What is Behind the Headlines?
Each day the NHS Choices team selects health stories that are making headlines. These, along with the scientific articles behind the stories, are sent to Bazian, a leading provider of evidence-based healthcare information. Bazian's clinicians and scientists analyse the research and produce impartial evidence-based assessments, which are edited and published by NHS Choices.
Read more about the production process.
New hepatitis C drug treatment 'shows promise'
"A new treatment for hepatitis C 'cured' 90% of patients with the infection in 12 weeks, scientists said," BBC News reports after a new drug protocol designed to target the protein that assists the spread of the virus through the body has shown promising results.
The study the BBC reports on involved 394 people with hepatitis C who had not responded to previous standard treatment, or who had responded but later relapsed.
They were randomised to either an active five-drug combination or a matching placebo for 12 weeks. The five drugs were ABT-450, ritonavir and ombitasvir, dasabuvir and ribavirin. At the end of the 12-week treatment period, the active treatment group stopped treatment, while all people in the placebo group switched to receiving 12 weeks' active treatment.
The people in the original active treatment group were only assessed 12 weeks after they had stopped taking their treatment, at which time the majority of them (96%) did demonstrate a response.
However, because of their unusual RCT design, by this time there was no comparison group as the placebo group had just then completed the same 12-week course of treatment. In this sense, the research was essentially a cohort study that has reported the outcomes for a group of people tested with a particular treatment.
Overall, the results suggest that this drug combination may be effective for people with the hepatitis C virus who have not responded to previous treatment. But whether this is more effective or more tolerable than other standard treatment options for such people remains to be proven. Side effects remain a big issue in terms of drug treatments for hepatitis C.
Where did the story come from?
The study was carried out by researchers from Johann Wolfgang Goethe University and Hannover Medical School in Germany and other institutions in Europe, the US, Canada and Australia. It was funded by the pharmaceutical company, AbbVie.
It is unclear whether there were any conflicts of interest, as relevant information was not provided in the study.
The study was published in the peer-reviewed medical journal, the New England Journal of Medicine, on an open access basis, so the study is free to read online.
BBC News is perhaps a little premature in hailing this treatment a breakthrough considering the limitations of the study's design. A randomised controlled trial comparing this combination with standard treatment is needed first. There were also some inaccuracies in the BBC's reporting, as the participants in the study did not have liver cirrhosis, as reported.
What kind of research was this?
This was a randomised controlled trial that aimed to examine the effectiveness and safety of a combination of drugs compared with inactive placebo in people with hepatitis C infection. It is reported to be a phase 3 randomised controlled trial, though arguably the study design does not meet the standards of a phase 3 RCT as there is no comparison with another treatment.
The study involved patients who had previously been treated with the standard treatment option for hepatitis C (specifically, genotype hepatitis C 1, which is the most common type of the virus), but who had not got better with this treatment.
This treatment is the combination of pegylated interferon and ribavirin, which is licensed for the treatment of hepatitis C. Previous research has shown that up to 50% of people with hepatitis C respond to this combination (as demonstrated by the virus being no longer detected in the blood).
An additional two drugs (telaprevir and boceprevir) have also been recommended as treatment options for use in combination with peginterferon–ribavirin in people who have the type 1 hepatitis C virus. Response rates have been shown to increase to up to around three-quarters in people who receive first-line treatment with one of these triple therapy combinations.
However, response rates to triple therapy can be lower in people who have previously been treated with peginterferon–ribavirin. There are many reports of patients not responding, or responding but later relapsing.
The peginterferon–ribavirin combination and the newer drugs telaprevir and boceprevir are also associated with side effects such as anaemia. There is therefore still a need for new, more effective and better-tolerated drug treatments to be developed.
This phase 3 randomised controlled trial investigated the use of non-interferon-based combination treatment with the drugs ABT-450, ritonavir and ombitasvir (in one formulation), dasabuvir and ribavirin. This combination was compared with matching placebo for 12 weeks.
Earlier phase studies demonstrated that the majority of people with type 1 hepatitis C infection who had previously not responded to peginterferon–ribavirin did respond to this five-drug combination.
This trial therefore aimed to further investigate the safety and effectiveness of this treatment combination in people with genotype 1 hepatitis C who had previously not got better with peginterferon–ribavirin.
These drugs can also all be taken by mouth, while peginterferon has to be given by injection under the skin.
What did the research involve?
The researchers included adults with genotype 1 hepatitis C (virus RNA level more than 10,000 international units per millilitre) who did not have liver cirrhosis.
The participants had also not responded to previous dual combination treatment with peginterferon–ribavirin.
Non-response to previous treatment included those with:
initial response and later relapse (undetectable viral RNA at treatment end but detectable levels within one year)
partial response (viral RNA levels decrease by a certain amount at week 12 of treatment, but detectable again by treatment end)
no response
The researchers did not include people who had previously not responded to triple therapy, or who had HIV infection or a recent history of drug or alcohol abuse.
People were recruited across 76 sites in North America, Europe and Australia. They were randomised to receive either inactive placebos or the active drug combination for 12 weeks, which included:
the co-formulation of ABT-450/r–ombitasvir (a once-daily dose of 150mg of ABT-450, 100mg ritonavir, and 25mg of ombitasvir)
dasabuvir (250mg twice daily)
ribavirin (1000mg daily if body weight was less than 75kg or 1200mg daily if body weight was equal to or greater than 75kg
People in the placebo group received matching placebo pills for these three sets of tablets. The study was double blind, meaning that neither participants nor researchers knew which treatment was being given.
The main outcome examined was the rate of a sustained virologic response (SVR) 12 weeks after the end of the study treatment. This is a term used to describe when the person has undetectable levels of the viral RNA in their blood. SVR for hepatitis C is defined as having an RNA level of less than 25 international units per millilitre.
Other outcomes examined included normalisation of liver enzyme levels, treatment response according to whether the genotype was 1a or 1b, and relapse after treatment.
Side effects of treatment were monitored throughout treatment and up to 30 days after the last drug dose.
All analyses were by intention to treat on the basis that all people who received at least one dose of the study drug were included in the analyses, regardless of whether they completed treatment.
Of note, the research describes that after the 12-week double-blind treatment period, people in the placebo group received the active treatment regimen on an open-label basis for 12 weeks.
As the outcomes were assessed 12 weeks after treatment end, this suggests that at the time of assessment people assigned to the placebo group had been receiving the active treatment for the past 12 weeks, while those assigned to the active treatment had completed 12 weeks of active treatment 12 weeks ago. A case could therefore be made that this was more of a cohort study than a textbook RCT.
What were the basic results?
Of 562 eligible people, 395 were randomised and 394 received at least one dose of their assigned treatment and were included in the analyses.
Twelve weeks after treatment was completed, 286 of 297 people in the active treatment group (96.3%) had a sustained virologic response. Looking by specific genotype, there was little difference in SVR rates between those with hepatitis C virus type 1a (96%) and 1b (96.7%).
According to previous response to peginterferon–ribavirin, SVR rates were 95.3% among those with initial response then relapse, 100% among those with previous partial response, and 95.2% among those with previous null response. Only 7 of 293 people (2.4%) who completed treatment had a post-treatment relapse.
SVR rates for those receiving placebo are not reported. However, at the time of outcome assessment, people in the placebo group had been receiving the active treatment for the past 12 weeks.
During the 12-week double-blind treatment period, side effects were reported by 91% of the active treatment group and 83% of the placebo group. Headache was the most common side effect in both groups, occurring in just over a third of people. Itching occurred significantly more often in the active treatment group (13.8% versus 5.2% in people taking placebo).
Three people in the active regimen group (1.0%) discontinued the study drugs because of side effects. Anaemia also occurred significantly more commonly in the active treatment group, with a decrease in haemoglobin below 10g per decilitre affecting about 5%.
How did the researchers interpret the results?
The researchers concluded that, "Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response."
Conclusion
Although designed as an RCT, the study had an analysis of drug effectiveness that becomes more like a single cohort of people receiving an active treatment, with no comparison arm.
People were assigned to the five-drug combination or matching placebos for 12 weeks. During this time, the side effects in both treatment groups were monitored and these could be compared, with itching and anaemia occurring more commonly in the active treatment group.
However, the double-blind drug treatment period was completed at 12 weeks and response outcomes were then assessed 12 weeks later. Twelve weeks later, the active treatment group demonstrated high response rates, with sustained virological response present in almost all (96%) of those who had been treated.
Problematically, however, there is no comparison group for these people. At the end of the 12-week double-blind treatment period, all people in the placebo group went on to receive 12 weeks' active treatment with the five-drug combination.
This means that at the time the outcomes were assessed in the active treatment group, the placebo group had also just completed 12 weeks of active treatment. The response rates for the placebo group are not reported.
Overall, the results suggest that the oral combination of ABT-450, ritonavir and ombitasvir (in one formulation) and dasabuvir and ribavirin may have potential in the treatment of hepatitis C.
However, the safety and effectiveness of this combination now need to be compared with other standard treatment options for this group of people – including repeat treatment with the peginterferon–ribavirin combination, and triple therapy with peginterferon–ribavirin and either telaprevir and boceprevir.
Only then will we know whether this five-drug combination may one day be licensed for this condition, and for which specific groups of people.
Analysis by Bazian. Edited by NHS Choices. Follow Behind the Headlines on Twitter. Join the Healthy Evidence forum.
Links to the headlines
Hepatitis C: New drug treatment 'is a breakthrough'. BBC News, April 12 2014
Links to the science
Zeuzem S, Jacobson IM, Baykal T, et al. Retreatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin. The New England Journal of Medicine. Published online April 10 2014
Source - Behind The Headlines
This blog is all about current FDA approved drugs to treat the hepatitis C virus (HCV) with a focus on treating HCV according to genotype, using information extracted from peer-reviewed journals, liver meetings/conferences, and interactive learning activities.
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Showing posts with label ABT-450/r. Show all posts
Showing posts with label ABT-450/r. Show all posts
Friday, April 18, 2014
Monday, November 18, 2013
AbbVie- Interferon-Free, 12-wk Regimen, 96 Percent SVR12 Genotype 1 Hepatitis C Patients
Related Investment Commentary: AbbVie steps closer to FDA filing as first hep C PhIII delivers promising results
Press Release
AbbVie Releases First of Six Phase III Results from Investigational All-Oral, Interferon-Free, 12-week Regimen, Showing 96 Percent SVR12 in Genotype 1 Hepatitis C Patients New to Therapy
- Confirms results of phase II studies, with consistent virologic response and tolerability profile
- Largest all-oral, interferon-free clinical program in genotype 1 (GT1) patients to date(1)
- On track for major regulatory submissions in Q2 2014
- Worldwide, about 160 million people are chronically infected with hepatitis C(2), most with GT1
AbbVie's multinational HCV program is the largest all-oral, interferon-free clinical program in GT1 patients being conducted to date. GT1 (with subtypes 1a and 1b) is the most prevalent genotype worldwide, with a higher prevalence of 1a in the U.S. and 1b in Europe. SAPPHIRE-I is the first of six phase III trials supporting AbbVie's investigational 3D regimen for the treatment of GT1 hepatitis C patients.
