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Australian Prescriber Apr 2015
Review
PubMed: 26648621
DOI: 10.18773/austprescr.2015.026 -
Drugs Dec 2013Simeprevir (Sovriad(TM)) is a new direct-acting antiviral drug and a second-generation small-molecule NS3/4A serine protease inhibitor developed by Janssen and Medivir... (Review)
Review
Simeprevir (Sovriad(TM)) is a new direct-acting antiviral drug and a second-generation small-molecule NS3/4A serine protease inhibitor developed by Janssen and Medivir for the oral treatment of adults with genotype 1 and/or genotype 4 chronic hepatitis C virus (HCV) infection (chronic hepatitis C). Simeprevir antiviral activity is achieved by its non-covalent binding to HCV protease, with a fast association and slow dissociation rate. The capsule formulation is approved in Japan and Canada for use in combination with pegylated interferon (peginterferon) and ribavirin for genotype 1 chronic hepatitis C, and has been filed for approval in the US in this indication. In addition, the capsule formulation has been filed for approval in the EU for use in combination with peginterferon and ribavirin for genotype 1 and 4 chronic hepatitis C. Phase III trials of the capsule formulation of simeprevir are underway in several other regions, including China. In the pivotal phase III trials, simeprevir was administered once daily for 12 weeks in combination with peginterferon and ribavirin for 24 or 48 weeks. This article summarizes the milestones in the development of simeprevir leading to this first approval for chronic hepatitis C.
Topics: Antiviral Agents; Clinical Trials, Phase III as Topic; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Protease Inhibitors; Simeprevir; Sulfonamides
PubMed: 24293133
DOI: 10.1007/s40265-013-0153-9 -
American Journal of Health-system... Sep 2015The pharmacology, pharmacokinetics, efficacy, safety, costs, and place in therapy of simeprevir and sofosbuvir in the management of hepatitis C virus (HCV) infection are... (Review)
Review
PURPOSE
The pharmacology, pharmacokinetics, efficacy, safety, costs, and place in therapy of simeprevir and sofosbuvir in the management of hepatitis C virus (HCV) infection are reviewed.
SUMMARY
Sofosbuvir and simeprevir are classified as direct-acting agents because they target specific proteins essential to the replication of HCV. Phase III trials demonstrated that simeprevir in combination with peginterferon alfa and ribavirin was superior to placebo combined with peginterferon alfa and ribavirin in achieving a sustained virological response in both treatment-naive patients and patients who relapsed after treatment with peginterferon alfa-2a or alfa-2b and ribavirin. Q80K polymorphism substantially decreases the efficacy of simeprevir. Clinical trials revealed that sofosbuvir in combination with ribavirin was superior to peginterferon plus ribavirin against HCV genotype 2 infection and as effective as peginterferon plus ribavirin against HCV genotype 3 infection. These findings were significant because they demonstrated the effectiveness of an anti-HCV regimen that did not include peginterferon alfa. Sofosbuvir has much better adverse-effect and drug interaction profiles than previous hepatitis C antiviral agents. Both simeprevir and sofosbuvir are approved for the treatment of chronic hepatitis C in combination with other antiviral medications. Simeprevir has been approved specifically for patients infected with HCV genotype 1 with compensated liver disease (including cirrhosis) in combination with peginterferon alfa-2a or alfa-2b and ribavirin. Sofosbuvir has shown efficacy in HCV genotypes 1-4.
CONCLUSION
Simeprevir and sofasbuvir have advantages in response rates and convenient dosage forms and frequency compared with other HCV treatments; however, they are more expensive than previous HCV therapies.
Topics: Antiviral Agents; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Simeprevir; Sofosbuvir; Virus Replication
PubMed: 26294237
DOI: 10.2146/ajhp140290 -
Clinical Therapeutics Feb 2015Chronic hepatitis C infection affects a large proportion of the world's population and can lead to significant morbidity and mortality. The standard of care for... (Review)
Review
PURPOSE
Chronic hepatitis C infection affects a large proportion of the world's population and can lead to significant morbidity and mortality. The standard of care for treatment of hepatitis C infection has been peginterferon and ribavirin, with or without a first-generation protease inhibitor. In late 2013 and early 2014, sofosbuvir and simeprevir obtained regulatory approval, offering the first possibility for all-oral treatment regimens. We provide a review of the clinical efficacy and safety of sofosbuvir- and simeprevir-containing regimens.
