Cross-resistance

Cross-resistance is expected among NS5A inhibitors, NS3/4A protease inhibitors, and non-nucleoside NS5B inhibitors by class. The impact of prior dasabuvir, ombitasvir, or paritaprevir treatment experience on the efficacy of other NS5A inhibitors, NS3/4A protease inhibitors, or NS5B inhibitors has not been studied.

Clinical efficacy and safety

The efficacy and safety of Exviera in combination with ombitasvir/paritaprevir/ritonavir with and without ribavirin was eva luated in six randomised Phase 3 clinical trials, including one trial exclusively in subjects with compensated cirrhosis (Child-Pugh A), in over 2,300 subjects with genotype 1 chronic hepatitis C infection as summarised in Table 6.

Table 6. Phase 3 randomised, global multicentre trials conducted with Exviera and ombitasvir/paritaprevir/ritonavir with or without ribavirin (RBV).

1. Double-blind unless otherwise noted.

2. Treated is defined as subjects who were randomised and received at least one dose of Exviera and ombitasvir/paritaprevir/ritonavir.

3. Treatment duration was 12 weeks for all arms, except for TURQUOISE II which included a 24 week arm.

4. Treatment naïve was defined as not having received any prior therapy for HCV infection.

5. Peginterferon+ribavirin -experienced subjects were defined as either: prior relapsers (subjects with HCV RNA undetectable at or after the end of at least 36 weeks of pegIFN/RBV treatment, but HCV RNA was detectable within 52 weeks of treatment follow-up) or prior partial responders (received at least 20 weeks of pegIFN/RBV and achieved a greater than or equal to 2 log₁₀ IU/mL reduction in HCV RNA at week 12, but not achieving HCV RNA undetectable at end of treatment) or prior null-responders (received at least 12 weeks of pegIFN/RBV treatment and failed to achieve a 2 log₁₀ IU/mL reduction in HCV RNA at week 12 or received at least 4 weeks of pegIFN/RBV treatment and achieved a < 1 log₁₀ IU/mL reduction in HCV RNA at week 4).

In all six trials, the Exviera dose was 250 mg twice daily and the ombitasvir/paritaprevir/ritonavir dose was 25 mg/150 mg/100 mg once daily. For subjects who received ribavirin, the ribavirin dose was 1000 mg per day for subjects weighing less than 75 kg or 1200 mg per day for subjects weighing greater than or equal to 75 kg.

Sustained virologic response (SVR) was the primary endpoint to determine the HCV cure rate in the Phase 3 studies and was defined as unquantifiable or undetectable HCV RNA 12 weeks after the end of treatment (SVR12). Treatment duration was fixed in each trial and was not guided by subjects' HCV RNA levels (no response guided algorithm). Plasma HCV RNA values were measured during the clinical trials using the COBAS TaqMan HCV test (version 2.0), for use with the High Pure System. The assay had a lower limit of quantification (LLOQ) of 25 IU per mL.

Clinical trials in treatment-naïve adults

SAPPHIRE-I – genotype 1, treatment-naïve

SAPPHIRE-I was a randomised, global multicentre, double-blind, placebo-controlled trial conducted in 631 treatment-naïve adults with genotype 1 chronic hepatitis C virus infection without cirrhosis. Exviera and ombitasvir/paritaprevir/ritonavir were g