"SAPPHIRE-I demonstrates that patients new to therapy with genotype 1 HCV achieved high rates of virologic response with AbbVie's interferon-free, all-oral 3D regimen plus ribavirin, and the SVR rate is consistent with results from our phase II studies," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "SAPPHIRE-I is the first of these studies to report results, and based on the progress of our clinical program to date, we are on track for major regulatory submissions in the second quarter of 2014."
AbbVie will disclose detailed SAPPHIRE-I results at future scientific congresses and in publications.
About Study M11-646 (SAPPHIRE-I)
SAPPHIRE-I is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with ABT-333 (250mg), ribavirin (weight-based), both dosed twice daily, and the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg) and dosed once daily in non-cirrhotic, GT1a and GT1b HCV-infected, treatment-naive adult patients.
The study population consisted of 631 GT1 treatment-naive patients with no evidence of liver cirrhosis with 473 patients randomized to the 3D regimen plus ribavirin for 12 weeks, and 158 patients randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the 3D regimen plus ribavirin for 12 weeks.
Following 12 weeks of treatment with AbbVie's 3D regimen plus ribavirin, 96 percent (n=455/473) of patients achieved SVR12 based on intent-to-treat analysis where patients with missing values for any reason were considered treatment failures. In the active treatment arm, patients with GT1b infection achieved 98 percent SVR12 (148/151), while patients with GT1a achieved 95 percent SVR12 (307/322).
The most commonly reported adverse events in the 3D and placebo arms, respectively, were fatigue, headache and nausea. Discontinuations due to adverse events were reported in 0.6 percent of patients receiving the 3D regimen and 0.6 percent of patients receiving placebo. The rate of virologic relapse or breakthrough was low, occurring in 1.7 percent of patients receiving the 3D regimen.
Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.
AbbVie's HCV Development Program
The clinical program supporting our 3D regimen includes more than 2,300 genotype 1 patients in greater than 25 countries around the world. The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral 3D regimen with or without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis. Results from the remaining five studies in AbbVie's phase III program will be available in the coming months, supporting regulatory submissions starting in the second quarter of 2014.
Overview of AbbVie's phase III clinical programs is as follows:
The 3D regimen consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's investigational 3D regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).
ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.
Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.
There are special safety considerations when prescribing these drugs in approved populations.
Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.
Ribavirin monotherapy is not effective for the treatment for chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, automimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score >6.
See approved product labels for more information.
About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.
Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.
Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.
[1] Comparison based on review of data from clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013
[2] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.
Press Release
AbbVie Releases First of Six Phase III Results from Investigational All-Oral, Interferon-Free, 12-week Regimen, Showing 96 Percent SVR12 in Genotype 1 Hepatitis C Patients New to Therapy
- Confirms results of phase II studies, with consistent virologic response and tolerability profile
- Largest all-oral, interferon-free clinical program in genotype 1 (GT1) patients to date(1)
- On track for major regulatory submissions in Q2 2014
- Worldwide, about 160 million people are chronically infected with hepatitis C(2), most with GT1
Nov 18, 2013
NORTH CHICAGO, Ill., Nov. 18, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) released the first phase III results for the investigational three direct-acting-antiviral (3D) regimen plus ribavirin in patients chronically infected with genotype 1 (GT1) hepatitis C virus (HCV). In the 631-patient SAPPHIRE-I study, patients new to therapy receiving 12 weeks of AbbVie's 3D regimen achieved a sustained virologic response at 12 weeks post-treatment (SVR12) of 96 percent. The majority of patients were GT1a, considered the more difficult-to-treat subtype, and the SVR12 rates of GT1a and GT1b were 95 percent and 98 percent, respectively. The rate of virologic relapse or breakthrough was low, occurring in 1.7 percent of patients receiving the 3D regimen. In addition, discontinuation rates due to adverse events were low, and of an equal percentage (0.6 percent) in both active and placebo groups.
"SAPPHIRE-I demonstrates that patients new to therapy with genotype 1 HCV achieved high rates of virologic response with AbbVie's interferon-free, all-oral 3D regimen plus ribavirin, and the SVR rate is consistent with results from our phase II studies," said Scott Brun, M.D., vice president, pharmaceutical development, AbbVie. "SAPPHIRE-I is the first of these studies to report results, and based on the progress of our clinical program to date, we are on track for major regulatory submissions in the second quarter of 2014."
AbbVie will disclose detailed SAPPHIRE-I results at future scientific congresses and in publications.
About Study M11-646 (SAPPHIRE-I)
SAPPHIRE-I is a global, multi-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 12 weeks of treatment with ABT-333 (250mg), ribavirin (weight-based), both dosed twice daily, and the fixed-dose combination of ABT-450/ritonavir (150/100mg) co-formulated with ABT-267 (25mg) and dosed once daily in non-cirrhotic, GT1a and GT1b HCV-infected, treatment-naive adult patients.
The study population consisted of 631 GT1 treatment-naive patients with no evidence of liver cirrhosis with 473 patients randomized to the 3D regimen plus ribavirin for 12 weeks, and 158 patients randomized to placebo for the initial 12 weeks. Patients initially randomized to placebo for the first 12 weeks then received open-label treatment with the 3D regimen plus ribavirin for 12 weeks.
Following 12 weeks of treatment with AbbVie's 3D regimen plus ribavirin, 96 percent (n=455/473) of patients achieved SVR12 based on intent-to-treat analysis where patients with missing values for any reason were considered treatment failures. In the active treatment arm, patients with GT1b infection achieved 98 percent SVR12 (148/151), while patients with GT1a achieved 95 percent SVR12 (307/322).
The most commonly reported adverse events in the 3D and placebo arms, respectively, were fatigue, headache and nausea. Discontinuations due to adverse events were reported in 0.6 percent of patients receiving the 3D regimen and 0.6 percent of patients receiving placebo. The rate of virologic relapse or breakthrough was low, occurring in 1.7 percent of patients receiving the 3D regimen.
Additional information about AbbVie's phase III studies can be found on www.clinicaltrials.gov.
AbbVie's HCV Development Program
The clinical program supporting our 3D regimen includes more than 2,300 genotype 1 patients in greater than 25 countries around the world. The AbbVie HCV clinical development program is intended to advance scientific knowledge and clinical care by investigating an interferon-free, all-oral 3D regimen with or without ribavirin with the goal of producing high SVR rates in as many patients as possible, including those that typically do not respond well to treatment, such as previous non-responders to interferon-based therapy or patients with advanced liver fibrosis or cirrhosis. Results from the remaining five studies in AbbVie's phase III program will be available in the coming months, supporting regulatory submissions starting in the second quarter of 2014.
Overview of AbbVie's phase III clinical programs is as follows:
Study
|
Patients (N)
|
Treatment Regimen
|
Treatment Duration
|
SAPPHIRE-I
|
GT1, treatment-naive
(631)
|
• ABT-450/rb +ABT-267c
• ABT-333
• Ribavirin
|
12 weeks
|
• Placebo
|
12 weeks, then active treatment for 12 weeks
| ||
SAPPHIRE-II
|
GT1, treatment-experienced
(400a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• Placebo
|
12 weeks, then active treatment for 12 weeks
| ||
PEARL-II
|
GT1b, treatment-experienced
(210 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
|
12 weeks
| ||
PEARL-III
|
GT1b, treatment-naive
(400 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
• Placebo
|
12 weeks
| ||
PEARL-IV
|
GT1a, treatment-naive
(300 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
• Placebo
|
12 weeks
| ||
TURQUOISE-II
|
GT1, treatment-naive and treatment-experienced (with compensated cirrhosis)
(380 a)
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
12 weeks
|
• ABT-450/r +ABT-267
• ABT-333
• Ribavirin
|
24 weeks
|
a projected study population
|
b ABT-450/ritonavir
|
c ABT-267 is co-formulated with ABT-450/r, administered as two pills once daily
|
The 3D regimen consists of boosted protease inhibitor ABT-450/ritonavir, NS5A inhibitor ABT-267, and non-nucleoside polymerase inhibitor ABT-333. The combination of three different mechanisms of action interrupts the HCV replication process with the goal of optimizing SVR rates across different patient populations. In May of 2013, AbbVie's investigational 3D regimen with and without ribavirin for HCV GT1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA).
ABT-450 was discovered during the ongoing collaboration between AbbVie and Enanta Pharmaceuticals (NASDAQ: ENTA) for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.
Safety Information for Ribavirin and Ritonavir
Ribavirin and ritonavir are not approved for the investigational use discussed above, and no conclusions can or should be drawn regarding the safety or efficacy of these products for this use.
There are special safety considerations when prescribing these drugs in approved populations.
Ritonavir must not be used with certain medications due to significant drug-drug interactions and in patients with known hypersensitivity to ritonavir or any of its excipients.
Ribavirin monotherapy is not effective for the treatment for chronic hepatitis C virus and must not be used alone for this use. Ribavirin causes significant teratogenic effects and must not be used in women who are pregnant or breast-feeding and in men whose female partners are pregnant. Ribavirin must not be used in patients with a history of severe pre-existing cardiac disease, severe hepatic dysfunction or decompensated cirrhosis of the liver, automimmune hepatitis, hemoglobinopathies, or in combination with peginterferon alfa-2a in HIV/HCV co-infected patients with cirrhosis and Child-Pugh score >6.
See approved product labels for more information.
About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. The company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com. Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.
Forward-Looking Statements
Some statements in this news release may be forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995. The words "believe," "expect," "anticipate," "project" and similar expressions, among others, generally identify forward-looking statements. AbbVie cautions that these forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those indicated in the forward-looking statements. Such risks and uncertainties include, but are not limited to, challenges to intellectual property, competition from other products, difficulties inherent in the research and development process, adverse litigation or government action, and changes to laws and regulations applicable to our industry.
Additional information about the economic, competitive, governmental, technological and other factors that may affect AbbVie's operations is set forth in Item 1A, "Risk Factors," in AbbVie's 2012 Annual Report on Form 10-K/A, which has been filed with the Securities and Exchange Commission. AbbVie undertakes no obligation to release publicly any revisions to forward-looking statements as a result of subsequent events or developments, except as required by law.
[1] Comparison based on review of data from clinicaltrials.gov for phase 3a programs of Gilead, BMS and BI as of November 15, 2013
[2] Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15.