METHODS
Studies were identified in PubMed using the terms sofosbuvir and simeprevir in combination with hepatitis C. Abstracts of additional studies presented at professional meetings but not yet published were also reviewed. All Phase 3 trials published by August 1, 2014, as well as Phase 2 studies for which there was not a corresponding Phase 3 trial, were included in the review.
FINDINGS
Simeprevir was studied with peginterferon and ribavirin in 7 published Phase 3 trials, with overall efficacy rates of 59% to 100%. Sofosbuvir was studied with ribavirin and with or without peginterferon in 6 Phase 3 trials with overall efficacy rates of 50% to 93%. Patient groups with lower response rates tended to have cirrhosis and be older, men, and previous null responders. Simeprevir and sofosbuvir were studied in combination in 1 Phase 2a study with overall efficacy of 92%. Additional studies demonstrated the efficacy and safety of sofosbuvir regimens in patients before and after liver transplantation. Overall, the simeprevir- and sofosbuvir-containing regimens were tolerated better or as well as peginterferon and ribavirin regimens, with fatigue, headache, and nausea the most common adverse events.
IMPLICATIONS
Results from numerous Phase 3 clinical trials indicate that sofosbuvir- and simeprevir-containing regimens are highly effective and safe for the treatment of chronic hepatitis C infection. The approval of these 2 agents has led to a complete overhaul of published guidelines, with sofosbuvir- and simeprevir-containing regimens included in preferred regimens.
Topics: Antiviral Agents; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Female; Genotype; Headache; Hepacivirus; Hepatitis C; Hepatitis C, Chronic; Humans; Interferon-alpha; Liver Cirrhosis; Male; Nausea; Polyethylene Glycols; Protease Inhibitors; Ribavirin; Simeprevir; Sofosbuvir
PubMed: 25601269
DOI: 10.1016/j.clinthera.2014.12.012 -
Expert Opinion on Pharmacotherapy Dec 2013The addition of protease inhibitors such as telaprevir and boceprevir with PEGylated interferon and ribavirin has significantly improved cure rates for genotype 1... (Review)
Review
INTRODUCTION
The addition of protease inhibitors such as telaprevir and boceprevir with PEGylated interferon and ribavirin has significantly improved cure rates for genotype 1 hepatitis C virus (HCV) infection. Simeprevir (TMC435) is a second-generation protease inhibitor that is in development for the treatment of genotype 1 HCV infection.
AREAS COVERED
The authors present: i) an overview of Phases I - III clinical trials of simeprevir for HCV infection based on peer-reviewed literature and congress presentations and ii) an evaluation of the efficacy and safety of simeprevir in the treatment of HCV infection.
EXPERT OPINION
Simeprevir is a once-daily oral medication that combined with PEGylated interferon and ribavirin appears to be a potent and safe agent to treat genotype 1 HCV infection for patients who are treatment-naïve and prior treatment-failures. Compared to telaprevir and boceprevir, simeprevir will likely be the protease inhibitor of choice for genotype 1 HCV infection based on ease of use, lower rates of adverse events, including rash and anemia, and no significant reported drug-drug interactions. Associated side effects inherent with interferon-based regimens may be problematic for patients. As HCV therapies evolve into interferon-free regimens, simeprevir may potentially be combined with other oral direct-acting agents without interferon to treat HCV infection.
