Regulatory Decision Summary for DAKLINZA

Health Canada considers that the benefit of treating chronic HCV infection with Daklinza in combination with sofosbuvir, with or without ribavirin, outweigh the known risks associated with the proposed regimen in the following patient populations:

1. co-infected with HCV and human immunodeficiency virus type 1 (HIV-1);
2. in patients with decompensated cirrhosis (Child-Pugh score A, B or C); and
3. in patients with HCV recurrence after liver transplantation.

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.

Two Phase III studies, ALLY-1 and ALLY-2, were provided in support of the proposed regimen in specified patient populations. The efficacy of Daklinza was assessed by measuring the sustained virologic response rates at follow-up Week 12 (SVR12) across HCV genotypes -1, -2 and -3 in different subsets of patients infected with HCV.

Results from ALLY-1 demonstrated that a 12-week treatment with Daklinza in combination with sofosbuvir and ribavirin resulted in SVR12 rates of 82% (37/45) in HCV genotype-1 patients with Child-Pugh (CP) class-A, B or C. SVR12 rates were higher in subjects with CP class-A (11/12; 91.7%) or CP class-B (30/32; 93.8%) compared to CP class-C (9/16; 56%). The same regimen in post-liver transplant patients with HCV genotype-1 infection resulted in an SVR12 rate of 95% (39/41).

Ten out of 60 subjects (16.7%) in ALLY-1 did not achieve SVR12; 9 subjects relapsed and 1 subject had detectable HCV at the end of therapy. Polymorphism in the non-structural protein 5A (NS5A) at baseline resulted in lower SVR12 rates (71.4%; 10/14) compared to 86.0% (37/43) in subjects without NS5A polymorphism.

Results from study ALLY-2 showed that efficacy of Daklinza in combination with sofosbuvir was similar between patients infected with HCV alone as compared to patients co-infected with HCV and HIV-1. Furthermore, Daklinza in combination with sofosbuvir, given to treatment-naïve genotype-1HCV patients produced SVR12 rates of 96.4% (80/83 subjects). In genotype-1 HCV treatment-experienced patients who received Daklinza and sofosbuvir for 12 weeks, the SVR12 rate was 97.7% (43/44 subjects).

Collective safety data for Daklinza in combination with sofosbuvir with or without ribavirin from the two studies presented in this submission in addition to known safety data support the use of Daklinza 60 mg in combination with sofosbuvir 400 mg as safe and well-tolerated in these patient populations. Safety data was found to be consistent with the known safety profile of each individual component. In ALLY-2, no deaths or serious adverse events (SAEs) were reported. Most common (reported in >10% of subjects) adverse events (AEs) were fatigue, nausea and headache. High rates of treatment adherence, low rates of premature discontinuations due to AEs, SAEs, and low rates of Grade 3/4 laboratory abnormalities were reported. Several drug-drug interaction studies showed that dose adjustment is necessary when the proposed regimen is used with certain antiretroviral regimens.

Based on the evidence provided, the anticipated benefits of Daklinza are considered to outweigh the possible risks under the conditions of use recommended in the Daklinza Product Monograph at this time.