SOURCE AbbVie
For further information: Media, Elizabeth Hoff, +1 (847) 935-4236, elizabeth.hoff@abbvie.com, or Javier Boix, +1 (847) 937-6113, javier.boix@abbvie.com; or Investor Relations, Elizabeth Shea, +1 (847) 935-2211, elizabeth.shea@abbvie.com
Sunday, November 3, 2013
AASLD-New Data from from AbbVie's Study, ABT-450 Containing Regimen
Related:
AbbVie’s two-drug, interferon-free combination cures genotype 1b hepatitis C infection in 95%
AbbVie is already testing ABT-450, an HCV protease inhibitor boosted by ritonavir, and ABT-267, an Ns5A inhibitor, in several phase III studies in combination with a third drug, the non-nucleoside polymerase inhibitor ABT-333. These trials will begin to report results by the end of 2013, and it is likely that AbbVie will submit a licensing application in early 2014 for this three-drug, interferon-free combination in order to achieve marketing approval in the second half of 2014.....
New Data from from AbbVie's Study, ABT-450 Containing Regimen
WATERTOWN, Mass.--(BUSINESS WIRE)--
Enanta Pharmaceuticals, Inc., (NASDAQ: ENTA a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, today announced that additional data from AbbVie's M13-393 study, referred to as PEARL-I, will be presented in an oral presentation at 5:15 p.m. ET today at The Liver Meeting, the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C.
In PEARL-I, SVR12 rates of 95% (40/42) in hepatitis C (HCV) GT-1b treatment-naïve patients and 90% (36/40) among prior null responders will be presented in this intent-to-treat analysis. Two patients in the treatment-naive arm did not achieve SVR12 due to loss to follow up. In the null responder arm, one patient experienced breakthrough and three patients relapsed.
PEARL-I is a phase-2b, interferon-free, 320 patient study being conducted by AbbVie to evaluate the once-daily, two-DAA regimen consisting of ABT-450/r (protease inhibitor plus ritonavir) + ABT-267 (AbbVie's NS5A inhibitor) in HCV treatment-naïve patients and treatment-experience patients. GT-1b treatment arms are ribavirin-free and also include cirrhotic patients while GT-4 arms explore treatment with and without ribavirin.
“We are very encouraged by the strong SVR12 rates from this simplified 2-DAA, once-daily regimen that includes our lead HCV protease inhibitor, ABT-450,” commented Jay R. Luly, Ph.D., President and Chief Executive Officer. “We look forward to data from Phase 3 studies of three-DAA regimens containing ABT-450 being reported in the coming months.”
Protease Inhibitor Collaboration with AbbVie (formerly the research-based pharmaceutical business of Abbott Laboratories)
In December 2006, Enanta and Abbott announced a worldwide agreement to collaborate on the discovery, development and commercialization of HCV NS3 and NS3/4A protease inhibitors and HCV protease inhibitor-containing drug combinations. ABT-450 is a protease inhibitor identified as a lead compound through the collaboration. Under the agreement, AbbVie is responsible for all development and commercialization activities for ABT-450. Enanta received $57 million in connection with signing the collaboration agreement, has received $55 million in subsequent clinical milestone payments, and is eligible to receive an additional $195 million in payments for regulatory milestones, as well as double-digit royalties worldwide on any revenue allocable to the collaboration's protease inhibitors. Also, for any additional collaborative HCV protease inhibitor product candidate developed under the agreement, Enanta holds an option to modify the U.S. portion of it rights to receive milestone payments and worldwide royalties. With this option, Enanta can fund 40 percent of U.S. development costs and U.S. commercialization efforts (sales and promotion costs) for the additional protease inhibitor in exchange for 40 percent of any U.S. profits ultimately achieved after regulatory approval instead of receiving payments for U.S. commercial regulatory approval milestones and royalties on U.S. sales of that protease inhibitor.
About Enanta
Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs in the infectious disease field. Enanta is discovering and developing novel inhibitors designed for use against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes – protease (partnered with AbbVie), NS5A (partnered with Novartis) and nucleotide polymerase – as well as a host-targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, Enanta has created a new class of antibiotics, called Bicyclolides, for the treatment of multi-drug resistant bacteria, with a focus on developing an intravenous and oral treatment for hospital and community MRSA (methicillin-resistant Staphylococcus aureus) infections.
Forward Looking Statements Disclaimer
This press release contains forward-looking statements, including with respect to clinical data, plans for announcing additional data, and the planned clinical development of ABT-450. Statements that are not historical facts are based on our management's current expectations, estimates, forecasts and projections about our business and the industry in which we operate and our management's beliefs and assumptions. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors that may affect actual results include final results of ongoing clinical trials, the development and marketing efforts of AbbVie (our collaborator on ABT-450), regulatory actions affecting clinical development of ABT-450 and clinical development of competitive product candidates. Enanta cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Enanta undertakes no obligation to update or revise these statements, except as may be required by law.
Source
AbbVie’s two-drug, interferon-free combination cures genotype 1b hepatitis C infection in 95%
AbbVie is already testing ABT-450, an HCV protease inhibitor boosted by ritonavir, and ABT-267, an Ns5A inhibitor, in several phase III studies in combination with a third drug, the non-nucleoside polymerase inhibitor ABT-333. These trials will begin to report results by the end of 2013, and it is likely that AbbVie will submit a licensing application in early 2014 for this three-drug, interferon-free combination in order to achieve marketing approval in the second half of 2014.....
New Data from from AbbVie's Study, ABT-450 Containing Regimen
WATERTOWN, Mass.--(BUSINESS WIRE)--
Enanta Pharmaceuticals, Inc., (NASDAQ: ENTA a research and development-focused biotechnology company dedicated to creating small molecule drugs in the infectious disease field, today announced that additional data from AbbVie's M13-393 study, referred to as PEARL-I, will be presented in an oral presentation at 5:15 p.m. ET today at The Liver Meeting, the 64th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C.
In PEARL-I, SVR12 rates of 95% (40/42) in hepatitis C (HCV) GT-1b treatment-naïve patients and 90% (36/40) among prior null responders will be presented in this intent-to-treat analysis. Two patients in the treatment-naive arm did not achieve SVR12 due to loss to follow up. In the null responder arm, one patient experienced breakthrough and three patients relapsed.
PEARL-I is a phase-2b, interferon-free, 320 patient study being conducted by AbbVie to evaluate the once-daily, two-DAA regimen consisting of ABT-450/r (protease inhibitor plus ritonavir) + ABT-267 (AbbVie's NS5A inhibitor) in HCV treatment-naïve patients and treatment-experience patients. GT-1b treatment arms are ribavirin-free and also include cirrhotic patients while GT-4 arms explore treatment with and without ribavirin.
“We are very encouraged by the strong SVR12 rates from this simplified 2-DAA, once-daily regimen that includes our lead HCV protease inhibitor, ABT-450,” commented Jay R. Luly, Ph.D., President and Chief Executive Officer. “We look forward to data from Phase 3 studies of three-DAA regimens containing ABT-450 being reported in the coming months.”
Protease Inhibitor Collaboration with AbbVie (formerly the research-based pharmaceutical business of Abbott Laboratories)
In December 2006, Enanta and Abbott announced a worldwide agreement to collaborate on the discovery, development and commercialization of HCV NS3 and NS3/4A protease inhibitors and HCV protease inhibitor-containing drug combinations. ABT-450 is a protease inhibitor identified as a lead compound through the collaboration. Under the agreement, AbbVie is responsible for all development and commercialization activities for ABT-450. Enanta received $57 million in connection with signing the collaboration agreement, has received $55 million in subsequent clinical milestone payments, and is eligible to receive an additional $195 million in payments for regulatory milestones, as well as double-digit royalties worldwide on any revenue allocable to the collaboration's protease inhibitors. Also, for any additional collaborative HCV protease inhibitor product candidate developed under the agreement, Enanta holds an option to modify the U.S. portion of it rights to receive milestone payments and worldwide royalties. With this option, Enanta can fund 40 percent of U.S. development costs and U.S. commercialization efforts (sales and promotion costs) for the additional protease inhibitor in exchange for 40 percent of any U.S. profits ultimately achieved after regulatory approval instead of receiving payments for U.S. commercial regulatory approval milestones and royalties on U.S. sales of that protease inhibitor.
About Enanta
Enanta Pharmaceuticals is a research and development-focused biotechnology company that uses its robust chemistry-driven approach and drug discovery capabilities to create small molecule drugs in the infectious disease field. Enanta is discovering and developing novel inhibitors designed for use against the hepatitis C virus (HCV). These inhibitors include members of the direct acting antiviral (DAA) inhibitor classes – protease (partnered with AbbVie), NS5A (partnered with Novartis) and nucleotide polymerase – as well as a host-targeted antiviral (HTA) inhibitor class targeted against cyclophilin. Additionally, Enanta has created a new class of antibiotics, called Bicyclolides, for the treatment of multi-drug resistant bacteria, with a focus on developing an intravenous and oral treatment for hospital and community MRSA (methicillin-resistant Staphylococcus aureus) infections.
Forward Looking Statements Disclaimer
This press release contains forward-looking statements, including with respect to clinical data, plans for announcing additional data, and the planned clinical development of ABT-450. Statements that are not historical facts are based on our management's current expectations, estimates, forecasts and projections about our business and the industry in which we operate and our management's beliefs and assumptions. The statements contained in this release are not guarantees of future performance and involve certain risks, uncertainties and assumptions, which are difficult to predict. Therefore, actual outcomes and results may differ materially from what is expressed in such forward-looking statements. Important factors that may affect actual results include final results of ongoing clinical trials, the development and marketing efforts of AbbVie (our collaborator on ABT-450), regulatory actions affecting clinical development of ABT-450 and clinical development of competitive product candidates. Enanta cautions investors not to place undue reliance on the forward-looking statements contained in this release. These statements speak only as of the date of this release, and Enanta undertakes no obligation to update or revise these statements, except as may be required by law.
Source
Tuesday, October 1, 2013
AASLD- AbbVie To Present Data From Phase II Hepatitis C Program
AbbVie To Present Investigational Data From Phase II Hepatitis C Program At The Liver Meeting
PHASE III TOP-LINE RESULTS EXPECTED BEGINNING LATER IN 2013
NORTH CHICAGO, Ill., Oct. 1, 2013 /PRNewswire/ -- AbbVie (NYSE: ABBV) announced that new data from its phase II hepatitis C clinical development program will be presented at The Liver Meeting, the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) in Washington, D.C., November 1-5, 2013. In total, eight abstracts will be presented, four of which include additional analyses from the phase IIb AVIATOR study. The data examine sustained virologic response (SVR) concordance, patient adherence to the regimen, patient reported outcomes and the impact of ribavirin dose reduction.
The Liver Meeting will precede AbbVie's reporting of initial results from the pivotal phase III clinical trials of the safety and efficacy of AbbVie's investigational triple direct-acting antiviral (DAA) regimen for the treatment of hepatitis C. Reporting of those results is expected to begin later this year.
"At AbbVie, we are committed to researching new therapies that maximize sustained virologic response with the hope of providing much needed new options for people with hepatitis C," said Barry Bernstein, M.D., vice president, infectious disease development, AbbVie. "We are very encouraged as we await top-line results from our phase III program, which we will share later this year."