Topics: Antiviral Agents; Clinical Trials, Phase III as Topic; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Interferon alpha-2; Interferon-alpha; Polyethylene Glycols; Protease Inhibitors; Randomized Controlled Trials as Topic; Recombinant Proteins; Ribavirin; Simeprevir; Sulfonamides
PubMed: 24138198
DOI: 10.1517/14656566.2013.850074 -
Expert Review of Anti-infective Therapy Aug 2014Simeprevir is a second-wave hepatitis C virus NS3/4A protease inhibitor that was designed to optimize its antiviral activity, safety, drug-drug interactions, and... (Review)
Review
Simeprevir is a second-wave hepatitis C virus NS3/4A protease inhibitor that was designed to optimize its antiviral activity, safety, drug-drug interactions, and pharmacokinetic profile. When used to treat patients with hepatitis C virus genotype 1, simeprevir is coadministered with peginterferon and ribavirin for 12 weeks, followed by double therapy with Peg-IFN and ribavirin for an additional 12 or 36 weeks. Phase III studies achieved a sustained virologic response in 80-90% of treatment-naïve patients (International Phase III studies QUEST-1/2: 80/81%; Japanese Phase III trial CONCERTO-1: 89%). Unlike with the first protease inhibitors, telaprevir or boceprevir, used in triple therapy, when using simeprevir the frequency of clinically problematic adverse events such as anemia, rash, and digestive symptoms is almost comparable to that of double therapy. The advent of simeprevir has enabled interferon therapy, which started as monotherapy in early 1990s, to reach its maximum efficacy and arrive at what can be considered its final form at least in genotype 1b.
Topics: Antiviral Agents; Clinical Trials as Topic; Drug Administration Schedule; Drug Design; Drug Evaluation, Preclinical; Drug Therapy, Combination; Genotype; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Interferon alpha-2; Interferon-alpha; Molecular Structure; Polyethylene Glycols; RNA, Viral; Recombinant Proteins; Ribavirin; Simeprevir; Sulfonamides; Treatment Outcome
PubMed: 24882512
DOI: 10.1586/14787210.2014.925800 -
Drugs Feb 2015Simeprevir (Olysio™; Galexos™; Sovriad®) is an orally-administered NS3/4A protease inhibitor for use in combined drug regimens against chronic hepatitis C virus... (Review)
Review
Simeprevir (Olysio™; Galexos™; Sovriad®) is an orally-administered NS3/4A protease inhibitor for use in combined drug regimens against chronic hepatitis C virus (HCV) infection. This article reviews studies relevant to the EU simeprevir label. In proof-of-concept studies, simeprevir had potent antiviral activity against all HCV genotypes, except genotype 3. In trials in patients with chronic HCV genotype 1 infection, week-12 sustained virological response (SVR12) rates in treatment-naïve patients and prior relapsers were significantly higher with simeprevir plus peginterferon-α/ribavirin (PR) [79-89 %] than with placebo plus PR (36-62 %). In prior partial/null responders, the SVR12 rate with simeprevir plus PR (54 %) was noninferior to that with telaprevir plus PR (55 %). Simeprevir plus PR was also efficacious in patients with HCV genotype 1/HIV-1 co-infection. In prior null responders without severe liver fibrosis (cohort 1) and treatment-naïve patients with severe liver fibrosis (cohort 2) treated with simeprevir plus sofosbuvir, the SVR12 rate for the two cohorts combined was 92 %. In patients with chronic HCV genotype 4 infection, the SVR12 rates with simeprevir plus PR were 83, 87 and 40 % in treatment-naïve patients, prior relapsers and prior null responders, respectively. Grade 3-4 adverse event, serious adverse event and treatment withdrawal rates with simeprevir plus PR were similar to those with placebo plus PR. Skin rashes with simeprevir were mostly mild or moderate; serious photosensitivity reactions occur, but are rare. Simeprevir is efficacious and generally well tolerated in patients with chronic HCV genotypes 1 and 4 infection. Studies of simeprevir in interferon-free regimens and in other subpopulations with HCV infections will be of interest.
Topics: Administration, Oral; Antiviral Agents; Hepacivirus; Hepatitis C, Chronic; Heterocyclic Compounds, 3-Ring; Humans; Simeprevir; Sulfonamides
PubMed: 25559421
DOI: 10.1007/s40265-014-0341-2