Regulatory Decision Summary for SUNVEPRA

Health Canada considers that the benefit/risk profile of Sunvepra is favorable when used in combination with other agents for the treatment of chronic hepatitis C virus (HCV) infection with genotypes 1 or 4 in adult patients with compensated liver disease, including cirrhosis. The treatment regimen is dependent on the HCV genotype and subtype. Sunvepra must not be administered as a monotherapy. The recommended dose of Sunvepra for adults is 100 mg, taken orally, twice daily for 24 weeks.

Two Phase III randomized studies with Sunvepra and Daklinza (daclatasvir) were provided to support the safety and efficacy in different patient subpopulations infected with HCV genotype 1b, with or without cirrhosis, as follows: null or partial responders to peginterferon alfa and ribavirin; intolerant to or ineligible to be treated with peginterferon alfa and ribavirin; and treatment-naïve subjects. The dual therapy of Sunvepra (100 mg twice daily) and Daklinza (60 mg once daily) was effective in all of these patient subpopulations, providing an option for genotype 1b patients, with a treatment duration of 24 weeks. The primary endpoint was sustained virological response rate at 12 weeks (SVR12) following treatment completion. The SVR12 was 90.6% in treatment-naïve, 82.4% in prior non-responders to peginterferon alfa and ribavirin, and 82.6% in peginterferon alfa intolerant/ineligible patients. The SVR12 rates were similar when examined across various baseline factors including males and females, subjects ≥65 and <65 years of age, subjects with and without cirrhosis, subjects with baseline HCV ribonucleic acid (RNA) ≥800,000 IU/mL and <800,000 IU/mL, and subjects with interleukin 28B CC and non-CC genotypes. Patients showed high rates of treatment adherence (≥95.0%) over a 24-week treatment period.

One Phase III, open-label, multi-site, multinational single-arm study (with no control group) was provided in support of Sunvepra use in subjects with chronic HCV genotypes 1 or 4 infections, who were also null or partial responders to peginterferon alfa 2a or 2b plus ribavirin. Patients in this study received Sunvepra and Daklinza plus peginterferon alfa-2a and ribavirin (referred to as Quad regimen) for a treatment duration of 24 weeks. High SVR12 rates were achieved with genotype 1 (93.2%-95.5%) and genotype 4 (100%).

Most on-treatment adverse events with the Sunvepra and Daklinza dual therapy were mild to moderate in intensity, and the rate of adverse events leading to discontinuation of study therapy was low. Sunvepra has a potential for hepatotoxicity, which is discussed further below. The safety profile of the Sunvepra and Daklinza dual regimen among the various subgroups, including patients with cirrhosis and patients without cirrhosis, was consistent. Similarly, the safety profile for the first 12 weeks of treatment was consistent in treatment-naïve patients who received the Sunvepra with Daklinza dual therapy or placebo control. The safety profile of the Quad regimen was generally consistent with the safety profile of peginterferon and ribavirin as well as Sunvepra. It has a benefit/risk profile similar to that of peginterferon and ribavirin therapy.

Sunvepra is associated with several drug-drug interactions and as such is contraindicated with:

• drugs dependent on the cytochrome P-450 (CYP) 2D6 for clearance and for which elevated plasma concentrations are associated with serious ventricular arrhythmias and sudden death;
• moderate or strong inducers and inhibitors of CYP3A as co-administration with these drugs will affect the pharmacokinetics of Sunvepra and may lead to either a loss of therapeutic effect of Sunvepra or an increase in concentrations of Sunvepra, which may increase the likelihood and severity of liver-related adverse events; and
• strong inhibitors of organic anion transporting polypeptide (OATP) 1B1 or 2B1, as co-administration with these drugs may lead to a loss of therapeutic effect of Sunvepra.

Elevations in transaminases were identified as a potential safety concern in nonclinical studies and from earlier clinical trials with Sunvepra at 600 mg twice daily. In the clinical trial program, the dose of Sunvepra was reduced to 200 mg twice daily (tablet formulation which is equivalent to 100 mg of the soft gel capsules). The frequency of reported Grade 3/4 alanine amino transferase (ALT) elevations was higher in regimens including Sunvepra as compared to regimens without Sunvepra. Based on some cases of potential drug-induced liver injury observed with Sunvepra-containing regimens, monitoring of ALT and aspartate amino transferase (AST) levels is recommended in the Product Monograph. Levels of ALT and AST should be monitored once every 2 weeks for the initial 12 weeks of treatment and every 4 weeks thereafter until completion of therapy to manage the potential risk of hepatotoxicity, and assess for the potential need for early discontinuation of therapy.

The overall benefit-risk assessment is favorable for Sunvepra in the treatment of chronic HCV genotype 1 or genotype 4 infection under the conditions of use described in the Product Monograph.

For more information on Health Canadas decision, please view the Summary Basis of Decision.