Additionally, the oral presentation at AASLD will provide results from the PEARL-I study evaluating an interferon- and ribavirin-free, two-DAA investigational regimen in genotype 1b treatment-naïve patients and prior null responders. AbbVie is also investigating drug combinations for additional genotypes and next generations of DAAs as part of their ongoing commitment to the HCV community.
A brief summary of AbbVie's abstract titles is presented below.
About AbbVie's HCV Development Program
The AbbVie HCV clinical development program is intended to advance scientific knowledge by investigating an interferon-free, all-oral DAA regimen with the goal of producing high SVR rates in as many patients as possible, including those typically most difficult to cure. The large, multinational HCV program includes more than 2,200 patients from 30 countries.
AbbVie's hepatitis C portfolio includes investigational medicines with three different mechanisms of action targeting areas of the viral replication process including boosted protease inhibitor (ABT-450), polymerase (ABT-333) inhibitor and NS5A (ABT-267) inhibitor, currently being studied in clinical trials. ABT-450/r is co-formulated with ABT-267.
Details of AbbVie's phase III clinical programs are as follows:
Study Patients (n) Treatment Regimen Treatment Duration ------------ --------------------- --------------------- ------------------ SAPPHIRE I GT1, -- ABT450/r +ABT267** 12 weeks treatment-naïve -- ABT333 (600*) -- Ribavirin ------------ --------------------- --------------------- ------------------ SAPPHIRE II GT1, -- ABT450/r +ABT267** 12 weeks treatment-experienced -- ABT333 (400*) -- Ribavirin ------------ --------------------- --------------------- ------------------ PEARL II GT1b, -- ABT450/r +ABT267** 12 weeks treatment-experienced -- ABT333 (210*) -- Ribavirin ------------ --------------------- --------------------- ------------------ --ABT450/r +ABT267** 12 weeks ABT333 ------------ --------------------- --------------------- ------------------ PEARL III GT1b, -- ABT450/r +ABT267** 12 weeks treatment-naïve -- ABT333 (400*) -- Ribavirin ------------ --------------------- --------------------- ------------------ -- ABT450/r +ABT267** 12 weeks -- ABT333 ------------ --------------------- --------------------- ------------------ PEARL IV GT1a, treatment-naive -- ABT450/r +ABT267** 12 weeks (300*) -- ABT333 -- Ribavirin ------------ --------------------- --------------------- ------------------ -- ABT450/r +ABT267** 12 weeks -- ABT333 ------------ --------------------- --------------------- ------------------ TURQUOISE II GT1, -- ABT450/r +ABT267** 12 weeks treatment-naïve -- ABT333 and -- Ribavirin treatment-experienced (with compensated cirrhosis) (300*) ------------ --------------------- --------------------- ------------------ -- ABT450/r +ABT267** 24 weeks -- ABT333 -- Ribavirin ------------ --------------------- --------------------- ------------------*projected study population
**ABT-267 is co-formulated with ABT-450/r
In May of 2013, AbbVie's investigational DAA regimen with and without ribavirin for HCV genotype 1 was designated as a Breakthrough Therapy by the U.S. Food and Drug Administration (FDA). This designation is intended to help expedite the development of drugs for serious or life-threatening conditions and is based in part on preliminary clinical evidence demonstrating a drug or regimen may have substantial improvement on at least one clinically significant endpoint compared to available therapy.
AbbVie Hepatitis C Data at AASLD 2013
-- Trends in Liver-Related Healthcare Resource Utilization for HCV-Infected Individuals in the US: 2002-2010Poster #367November 2nd, 2:00PM ET; Poster HallThis study analyzed years 2002-2010 of the National Inpatient Sample (NIS) data set of hospital admissions from the Healthcare Cost and Utilization Project (HCUP) to determine the number of adult (age 20+ years) liver-related hospital admissions occurring in HCV-infected patients (identified by ICD-9 codes). -- Interferon- and Ribavirin-free Regimen of ABT-450/r + ABT-267 in HCV Genotype 1b-infected Treatment-Naïve Patients and Prior Null RespondersOral Presentation: Parallel Session 75November 3rd, 5:15PM ET; Hall EThis oral presentation includes data from the phase IIb PEARL-I study, which examines an interferon-free, ribavirin-free investigational regimen of ABT-450/r plus ABT-267 in 82 patients with HCV genotype 1b. -- Low Relapse Rate Leads to High Concordance of SVR4 and SVR12 with SVR24 After Treatment with ABT-450/r, ABT-267, ABT-333 + Ribavirin in Patients with Chronic HCV Genotype 1 Infection in the AVIATOR StudyPoster #1089November 3rd, 8:00AM ET; Poster HallThis study evaluated the concordance of SVR24 with rapid virologic response (RVR), SVR4 and SVR12 in treatment groups from the phase IIb AVIATOR study in 247 patients. -- High Medication Adherence in HCV-Infected Patients Taking a Triple-DAA Regimen for 12 WeeksPoster #1096November 3rd, 8:00AM ET; Poster HallThis study presents medication adherence data based on electronic compilation of drug dosing history among 327 patients receiving the investigational triple-DAA regimen plus ribavirin for 8, 12 or 24 weeks. -- Health-Related Quality of Life (HRQoL), Health State, Function and Wellbeing of Chronic HCV Patients Treated with Interferon-Free, Oral DAA Regimens: Patient Reported Outcome (PRO) Results from the AVIATOR StudyPoster #1113November 3rd, 8:00AM ET; Poster HallThis intent-to-treat analysis from the phase IIb AVIATOR study includes patient reported outcomes (PRO) in patients receiving 12-week, ribavirin-containing investigational triple-DAA regimen. -- Safety of Ribavirin-containing Regimens of ABT-450/r, ABT-333, and ABT-267 for the Treatment of HCV Genotype 1 Infection and Efficacy in Subjects with Ribavirin Dose ReductionsPoster #1118November 3rd, 8:00AM ET; Poster HallThis study examined the safety of a ribavirin-containing, investigational triple-DAA, interferon-free regimen and the effects of ribavirin dose reductions on treatment response. -- HCV RNA "Target Detected" after "Target Not Detected" During IFN-Free Treatment: Time to Worry or Not?Poster #1125November 3rd, 8:00AM ET; Poster HallThis study examined the frequency of TDANs (Target Detected After Not Detected) and the likelihood of subsequent virologic failure in subjects from the phase IIb AVIATOR study treated with ABT- 450/r plus ABT-267 plus ABT-333 plus ribavirin for 12 or 24 weeks in treatment naïve and null responders. -- Adherence to Interferon-containing Therapy Among Veteran Affairs Hepatitis C PatientsPoster #1909November 5th, 8:00AM ET; Poster HallData from the United States Veterans Health Administration (VHA) Medical SAS Dataset (years 2008 to 2011) were used in this analysis.
The list of accepted abstracts for The Liver Meeting can be accessed on www.aasld.org .
ABT-450 was discovered during the course of the ongoing collaboration between AbbVie and Enanta Pharmaceuticals for HCV protease inhibitors and regimens that include protease inhibitors. ABT-450 is being developed by AbbVie for use in combination with AbbVie's other investigational medicines for the treatment of HCV.
About the Hepatitis C Virus
Across the world, about 160 million people are chronically infected with hepatitis C.[1] Hepatitis C is an inflammation of the liver caused by an infection with the hepatitis C virus (HCV).[2] HCV is transmitted when an infected person's blood enters the bloodstream of another person.[3]
For the hepatitis C virus, there are six major HCV genotypes (GT1-6).([4]) Presently, there is no vaccine for the hepatitis C virus (HCV) infection.(3) Decision to treat is dependent on a number of factors such as the amount of liver damage present, other conditions the patient may have, amount of virus in the body, and viral genotype.(4) If treatment is needed, a hepatitis C infection is typically treated with a combination of antivirals.(3)
About AbbVie
AbbVie is a global, research-based biopharmaceutical company formed in 2013 following separation from Abbott. With its 125-year history, the company's mission is to use its expertise, dedicated people and unique approach to innovation to develop and market advanced therapies that address some of the world's most complex and serious diseases. In 2013, AbbVie employs approximately 21,000 people worldwide and markets medicines in more than 170 countries. For further information on the company and its people, portfolio and commitments, please visit www.abbvie.com.
Follow @abbvie on Twitter or view careers on our Facebook or LinkedIn page.
1. Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect. 2011; 17(2):107-15. 2. World Health Organization. Global Alert and Response (GAR): Hepatitis C. 2003. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo2003/en/index1.html. Accessed April 9, 2013. 3. World Health Organization. Hepatitis C Fact Sheet 2012. http://www.who.int/mediacentre/factsheets/fs164/en/ Accessed April 9, 2013. 4. European Association for the Study of the Liver. Clinical Practice Guidelines: Management of hepatitis C virus infection. Journal of Hepatology. 2011; 55: 245--264.
OURCE AbbVie Inc.
/CONTACT: Media: Elizabeth Hoff, +1 (847) 935-4236; Javier Boix, +1 (847) 937-6113; Or Investor Relations: Elizabeth Shea, +1 (847) 935-2211
/Web site: http://www.abbvie.com
Friday, July 12, 2013
Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives
Direct-Acting Antivirals for the Treatment of Chronic Hepatitis C: Open Issues and Future Perspectives
The Scientific World Journal
Volume 2013 (2013), Article ID 704912, 9 pages
Full Text - http://dx.doi.org/10.1155/2013/704912
Hee Bok Chae, Seon Mee Park, and Sei Jin Youn
Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 1 Sunwhan-ro, Heungdok-gu, Cheongju 361-711, Republic of Korea
Received 30 March 2013; Accepted 6 May 2013
Academic Editors: Q. Z. Dong, Y. Hiasa, P. Loyer, and S.-N. Lu
In May 2011, the U.S. Food and Drug Administration (FDA) approved TVR and BOC for use in combination therapies with PegIFN-α and RBV for adult patients chronically infected with HCV genotype 1. The drugs are used to treat patients with compensated liver cirrhosis, who are treatment-naïve or who have been previously treated with IFN-based regimens [3, 4]. Both TVR and BOC inhibit the viral NS3/4A serine protease, which is essential for replication [5, 6].
2.1. Telaprevir (TVR)
Three phase III clinical trials have been conducted to evaluate the efficacy of TVR when administered to treatment-naïve chronic HCV (genotype 1) patients in combination with PegIFN-α-2a and RBV [7, 8]. In the ADVANCE trial, patients received TVR together with PegIFN-α and RBV (PR) for either 8 (T8PR) or 12 (T12PR) weeks, followed by PegIFN-α or RBV (PR) alone in a response-guided therapy [7]. Extended rapid virological response (eRVR) was defined as undetectable HCV RNA levels at weeks 4 and 12. The patients who did not achieve an eRVR received PegIFN-α plus RBV for a total of 48 weeks. The overall SVR rates for patients in the T8PR and T12PR groups were 69% and 75%, respectively. The SVR rate for the control group with only PR was 44% [7].
