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AbbVie Ltd is pleased to announce that Viekirax (ombitasvir/paritaprevir/ritonavir) and Exviera (dasabuvir), an interferon-free regimen, have been granted European approval for the treatment of patients with chronic hepatitis C virus (HCV) infection. The treatment has been approved with or without ribavirin for patients with genotype 1 chronic HCV infection, including those with compensated liver cirrhosis, HIV-1 co-infection, liver transplant recipients and patients on opioid substitution therapy. Additionally, Viekirax has been approved for use with ribavirin in genotype 4 chronic HCV-infected patients.
Viekirax, when co-administered with Exviera, combines three direct-acting antiviral agents with distinct mechanisms of action and non-overlapping resistance profiles to target HCV at multiple steps in the viral lifecycle. Viekirax consists of ombitasvir, an NS5A inhibitor, paritaprevir, an NS3/4A protease inhibitor, and ritonavir, while Exviera is composed of dasabuvir, a non-nucleoside NS5B polymerase inhibitor. Ritonavir is not active against HCV; however, as a pharmacokinetic enhancer of paritaprevir, it facilitates once-daily dosing, and results in higher drug exposures than with administration of paritaprevir alone.
The marketing authorisation for Viekirax and Exviera is supported by a clinical development programme consisting of six pivotal phase 3 trials which studied the efficacy and safety of the treatment regimen in more than 2,300 patients.1,2 In two such trials, the regimen was administered to patients with HCV genotype 1 infection and no cirrhosis who were previously untreated (Sapphire I), or who had previously been treated with peginterferon-ribavirin (Sapphire II). A third trial evaluated the regimen in previously untreated and previously treated adults with chronic HCV genotype 1 infection and compensated cirrhosis (Turquoise II).3-5
Study design
Sapphire I and Sapphire II were double-blind, placebo-controlled trials in which patients were randomly assigned to receive active treatment (n=473 and n=297, respectively) or matching placebos in a 3:1 ratio over a 12 week double-blind period. The active treatment regimen consisted of ombitasvir 25mg, paritaprevir 150mg and ritonavir 100mg, dosed once daily, with dasabuvir 250mg, dosed twice daily, plus ribavirin administered according to body weight.3,4
In Turquoise II, an open-label trial, 380 patients were randomly assigned in a ratio of approximately 1:1 to receive either 12 or 24 weeks of active treatment (n=208 and n=172, respectively). This study was not placebo-controlled, because of the risk of hepatic decompensation among untreated patients. Also, there was no active-comparator group owing to the increased toxic effects of standard interferon-containing regimens in patients who also have cirrhosis.5
In all three trials, the primary efficacy end point was sustained virologic response (HCV RNA level <25 IU/ml) at 12 weeks after the end of treatment.3-5
Sustained virologic response superior to historical control groups
Sapphire I and Sapphire II
Among those who received active treatment over the double-blind period in the placebo-controlled trials, the overall rates of sustained virologic response at post-treatment week 12 were 96.2% and 96.3%, respectively, which were non-inferior and superior to the rates in corresponding historical control groups (i.e. those who received telaprevir plus peginterferon-ribavirin, or, who had received retreatment with telaprevir plus peginterferon-ribavirin, respectively).
The efficacy of different treatment regimens with antiviral agents may vary according to HCV subgenotype (1a or 1b). In both of these trials, the rates of sustained virologic response at post-treatment week 12 were similar among patients with HCV genotype 1a infection (95.3% and 96%, respectively) and those with HCV genotype 1b infection (98.0% and 96.7%, respectively), which were superior to the historical control rates.
For those who had previously been treated with peginterferon-ribavirin (Sapphire II), rates were 95.3% among patients with a prior relapse, 100% among patients with a prior partial response, and 95.2% among patients with a prior null response.
Rates of sustained virologic response were high across subgroups defined by gender, race, age, body mass index, fibrosis score, IL28B genotype, and baseline viral load.3,4
Turquoise II
The rates of sustained virologic response at post-treatment week 12 was 91.8% of patients who received 12 weeks of treatment and 95.9% of patients who received 24 weeks of treatment. In both treatment groups, the primary efficacy end points met the pre-specified criteria for non-inferiority and superiority to the historical rate with telaprevir plus peginterferon-ribavirinamong patients with HCV genotype 1 infection and cirrhosis. The difference in rates was not significant (P=0.09). Rates of sustained virologic response in subgroups defined by HCV subgenotype, status with respect to prior treatment, and type of treatment failure among previously treated patients were superior to the historical rate, and were similar in the two treatment groups across the randomisation strata (see Figure 1).
Among patients with HCV genotype 1a infection and a prior null response, 92.9% of patients in the 24 week group had a sustained virologic response at post-treatment week 12, as compared with 80% of patients in the 12 week group. The numerically higher rate of sustained virologic response with the 24 week regimen suggests that the longer treatment duration is more effective in this subgroup of patients.
Rates did not differ substantially according to baseline characteristics such as race, body mass index, IL28B genotype, or baseline viral load.5
Figure 1. Sustained Virologic Response at Post-Treatment Week 12 in Patients with Chronic Hepatitis C Virus (HCV) Genotype 1 Infection and Cirrhosis (Turquoise II trial)
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Safety
The three most common adverse events across all three clinical trials in the active regimen groups were fatigue (34.7%, 33.3%, 32.7% [12 week group] and 46.5% [24 week group], respectively), headache (33%, 36.4%, 27.9% and 30.8%, respectively), and nausea (23.7%, 20.2%, 17.8% and 20.3%, respectively). Overall, the rates of serious adverse events and drug discontinuations due to adverse events were low.3-5
Conclusion
These clinical trials demonstrated that Viekirax, when co-administered with Exviera, an interferon-free regimen, results in high rates of sustained virologic response in HCV-infected patients regardless of baseline characteristics, such as prior treatment status, type of treatment failure among previously treated patients, HCV subgenotype or the presence of cirrhosis, and is associated with a low rate of treatment discontinuation. 3-5
Viekirax (ombitasvir 25mg/paritaprevir 150mg/ritonavir 100mg) should be taken once daily, and Exviera 250mg should be taken twice daily, with or without ribavirin taken twice daily, in the treatment of genotype 1 chronic HCV infection. Viekirax and Exviera are taken for 12 weeks with or without ribavirin, except in genotype 1a patients with cirrhosis, who should take it for 24 weeks.1,2
For the treatment of genotype 4 chronic hepatitis C patients, the regimen consists of Viekirax dosed once daily, taken with ribavirin dosed twice daily, for 12 weeks (no cirrhosis) or for 24 weeks (with cirrhosis).1
References:
- Viekirax Summary of Product Characteristics.
- Exviera Summary of Product Characteristics.
- Feld J.J. et al. N Engl J Med 2014;370:1594-603.
- Zeuzem S. et al. N Engl J Med 2014;370:1604-14.
- Poordad F. et al. N Engl J Med 2014;370:1973-82.
Full prescribing information and references available from AbbVie Ltd. Telephone (01) 4287900.
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Caroline McDermott
