (Victrelis) and telaprevir (Incivek) – are used with pegylated interferon plus ribavirin standard therapy, but all-oral combinations are currently under study. As with HIV treatment, using these new agents in suboptimal regimens can lead to resistance.
Boceprevir, which was approved by the European Commission last week, improved sustained virological response or cure rates when taken with pegylated interferon/ribavirin in the pivotal Phase 3 SPRINT-2 and RESPOND-2 trials. SPRINT-2 included 1097 previously untreated patients with HCV genotype 1 and RESPOND-2 included 403 people who did not respond or relapsed after a prior attempt at standard therapy.
It is well known that HCV genotype 1 is the most difficult to treat, but these trials also revealed differences between subtypes within this genotype. Genotype 1a is predominant in Northern Europe and North America, whilst genotype 1b is more common in Southern and Eastern Europe and Japan.
Daria Hazuda from Merck and colleagues compared frequencies of boceprevir resistance-associated variants (mutations) among people with HCV genotype 1a and 1b in SPRINT-2 and RESPOND-2.
These studies, conducted mainly in Western Europe and the US, enroled HCV mono-infected patients with compensated liver disease. Individuals co-infected with HIV or hepatitis B were excluded. A majority of patients in both studies were men; SPRINT-2 included 14% people of African descent, a group that responds poorly to interferon-based therapy.
In both trials participants received a four-week "lead-in" of pegylated interferon plus ribavirin before adding either boceprevir or placebo. Some participants continued treatment for the standard duration of 48 weeks, whilst others used response-guided therapy based on early HCV viral load reduction.
Hazuda's team collected plasma samples at baseline and again near the time of virological failure if patients did not achieve sustained virological response. The NS3/4a region of the HCV genome was sequenced and major resistance-associated variants were identified.
Among treatment-naive participants in SPRINT-2, sustained response rates were slightly but consistently higher for people with HCV genotype 1b. In the 48-week triple therapy group, rates were 73% for genotype 1b vs 62% for 1b, compared to 41% and 35%, respectively, using standard therapy alone. A similar pattern was observed in RESPOND-2, with sustained response rates of 71% for genotype 1b and 64% for 1a with triple therapy, compared to 18% and 24%, respectively, with pegylated interferon/ribavirin alone.
The researchers found that resistance-associated variants were more common among people with genotype 1a, consistent with the higher likelihood of treatment failure.
In SPRINT-2, 19% of all genotype 1a patients had these mutations compared to 10% of people with genotype 1b. In RESPOND-2 the corresponding rates were 16% and 11%, respectively. Looking only at people who did not achieve sustained response in SPRINT-2, 58% of genotype 1a patients and 48% of genotype 1b patients developed resistance mutations. In RESPOND-2, the rates were 48% and 41%, respectively.
The V36M and R155K resistance-associated variants were detected more often in people with HCV genotype 1a, whilst T54A/S, A156S, and V170A were predominant in patients with genotype 1b.
Hazuda explained that for certain positions in the genome it takes only a single mutation for wild-type HCV genotype 1a to become resistant to boceprevir, whereas two mutations are required for genotype 1b, giving a "biological rationale" for differences in response rates.
She further noted that people with poor response during the interferon lead-in phase defined as less than a 1 log drop in HCV RNA by week 4 of treatment were more likely to develop resistance mutations than those with good early response (69% vs 31%, respectively).
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