The ILLUMINATE, another TVR trial, focused on defining the utility of response-guided therapy (RGT) in patients that did achieve an eRVR. All patients received an initial 12-week course of TVR-based triple therapy, followed by treatment with PegIFN-α plus RBV [8]. Patients who achieved an eRVR at week 20 were randomized to receive either an additional 3- or 28-week course of PegIFN-α plus RBV. The overall SVR rate for all patients was 72%. The SVR rates for those patients (65%) who achieved an eRVR and received either an additional 3- or 28-week course of PegIFN-α plus RBV were 92% and 88%, respectively.
The REALIZE, the third trial of TVR, was conducted for patients who experienced treatment failure after SOC therapy [9]. The clinical trial had three arms. Patients in the first arm received T12PR triple therapy for 12 weeks, followed by a placebo plus PR for 4 weeks and then PR alone for 32 weeks. The patients in the second arm received placebo plus PR (lead-in phase) for the first 4 weeks, followed by TVR-based triple therapy for 12 weeks and then PR alone for 32 weeks (48 weeks in total). The patients in the third arm received PR alone for 48 weeks (control group). The overall SVR rates for the three groups were 64%, 66%, and 17%, respectively. The best response rate was observed for those patients in each group that had previously relapsed after PR therapy (83%, 88%, and 24%, resp.) [9].
In summary, the triple regimen including TVR showed good response in genotype 1 patients. The SVR rate can be maximized using a response-guided paradigm. The triple regimen was also effective in treatment-failure patients, especially who relapsed after PR therapy.
2.2. Boceprevir
Let us look at two important phase III clinical trials on BOC. The first one, SPRINT-2, evaluated the efficacy of BOC in two cohorts of treatment-naïve patients [10]. All patients were first treated with a lead-in therapy comprising PegIFN-α-2b plus weight-based RBV for a period of 4 weeks, followed by one of three regimens. After the lead-in, patients were assigned to one of three groups. (1) Group 1, PegIFN-α-2b, RBV, and placebo for an additional 44 weeks. (2) Group 2, BOC, PegIFN-α-2b, and RBV for an additional 24 weeks, followed by 20 more weeks of PegIFN-α-2b if HCV RNA was detectable at weeks 8 and 24. (3) Group 3, BOC, PegIFN-α-2b, and RBV for an additional 44 weeks, that is, SOC therapy (Figure 2) [11]. The overall SVR rates were higher in the BOC-treated arms (63% and 66%) than in the SOC arm (38%), but differed according to race. In black patients, the SVR rates were 42% in the RGT arm, 53% in the fixed duration arm, and 23% in the SOC arm.
The RESPOND-2 trial was a phase III clinical trial [12]. The subjects were prior partial responders or relapsers with PegIFN-α-2b and RBV. Null responders were not studied in this trial. (1) Group 1, PegIFN-α-2b, RBV, and placebo for an additional 44 weeks. (2) Group 2, BOC, PegIFN-α-2b, and RBV for an additional 32 weeks, followed by 12 more weeks of PegIFN-α-2b and RBV if HCV RNA was detectable at week 8, but undetectable at week 12. (3) Group 3, BOC, PegIFN-α-2b, and RBV for an additional 44 weeks. Therapy was discontinued in patients who were HCV RNA positive at week 12 (Figure 2) [11]. The overall SVR rates at week 24 were 21%, 59%, and 66%, respectively in Group 1, Group 2 (RGT), and Group 3 (48 weeks). These triple therapy appear to yield even higher rates of SVR, 29, 69, and 75% in prior relapsers than in partial responders (7%, 40%, and 50%).
2.3. Vaniprevir (MK-7009)
Vaniprevir is a macrocyclic hepatitis C virus nonstructural protein 3/4A protease inhibitor. Treatment-naïve patients with HCV genotype 1 infection were randomized to receive open-label PegIFN and RBV in combination with blinded placebo or vaniprevir (300 mg bid, 600 mg bid, 600 mg qd, and 800 mg qd) for 28 days, and then open-label PegIFN and RBV for an additional 44 weeks. Across all doses, vaniprevir was associated with HCV RNA levels approximately 3 log10 IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%–83.3% versus 5.6%; for all comparisons). Vomiting appeared to be more common at higher vaniprevir doses (40% in 600 mg bid group) [13].
2.4. Preliminary Data from Patients with Other Genotypes Treated with DAAs
2.4.1. HCV Genotype 2
The SVR rate for patients infected with HCV genotype 2 and treated with SOC is almost 80%. There is no space for DAAs to show any increase of treatment effect because it is enough high. DAAs may be less effective in this patient group than in patients infected with HCV genotype 1. TVR, the first agent to directly target viral replication, is effective against HCV-2 but not against HCV-3 (see below). Foster et al. evaluated combined treatment with TVR plus PegIFN-α-2a and RBV in five patients infected with HCV-2 and compared the results with those obtained after treating nine patients with TVR alone or treating nine patients with PR (control group). Triple combination therapy yielded an SVR rate of 100%, which is remarkable considering the 89% rate observed in patients receiving standard PR [26]. Other NS3/4A protease inhibitors, nucleoside and non-nucleoside reverse replicase inhibitors, and NS5A inhibitors have antiviral activity against HCV-2. One of the most promising drugs is a nucleotide analogue polymerase inhibitor called PSI-7977 [27]. An open-label study (the PROTON study) evaluated the efficacy of PSI-7977 in 15 patients infected with HCV-2, in 10 patients infected with HCV-3, and in a larger group of patients with HCV-1 infection [28]. That study reported an RVR of 96% after the triple combination of 400 mg of PSI-7977 plus PR. Twenty-four HCV-2 and HCV-3 patients who completed the 12 weeks of treatment achieved SVR (96%).
2.4.2. HCV Genotype 3
The SVR rate for patients infected with HCV genotype 3 and treated with SOC is almost 80% [29]. TVR and BOC have revolutionized the treatment of genotype 1 HCV. Indeed, both have recently been recommended for use in combination with standard PR regimen for the treatment of patients chronically infected with HCV genotype 1. However, both BOC and TVR are ineffective against HCV-3.
2.5. Future Therapeutic Options
Two available DAAs, TVR and BOC, have several limitations. The role of these drugs is a supplement to PegIFN. These two drugs can cause severe side effects, for example, anemia, rash, and hyperbilirubinemia. Lastly, their dosing schedule is three times a day. The therapeutic drugs that are being developed for future use try to resolve these limitations of currently available DAAs. These new drugs fall into three categories: second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors.
2.5.1. Second-Wave Protease Inhibitors
Second-wave protease inhibitors offer several advantages over currently available drugs. In the near future, improved pharmacokinetics will allow a once-a-day dosing schedule, which means that the side-effect profiles should be more tolerable. Second-wave protease inhibitors have similar genotype coverage and similar resistance profiles to those of TVR and BOC and will replace the first-generation protease inhibitors currently used for PR combination therapy, thereby becoming the initial partners in the first generation of “all-oral regimens.”
Simeprevir (TMC435) is an NS3/4A protease inhibitor that is taken orally once per day; the drug is currently undergoing phase III clinical trials for the treatment of HCV infection [30]. The PILLAR study (a phase IIb trial) was designed to test the efficacy of simeprevir when used in combination with PR for either 24 or 48 weeks. An SVR was achieved in 68–76% of patients treated with this triple therapy regimen, and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy. The result of subgroup analysis was very high SVR (93–96%) [14]. Adverse effects were similar to those observed after SOC therapy. The lowest rate of relapse (8%) was found in the study arm receiving TMC 435 (150 mg/day) plus PR for 24 weeks.
The ASPIRE trial was a phase IIb trial for genotype 1 patients who had failed previous treatment with PR therapy. All patients received PR for 48 weeks. The best results were observed in the group treated with triple therapy with simeprevir 150 mg (SVR) plus PR in comparison with placebo plus PR, which achieved an SVR of 85% versus 37% in prior relapsers, 75% versus 9% in partial responders, and 51% versus 19% in prior nonresponders [15].
Faldaprevir (BI201335) is another NS3/4A protease inhibitor that has completed phase II testing (the SILEN-C1 study) and can be administered using a once-per-day dosing schedule. The treatment regimen included BI201335 in addition to PR for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy [17]. The overall SVR rate was 83% for the 240 mg dose. Ninety-two percent of the patients that showed an eRVR also achieved an SVR, regardless of the duration of subsequent PR therapy. Adverse events (mostly gastrointestinal) meant that treatment was discontinued in 7.3% of subjects.
Asunaprevir (BMS-650032) is a twice-daily protease inhibitor that is being developed for use with daclatasvir (an NS5A inhibitor) and BMS 791325 (a non-nucleoside inhibitor) in both IFN-containing and IFN-free regimens. Asunaprevir plus daclatasvir was the first regimen to cure HCV-infected patients without the need for IFN [16]. However, asunaprevir is not an ideal protease inhibitor because a twice-per-day schedule may be associated with hepatotoxicity.
2.5.2. Second-Generation Protease Inhibitors
Two second-generation protease inhibitors, MK-5172 and ACH-2684, are currently under clinical trial. MK-5172 is a novel macrocyclic NS3/4a protease inhibitor that is currently undergoing phase II clinical trials. R155 is the main overlapping position for drug resistance, and different mutations at this site within the NS3 protease confer resistance to nearly all protease inhibitors. However, MK-5172 shows potent antiviral activity against HCV viruses harboring mutations at position R155. Based on its preclinical profile, MK-5172 is expected to have broad-spectrum activity against multiple HCV genotypes (including genotype 3) and other clinically important drug-resistant variants. Indeed, trials in genotype-1-positive patients show that 75% had HCV RNA levels below the limit of detection. In addition, the drug was generally well tolerated [31].
ACH-2684 is a macrocyclic, noncovalent, reversible inhibitor of the NS3 protease. Phase Ib clinical trials showed that administration of ACH-2684 to patients infected with HCV genotype 1 achieved a mean 3.73 log10 reduction in HCV RNA levels after 3 days of monotherapy at a single dose of 400 mg/day. In addition, ACH-2684 was safe and well tolerated [32]. Thus, this drug shows great promise, although further clinical trials are needed.
2.5.3. Polymerase Inhibitor-Nucleoside Inhibitors
Two HCV nucleos(t)ide analogues have entered phase II/III clinical trials: mericitabine and sofosbuvir.
2.5.4. Nucleoside Inhibitors in Clinical Trials with Interferon
Mericitabine (RG 7128): the JUMP-C trial (phase II) investigated the safety and efficacy of mericitabine (RG 7128) (1000 mg bid) plus PR after 24 weeks of response-guided therapy. The overall SVR rates were higher in patients treated with mericitabine plus PR than in patients treated with PR alone (58% versus 36%) [22].
