Regulatory Decision Summary for DAKLINZA

The use of Daklinza in patients with HCV GT-3 was considered qualified under the Notice of Compliance with Conditions (NOC/c) guidance given promising efficacy with demonstrated safety. This submission was to demonstrate the safety and efficacy of Daklinza in order to lift the condition of the NOC/c approval.

The recommended dose of Daklinza for adults is 60 mg, taken orally, twice daily for 12 weeks. Daklinza must not be administered as a monotherapy.

This submission included an open-label Phase III study (ALLY-3) to evaluate results of the efficacy and safety of Daklinza in combination with sofosbuvir, with or without ribavirin (RBV), in the treatment of infection with chronic HCV GT-3 in adult patients without cirrhosis. The primary endpoint was sustained virologic response (SVR) defined as hepatitis C viral RNA below the lower limit of quantification (<LLOQ) 12 weeks (SVR12) after the end of treatment.

Results from ALLY-3 demonstrated high SVR12 response rates with 12 weeks of treatment against GT-3 for the overall population and for the subgroups of treatment naïve and treatment experienced patients. SVR12 rates of 96% were seen in patients without cirrhosis and 97% and 94%, respectively for the corresponding subgroups of treatment-naïve and treatment-experienced patients. The overall SVR12 rate for the cirrhotic population was 63% with 58% in treatment-naïve and 69% in treatment-experienced patients.

Similar high SVR12 response rates were also seen in the overall patient population and non-cirrhotic patients with or without baseline polymorphism. Lower SVR12 rates, however, were seen in cirrhotic patients with or without baseline polymorphism. These observations suggested that cirrhosis was predictive of low response rates. The impact of baseline polymorphism on SVR12 and relationship of baseline polymorphism to virologic failures are described in the Product Monograph.

High SVR12 rates (> 80%) have been found across most subgroups of GT-3 infected patients, including patients with high baseline viral load (HCV ≥800,000 IU/mL), patients carrying the interleukin-28B gene and "Black" patients.

Patients treated with Daklinza reported no viral breakthrough on treatment, one patient had detectable HCV RNA at the end of treatment, and 16 patients relapsed post-treatment; 9.0% in treatment-naïve and 14% in treatment-experienced patients. Most of the relapses occurred in patients with baseline cirrhosis.

The use of RBV has been recommended in combination with Daklinza and sofosbuvir only for patients with cirrhosis and post-liver transplant patients to achieve high cure rates. Although the addition of RBV did not appear to limit treatment, RBV dose reduction strategies, based on hemoglobin and creatinine clearance measurements, have been adopted as risk management strategies in order to reduce the potential side effects attributed to RBV.

Daklinza was well-tolerated and safe when co-administered with sofosbuvir. No new safety signals have emerged during the clinical study or from the post-marketing surveillance activity. The addition of RBV in some subgroups of patients did not impact negatively on the safety profile of the dual regimen. The risks associated with Daklinza include the reactivation of hepatitis B virus (HBV) in co-infected patients, re-affirmation of a serious drug-drug interaction between sofosbuvir and amiodarone based on post-marketing surveillance activity, and the low SVR12 rates reported in GT-3 infected patients with cirrhosis using the dual therapy.

Health Canada considers that the benefit/risk profile of Daklinza is favorable for use in combination with sofosbuvir with or without RBV for the treatment of chronic hepatitis C in adult patients with HCV GT-3 under the conditions of use described in the Product Monograph.