Sofosbuvir (GS-7977): the ATOMIC study (another phase II trial) evaluated combined treatment with sofosbuvir plus PR in 316 noncirrhotic patients infected with HCV genotypes 1, 4, or 6. This study evaluated the proper duration of treatment for genotype 1 patient. Patients infected with HCV genotype 1 were randomized into two groups: one group received sofosbuvir plus PegIFN/RBV for 12 or 24 weeks, and the other received sofosbuvir plus PR for 12 or 24 weeks, followed by rerandomization (1 : 1) into two further groups that received either an additional 12 weeks of sofosbuvir alone or an additional 12 weeks of sofosbuvir plus RBV. The results of an interim analysis showed that patients who received 12 weeks of therapy with the triple combination of sofosbuvir plus PR achieved SVR rates of 90% [20].
2.5.5. Nucleoside Inhibitors in Clinical Trials without Interferon
Mericitabine (RG 7128): the INFORM-1 study provided the first proof of principle that combined treatment with mericitabine plus danoprevir (an NS3/4 protease inhibitor) in the absence of IFN is effective at reducing HCV RNA levels. At day 14, the highest combined dose (1000 mg mericitabine and 900 mg danoprevir bid) resulted in a median −5.1 log10 IU/mL reduction in HCV RNA levels in treatment-naïve patients and a median −4.9 log10 IU/mL reduction in HCV RNA levels in patients that did not respond to previous PR therapy [23].
The INFORM-SVR trial (a phase IIb trial) evaluated the efficacy of a 12- or 24-week interferon-free regimen comprising ritonavir-boosted danoprevir (DNV/r, 100 mg/100 mg) plus mericitabine (1000 mg, bid), either with or without RBV, in treatment-naïve patients infected with HCV genotype 1. The data showed that 71% of the patients infected with HCV genotype 1b who received 24 weeks of DNV/r, mericitabine, and RBV achieved an SVR; however, only 26% of patients infected with genotype 1a achieved an SVR. Higher SVR rates were reported in patients who were rapid virological responders [24].
Sofosbuvir (GS-7977/PSI-7977): the ELECTRON trial evaluated the efficacy of sofosbuvir plus RBV in the absence of IFN. The results showed that treatment-naïve patients infected with HCV genotypes 2 or 3 achieved an SVR rate of 100%. In addition, patients infected with HCV genotype 1, who did not respond to previous treatment with PR, received sofosbuvir plus RBV for 12 weeks; however, 89% of patients relapsed after the end of treatment [21].
2.5.6. Interferon-Free Combination Trials
The SOUND-C2 study (faldaprevir plus BI 207127, with or without RBV): the Sound-C2 study is an open-label, randomized, phase IIb study of 362 treatment-naïve patients infected with HCV genotype 1 who were allocated to one of five treatment arms [18]. The final results showed that up to 85% of HCV patients infected with genotype 1b achieved an SVR. The optimal regimen was 28 weeks of faldaprevir (120 mg once daily), and BI 207127 (600 mg bid). The overall SVR rate was 70%, compared with 85% in the prevalent genotype-1b patient subgroup [19].
The Aviator study (ABT-450/r, ABT-267, or ABT-333 plus RBV): the Aviator phase IIb study assessed the safety and efficacy of ABT-450/r, ABT-267, or ABT-333 plus RBV (administered for 8, 12, or 24 weeks) in noncirrhotic treatment-naïve patients and in patients who did not respond to previous treatment with PR [33]. The SVR in treatment-naïve patients infected with genotype 1 HCV was 97.5% after 12 weeks, whereas the SVR in PR nonresponders infected with genotype 1 was 93.3%. Treatment-naïve patients infected with genotype 1a achieved an SVR of 96% after 12 weeks, whereas PR nonresponders achieved an SVR of 89%. For those patients infected with genotype 1b, the SVR was 100% for both treatment-naïve and PR nonresponders.
Daclatasvir plus sofosbuvir with or without RBV: this trial was designed to test the efficacy of combined treatment with daclatasvir plus sofosbuvir against HCV genotypes 1, 2, and 3. Daclatasvir plus sofosbuvir were administered, either with or without RBV, for 12 or 24 weeks and either with or without a 7-day run-in with sofosbuvir [34]. A total of 44 patients infected with genotypes 2 or 3 HCV were enrolled in three arms: one arm comprised a 7-day run-in with sofosbuvir followed by 23 weeks of daclatasvir plus sofosbuvir; another arm comprised daclatasvir plus sofosbuvir for 24 weeks; and the other comprised daclatasvir plus sofosbuvir plus RBV for 24 weeks. Eighty-eight percent of patients in the first group achieved an SVR at week 12, compared with 100% in the second group and 86% in the third group.
Daclatasvir, asunaprevir, and BMS-791325: daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in phase III of development. Asunaprevir is an NS3 protease inhibitor that is also undergoing phase III development along with daclatasvir. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase and is currently undergoing phase II development as a component of daclatasvir-based treatment regimens. This phase II study examined the efficacy of these DAAs in HCV G1 treatment-naïve patients [25]. The trial split patients into two groups. Group 1 received a 24-week course of daclatasvir, asunaprevir, and BMS-79132. Group 2 received a 12-week course of daclatasvir, asunaprevir, and BMS-79132. The result was that 94% of patients showed an undetectable viral load at week 4 and at the end of the trial in Group 1. One hundred percent of patients had an undetectable viral load at the end of the trial in group 2.
2.6. Optimized Treatment Algorithms for the Management of HCV Patients
This paper did not focus on general approaches for treating patients that are chronically infected with HCV. Instead, it focused on treatments based on DAAs and particularly on clinical trials of DAAs that target HCV genotype 1. HCV genotypes 2 and 3 can be effectively treated with current SOC therapy. Genotype 4 is the most difficult genotype to treat. The standard treatment for HCV genotype 4 is a 48-week course of PR. Furthermore, patients infected with HCV genotype 4 who have previously relapsed, or are non-responders, are unlikely be cured by the PR regimen. The optimized treatment algorithms are shown in Figures 3 and 4 [35].
The Scientific World Journal
Volume 2013 (2013), Article ID 704912, 9 pages
Full Text - http://dx.doi.org/10.1155/2013/704912
Hee Bok Chae, Seon Mee Park, and Sei Jin Youn
Department of Internal Medicine, Chungbuk National University Hospital, Chungbuk National University College of Medicine, 1 Sunwhan-ro, Heungdok-gu, Cheongju 361-711, Republic of Korea
Received 30 March 2013; Accepted 6 May 2013
Academic Editors: Q. Z. Dong, Y. Hiasa, P. Loyer, and S.-N. Lu
Copyright © 2013 Hee Bok Chae et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.
1. Introduction
Until now, combined treatment with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) (known as PR therapy) has been the standard of care (SOC) for patients chronically infected with hepatitis C virus (HCV). However, direct-acting antiviral agents (DAAs) are assuming a more prominent role. At present, only two first-generation DAAs (telaprevir (TVR) and boceprevir (BOC)) are available, although many other candidate DAAs are being developed. TVR and BOC are used only in developed countries to treat patients chronically infected with HCV. They are not used commonly in developing countries because of their high cost.
We can classify DAAs according to their action sites, such as protease inhibitor, polymerase inhibitor, NS5B inhibitor, and NS5A inhibitor. The main mechanism of action of DAAs is the inhibition of enzyme, for example, protease or polymerase, but the NS5A inhibitor has a different mechanism of action from other DAAs. It inhibits the assembly of this replication complex (Table 1) (Figure 1) [1, 2]. Another approach to HCV therapy is to target the host factors that the virus uses for its own life cycle, for example, cyclophilin inhibitors or nitazoxanide. In this paper, we will focus on only DAAs and will not cover other treatment options, like cyclophilin, HCV vaccine. We will discuss the efficacy and limitations of both currently approved and new candidate drugs.
2. Currently Available DAAs
Abstract
Currently, two direct-acting antivirals (DAAs) show well-established efficacy against hepatitis C virus (HCV), namely, first-wave protease inhibitors telaprevir and boceprevir. Most clinical trials have examined DAAs in combination with standard of care (SOC) regimens. Future therapeutic drugs were divided into three categories. They are second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors. Second-wave protease inhibitors are more improved form and can be administered once a day. Oral drug combinations can be favored because interferon (IFN) not only has to be given as intradermal injection, but also can cause several serious side effects. Combination of drugs with different mechanisms shows a good sustained virological response (SVR). But several mutations are associated with viral resistance to DAAs. Therefore, genotypic resistance data may provide insights into strategies aimed at maximizing SVR rates and minimizing resistance. Combined drug regimens are necessary to prevent the emergence of drug-resistant HCV. Many promising DAA candidates have been identified. Of these, a triple regimen containing sofosbuvir shows promise, and treatment with daclatasvir plus asunaprevir yields a high SVR rate (95%). Oral drug combinations will be standard of care in the near future.
1. Introduction
Until now, combined treatment with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) (known as PR therapy) has been the standard of care (SOC) for patients chronically infected with hepatitis C virus (HCV). However, direct-acting antiviral agents (DAAs) are assuming a more prominent role. At present, only two first-generation DAAs (telaprevir (TVR) and boceprevir (BOC)) are available, although many other candidate DAAs are being developed. TVR and BOC are used only in developed countries to treat patients chronically infected with HCV. They are not used commonly in developing countries because of their high cost.
We can classify DAAs according to their action sites, such as protease inhibitor, polymerase inhibitor, NS5B inhibitor, and NS5A inhibitor. The main mechanism of action of DAAs is the inhibition of enzyme, for example, protease or polymerase, but the NS5A inhibitor has a different mechanism of action from other DAAs. It inhibits the assembly of this replication complex (Table 1) (Figure 1) [1, 2]. Another approach to HCV therapy is to target the host factors that the virus uses for its own life cycle, for example, cyclophilin inhibitors or nitazoxanide. In this paper, we will focus on only DAAs and will not cover other treatment options, like cyclophilin, HCV vaccine. We will discuss the efficacy and limitations of both currently approved and new candidate drugs.
Table 1: Characteristics of HCV direct-acting antiviral classes. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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PK: pharmacokinetics; qd: once a day; tid: three times a day; RBV: ribavirin. Modified from [1]. SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis; TVR: telaprevir; BCV: boceprevir; SMV: simeprevir; ASV: asunaprevir; FDV: faldaprevir; SOF: sofosbuvir; MRB: mericitabine; DCV: daclatasvir. Figure 1: Targets for direct-acting antivirals. Modified from [2]. Click Figure To Enlarge |
In May 2011, the U.S. Food and Drug Administration (FDA) approved TVR and BOC for use in combination therapies with PegIFN-α and RBV for adult patients chronically infected with HCV genotype 1. The drugs are used to treat patients with compensated liver cirrhosis, who are treatment-naïve or who have been previously treated with IFN-based regimens [3, 4]. Both TVR and BOC inhibit the viral NS3/4A serine protease, which is essential for replication [5, 6].
2.1. Telaprevir (TVR)
Three phase III clinical trials have been conducted to evaluate the efficacy of TVR when administered to treatment-naïve chronic HCV (genotype 1) patients in combination with PegIFN-α-2a and RBV [7, 8]. In the ADVANCE trial, patients received TVR together with PegIFN-α and RBV (PR) for either 8 (T8PR) or 12 (T12PR) weeks, followed by PegIFN-α or RBV (PR) alone in a response-guided therapy [7]. Extended rapid virological response (eRVR) was defined as undetectable HCV RNA levels at weeks 4 and 12. The patients who did not achieve an eRVR received PegIFN-α plus RBV for a total of 48 weeks. The overall SVR rates for patients in the T8PR and T12PR groups were 69% and 75%, respectively. The SVR rate for the control group with only PR was 44% [7].
The ILLUMINATE, another TVR trial, focused on defining the utility of response-guided therapy (RGT) in patients that did achieve an eRVR. All patients received an initial 12-week course of TVR-based triple therapy, followed by treatment with PegIFN-α plus RBV [8]. Patients who achieved an eRVR at week 20 were randomized to receive either an additional 3- or 28-week course of PegIFN-α plus RBV. The overall SVR rate for all patients was 72%. The SVR rates for those patients (65%) who achieved an eRVR and received either an additional 3- or 28-week course of PegIFN-α plus RBV were 92% and 88%, respectively.
The REALIZE, the third trial of TVR, was conducted for patients who experienced treatment failure after SOC therapy [9]. The clinical trial had three arms. Patients in the first arm received T12PR triple therapy for 12 weeks, followed by a placebo plus PR for 4 weeks and then PR alone for 32 weeks. The patients in the second arm received placebo plus PR (lead-in phase) for the first 4 weeks, followed by TVR-based triple therapy for 12 weeks and then PR alone for 32 weeks (48 weeks in total). The patients in the third arm received PR alone for 48 weeks (control group). The overall SVR rates for the three groups were 64%, 66%, and 17%, respectively. The best response rate was observed for those patients in each group that had previously relapsed after PR therapy (83%, 88%, and 24%, resp.) [9].
In summary, the triple regimen including TVR showed good response in genotype 1 patients. The SVR rate can be maximized using a response-guided paradigm. The triple regimen was also effective in treatment-failure patients, especially who relapsed after PR therapy.
2.2. Boceprevir
Let us look at two important phase III clinical trials on BOC. The first one, SPRINT-2, evaluated the efficacy of BOC in two cohorts of treatment-naïve patients [10]. All patients were first treated with a lead-in therapy comprising PegIFN-α-2b plus weight-based RBV for a period of 4 weeks, followed by one of three regimens. After the lead-in, patients were assigned to one of three groups. (1) Group 1, PegIFN-α-2b, RBV, and placebo for an additional 44 weeks. (2) Group 2, BOC, PegIFN-α-2b, and RBV for an additional 24 weeks, followed by 20 more weeks of PegIFN-α-2b if HCV RNA was detectable at weeks 8 and 24. (3) Group 3, BOC, PegIFN-α-2b, and RBV for an additional 44 weeks, that is, SOC therapy (Figure 2) [11]. The overall SVR rates were higher in the BOC-treated arms (63% and 66%) than in the SOC arm (38%), but differed according to race. In black patients, the SVR rates were 42% in the RGT arm, 53% in the fixed duration arm, and 23% in the SOC arm.
Figure 2: Phase III trials of boceprevir in patients with hepatitis C genotype-1 infection. (a) SPRINT-2 trial in previously untreated patients. (b) RESPOND-2 trial for previously treated patients; patients were partial responders and relapsers and null-responders. PR: pegylated interferon-α-2b 1.5 μg/kg per week plus weight-based ribavirin 600–1400 mg per day. BOC: boceprevir 800 mg every 8 h. aHepatitis C RNA treatment weeks 8–24 undetectable. bHepatitis C RNA treatment week 8 detectable, treatment week 24 undetectable. cHepatitis C RNA treatment weeks 8–12 undetectable. dHepatitis C RNA treatment week 8 detectable, treatment week 12 undetectable. Excerpted from Pearlman [11].
Click To Enlarge
The RESPOND-2 trial was a phase III clinical trial [12]. The subjects were prior partial responders or relapsers with PegIFN-α-2b and RBV. Null responders were not studied in this trial. (1) Group 1, PegIFN-α-2b, RBV, and placebo for an additional 44 weeks. (2) Group 2, BOC, PegIFN-α-2b, and RBV for an additional 32 weeks, followed by 12 more weeks of PegIFN-α-2b and RBV if HCV RNA was detectable at week 8, but undetectable at week 12. (3) Group 3, BOC, PegIFN-α-2b, and RBV for an additional 44 weeks. Therapy was discontinued in patients who were HCV RNA positive at week 12 (Figure 2) [11]. The overall SVR rates at week 24 were 21%, 59%, and 66%, respectively in Group 1, Group 2 (RGT), and Group 3 (48 weeks). These triple therapy appear to yield even higher rates of SVR, 29, 69, and 75% in prior relapsers than in partial responders (7%, 40%, and 50%).
2.3. Vaniprevir (MK-7009)
Vaniprevir is a macrocyclic hepatitis C virus nonstructural protein 3/4A protease inhibitor. Treatment-naïve patients with HCV genotype 1 infection were randomized to receive open-label PegIFN and RBV in combination with blinded placebo or vaniprevir (300 mg bid, 600 mg bid, 600 mg qd, and 800 mg qd) for 28 days, and then open-label PegIFN and RBV for an additional 44 weeks. Across all doses, vaniprevir was associated with HCV RNA levels approximately 3 log10 IU/mL lower in vaniprevir-treated patients, compared to placebo recipients. Rates of RVR were significantly higher in each of the vaniprevir dose groups, compared to the control regimen (68.8%–83.3% versus 5.6%; for all comparisons). Vomiting appeared to be more common at higher vaniprevir doses (40% in 600 mg bid group) [13].
2.4. Preliminary Data from Patients with Other Genotypes Treated with DAAs
2.4.1. HCV Genotype 2
The SVR rate for patients infected with HCV genotype 2 and treated with SOC is almost 80%. There is no space for DAAs to show any increase of treatment effect because it is enough high. DAAs may be less effective in this patient group than in patients infected with HCV genotype 1. TVR, the first agent to directly target viral replication, is effective against HCV-2 but not against HCV-3 (see below). Foster et al. evaluated combined treatment with TVR plus PegIFN-α-2a and RBV in five patients infected with HCV-2 and compared the results with those obtained after treating nine patients with TVR alone or treating nine patients with PR (control group). Triple combination therapy yielded an SVR rate of 100%, which is remarkable considering the 89% rate observed in patients receiving standard PR [26]. Other NS3/4A protease inhibitors, nucleoside and non-nucleoside reverse replicase inhibitors, and NS5A inhibitors have antiviral activity against HCV-2. One of the most promising drugs is a nucleotide analogue polymerase inhibitor called PSI-7977 [27]. An open-label study (the PROTON study) evaluated the efficacy of PSI-7977 in 15 patients infected with HCV-2, in 10 patients infected with HCV-3, and in a larger group of patients with HCV-1 infection [28]. That study reported an RVR of 96% after the triple combination of 400 mg of PSI-7977 plus PR. Twenty-four HCV-2 and HCV-3 patients who completed the 12 weeks of treatment achieved SVR (96%).
2.4.2. HCV Genotype 3
The SVR rate for patients infected with HCV genotype 3 and treated with SOC is almost 80% [29]. TVR and BOC have revolutionized the treatment of genotype 1 HCV. Indeed, both have recently been recommended for use in combination with standard PR regimen for the treatment of patients chronically infected with HCV genotype 1. However, both BOC and TVR are ineffective against HCV-3.
2.5. Future Therapeutic Options
Two available DAAs, TVR and BOC, have several limitations. The role of these drugs is a supplement to PegIFN. These two drugs can cause severe side effects, for example, anemia, rash, and hyperbilirubinemia. Lastly, their dosing schedule is three times a day. The therapeutic drugs that are being developed for future use try to resolve these limitations of currently available DAAs. These new drugs fall into three categories: second-wave protease inhibitors, second-generation protease inhibitors, and polymerase inhibitors.
2.5.1. Second-Wave Protease Inhibitors
Second-wave protease inhibitors offer several advantages over currently available drugs. In the near future, improved pharmacokinetics will allow a once-a-day dosing schedule, which means that the side-effect profiles should be more tolerable. Second-wave protease inhibitors have similar genotype coverage and similar resistance profiles to those of TVR and BOC and will replace the first-generation protease inhibitors currently used for PR combination therapy, thereby becoming the initial partners in the first generation of “all-oral regimens.”
Simeprevir (TMC435) is an NS3/4A protease inhibitor that is taken orally once per day; the drug is currently undergoing phase III clinical trials for the treatment of HCV infection [30]. The PILLAR study (a phase IIb trial) was designed to test the efficacy of simeprevir when used in combination with PR for either 24 or 48 weeks. An SVR was achieved in 68–76% of patients treated with this triple therapy regimen, and approximately 80% of subjects were eligible to receive shortened 24 weeks of therapy. The result of subgroup analysis was very high SVR (93–96%) [14]. Adverse effects were similar to those observed after SOC therapy. The lowest rate of relapse (8%) was found in the study arm receiving TMC 435 (150 mg/day) plus PR for 24 weeks.
The ASPIRE trial was a phase IIb trial for genotype 1 patients who had failed previous treatment with PR therapy. All patients received PR for 48 weeks. The best results were observed in the group treated with triple therapy with simeprevir 150 mg (SVR) plus PR in comparison with placebo plus PR, which achieved an SVR of 85% versus 37% in prior relapsers, 75% versus 9% in partial responders, and 51% versus 19% in prior nonresponders [15].
Faldaprevir (BI201335) is another NS3/4A protease inhibitor that has completed phase II testing (the SILEN-C1 study) and can be administered using a once-per-day dosing schedule. The treatment regimen included BI201335 in addition to PR for 24 weeks at doses of 120 and 240 mg, followed by another 24 weeks of standard therapy [17]. The overall SVR rate was 83% for the 240 mg dose. Ninety-two percent of the patients that showed an eRVR also achieved an SVR, regardless of the duration of subsequent PR therapy. Adverse events (mostly gastrointestinal) meant that treatment was discontinued in 7.3% of subjects.
Asunaprevir (BMS-650032) is a twice-daily protease inhibitor that is being developed for use with daclatasvir (an NS5A inhibitor) and BMS 791325 (a non-nucleoside inhibitor) in both IFN-containing and IFN-free regimens. Asunaprevir plus daclatasvir was the first regimen to cure HCV-infected patients without the need for IFN [16]. However, asunaprevir is not an ideal protease inhibitor because a twice-per-day schedule may be associated with hepatotoxicity.
2.5.2. Second-Generation Protease Inhibitors
Two second-generation protease inhibitors, MK-5172 and ACH-2684, are currently under clinical trial. MK-5172 is a novel macrocyclic NS3/4a protease inhibitor that is currently undergoing phase II clinical trials. R155 is the main overlapping position for drug resistance, and different mutations at this site within the NS3 protease confer resistance to nearly all protease inhibitors. However, MK-5172 shows potent antiviral activity against HCV viruses harboring mutations at position R155. Based on its preclinical profile, MK-5172 is expected to have broad-spectrum activity against multiple HCV genotypes (including genotype 3) and other clinically important drug-resistant variants. Indeed, trials in genotype-1-positive patients show that 75% had HCV RNA levels below the limit of detection. In addition, the drug was generally well tolerated [31].
ACH-2684 is a macrocyclic, noncovalent, reversible inhibitor of the NS3 protease. Phase Ib clinical trials showed that administration of ACH-2684 to patients infected with HCV genotype 1 achieved a mean 3.73 log10 reduction in HCV RNA levels after 3 days of monotherapy at a single dose of 400 mg/day. In addition, ACH-2684 was safe and well tolerated [32]. Thus, this drug shows great promise, although further clinical trials are needed.
2.5.3. Polymerase Inhibitor-Nucleoside Inhibitors
Two HCV nucleos(t)ide analogues have entered phase II/III clinical trials: mericitabine and sofosbuvir.
2.5.4. Nucleoside Inhibitors in Clinical Trials with Interferon
Mericitabine (RG 7128): the JUMP-C trial (phase II) investigated the safety and efficacy of mericitabine (RG 7128) (1000 mg bid) plus PR after 24 weeks of response-guided therapy. The overall SVR rates were higher in patients treated with mericitabine plus PR than in patients treated with PR alone (58% versus 36%) [22].
Sofosbuvir (GS-7977): the ATOMIC study (another phase II trial) evaluated combined treatment with sofosbuvir plus PR in 316 noncirrhotic patients infected with HCV genotypes 1, 4, or 6. This study evaluated the proper duration of treatment for genotype 1 patient. Patients infected with HCV genotype 1 were randomized into two groups: one group received sofosbuvir plus PegIFN/RBV for 12 or 24 weeks, and the other received sofosbuvir plus PR for 12 or 24 weeks, followed by rerandomization (1 : 1) into two further groups that received either an additional 12 weeks of sofosbuvir alone or an additional 12 weeks of sofosbuvir plus RBV. The results of an interim analysis showed that patients who received 12 weeks of therapy with the triple combination of sofosbuvir plus PR achieved SVR rates of 90% [20].
2.5.5. Nucleoside Inhibitors in Clinical Trials without Interferon
Mericitabine (RG 7128): the INFORM-1 study provided the first proof of principle that combined treatment with mericitabine plus danoprevir (an NS3/4 protease inhibitor) in the absence of IFN is effective at reducing HCV RNA levels. At day 14, the highest combined dose (1000 mg mericitabine and 900 mg danoprevir bid) resulted in a median −5.1 log10 IU/mL reduction in HCV RNA levels in treatment-naïve patients and a median −4.9 log10 IU/mL reduction in HCV RNA levels in patients that did not respond to previous PR therapy [23].
The INFORM-SVR trial (a phase IIb trial) evaluated the efficacy of a 12- or 24-week interferon-free regimen comprising ritonavir-boosted danoprevir (DNV/r, 100 mg/100 mg) plus mericitabine (1000 mg, bid), either with or without RBV, in treatment-naïve patients infected with HCV genotype 1. The data showed that 71% of the patients infected with HCV genotype 1b who received 24 weeks of DNV/r, mericitabine, and RBV achieved an SVR; however, only 26% of patients infected with genotype 1a achieved an SVR. Higher SVR rates were reported in patients who were rapid virological responders [24].
Sofosbuvir (GS-7977/PSI-7977): the ELECTRON trial evaluated the efficacy of sofosbuvir plus RBV in the absence of IFN. The results showed that treatment-naïve patients infected with HCV genotypes 2 or 3 achieved an SVR rate of 100%. In addition, patients infected with HCV genotype 1, who did not respond to previous treatment with PR, received sofosbuvir plus RBV for 12 weeks; however, 89% of patients relapsed after the end of treatment [21].
2.5.6. Interferon-Free Combination Trials
The SOUND-C2 study (faldaprevir plus BI 207127, with or without RBV): the Sound-C2 study is an open-label, randomized, phase IIb study of 362 treatment-naïve patients infected with HCV genotype 1 who were allocated to one of five treatment arms [18]. The final results showed that up to 85% of HCV patients infected with genotype 1b achieved an SVR. The optimal regimen was 28 weeks of faldaprevir (120 mg once daily), and BI 207127 (600 mg bid). The overall SVR rate was 70%, compared with 85% in the prevalent genotype-1b patient subgroup [19].
The Aviator study (ABT-450/r, ABT-267, or ABT-333 plus RBV): the Aviator phase IIb study assessed the safety and efficacy of ABT-450/r, ABT-267, or ABT-333 plus RBV (administered for 8, 12, or 24 weeks) in noncirrhotic treatment-naïve patients and in patients who did not respond to previous treatment with PR [33]. The SVR in treatment-naïve patients infected with genotype 1 HCV was 97.5% after 12 weeks, whereas the SVR in PR nonresponders infected with genotype 1 was 93.3%. Treatment-naïve patients infected with genotype 1a achieved an SVR of 96% after 12 weeks, whereas PR nonresponders achieved an SVR of 89%. For those patients infected with genotype 1b, the SVR was 100% for both treatment-naïve and PR nonresponders.
Daclatasvir plus sofosbuvir with or without RBV: this trial was designed to test the efficacy of combined treatment with daclatasvir plus sofosbuvir against HCV genotypes 1, 2, and 3. Daclatasvir plus sofosbuvir were administered, either with or without RBV, for 12 or 24 weeks and either with or without a 7-day run-in with sofosbuvir [34]. A total of 44 patients infected with genotypes 2 or 3 HCV were enrolled in three arms: one arm comprised a 7-day run-in with sofosbuvir followed by 23 weeks of daclatasvir plus sofosbuvir; another arm comprised daclatasvir plus sofosbuvir for 24 weeks; and the other comprised daclatasvir plus sofosbuvir plus RBV for 24 weeks. Eighty-eight percent of patients in the first group achieved an SVR at week 12, compared with 100% in the second group and 86% in the third group.
Daclatasvir, asunaprevir, and BMS-791325: daclatasvir is the first NS5A replication complex inhibitor to be investigated in HCV clinical trials and is currently in phase III of development. Asunaprevir is an NS3 protease inhibitor that is also undergoing phase III development along with daclatasvir. BMS-791325 is a non-nucleoside inhibitor of the NS5B polymerase and is currently undergoing phase II development as a component of daclatasvir-based treatment regimens. This phase II study examined the efficacy of these DAAs in HCV G1 treatment-naïve patients [25]. The trial split patients into two groups. Group 1 received a 24-week course of daclatasvir, asunaprevir, and BMS-79132. Group 2 received a 12-week course of daclatasvir, asunaprevir, and BMS-79132. The result was that 94% of patients showed an undetectable viral load at week 4 and at the end of the trial in Group 1. One hundred percent of patients had an undetectable viral load at the end of the trial in group 2.
2.6. Optimized Treatment Algorithms for the Management of HCV Patients
This paper did not focus on general approaches for treating patients that are chronically infected with HCV. Instead, it focused on treatments based on DAAs and particularly on clinical trials of DAAs that target HCV genotype 1. HCV genotypes 2 and 3 can be effectively treated with current SOC therapy. Genotype 4 is the most difficult genotype to treat. The standard treatment for HCV genotype 4 is a 48-week course of PR. Furthermore, patients infected with HCV genotype 4 who have previously relapsed, or are non-responders, are unlikely be cured by the PR regimen. The optimized treatment algorithms are shown in Figures 3 and 4 [35].
Figure 3: Proposed algorithm for the use of protease inhibitors in treatment-naïve HCV genotype 1 infected patients. Pretreatment assessment should include careful consideration of lifestyle factors, comorbid conditions, potential drug interactions, and assessment for the presence of cirrhosis. In noncirrhotic patients, the presence of factors predictive of a poor response to therapy should be patients with no risk factors for a poor response to therapy; the decision to use a 4-week lead-in with peginterferon and ribavirin and to continue on SOC in those who achieve an RVR should only be taken following careful and balanced discussion with the patient. Excerpted from Ramachandrean et al. [35].
Figure 4: Proposed algorithm for the use of protease inhibitors in HCV genotype 1 infected patients who have had previous virological failure on treatment. Pretreatment assessment should include careful consideration of lifestyle factors, comorbid conditions, potential drug interactions, assessment for the presence of cirrhosis, and the presence of factors predictive of a poor response to therapy. Identification of the degree of previous response should be attempted. If this information is not available, patients should be considered as prior null responders to maximize cure rates. In cirrhotic prior null responders, the decision to watch and wait for novel therapies or to use a 4-week lead-in with peginterferon and ribavirin to identify patients more likely to achieve an SVR should only be taken following careful and balanced discussion with the patient. Excerpted from Ramachandrean et al. [35].
3. Conclusion
In conclusion, only two DAAs have been approved for the treatment of patients infected with HCV (TVR and BOC). Both are used in combination with PR therapy. Although several clinical trials examined the efficacy of IFN-free regimens (to avoid the side effects associated with IFN), most clinical trials have examined the efficacy of DAAs when used in combination with IFN. Response-guided therapy using the PegIFN-α regimen can be used with DAA therapy to select nonresponders. TVR and BOC play an important role in the treatment of patients chronically infected with HCV genotype 1. Genotypes 2 and 3 (but not genotype 4) can be effectively treated with SOC therapy. Of the emerging second-generation treatments, a triple regimen containing sofosbuvir shows great promise in terms of treatment efficacy. In addition, the combination of two oral drugs (daclatasvir and asunaprevir) achieved a high SVR rate (95%). Another oral drug combination (mericitabine and danoprevir) was examined in the INFORM study and achieved an SVR rate of 71%. Thus, future regimens may not require the use of IFN injections. Drug resistance will become a problem in the field of chronic HCV research; however, current data suggest that it is not yet a significant factor.
Authors’ Contribution
Hee Bok Chae acquired the data and wrote the paper. Seon Mee Park consulted a direction of the paper. Sei Jin Youn performed proofreading and critical revision.
Acknowledgments
This work was supported by a Chungbuk National University grant, 2012. Dr. Chae is a member of the advisory committee for both BMS Korea and Gilead Korea.
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