Regulatory Decision Summary for HOLKIRA PAK

Health Canada considers that the benefit/risk profile of Holkira Pak is favorable when used for the treatment of chronic hepatitis C virus (HCV) infection with genotype 1 in patients who are co-infected with the human immunodeficiency virus type 1 (HIV-1) as well as in Post-liver transplant recipients.

Holkira Pak is an all-oral regimen comprised of four medications: ombitasvir, paritaprevir, ritonavir, and dasabuvir. Two studies were provided in support of the efficacy and safety of Holkira Pak, one in HCV/HIV-1 co-infected patients (Study M14-004) and one in post-liver transplant patients infected with HCV genotype 1 (Study M12-999).

The study M14-004 was a Phase II/III randomized, multicenter open-label trial; the efficacy and safety of Holkira Pak and ribavirin was evaluated for 12 and 24 weeks in subjects who either had no cirrhosis or had compensated cirrhosis; all participants had HCV genotype 1 disease and were co-infected with HIV-1, using a stable specific antiretroviral therapy regimen that included tenofovir disoproxil fumarate plus emtricitabine or lamivudine, administered with ritonavir-boosted atazanavir or with raltegravir. Participants were either HCV treatment-naïve or had been previously treated with Peg-interferon/Ribavirin.

Holkira Pak was shown to yield high sustained viral response rates at 12 weeks (SVR12) after completing treatment in HCV/HIV-1 co-infected subjects ((51 of 56 (91.1%) subjects with HCV genotype 1a infection and 7 of 7 (100%) subjects with HCV genotype 1b infection)). In addition five of the six (83.3%) subjects with compensated cirrhosis in each study arm also achieved SVR12.

These data are consistent with SVR12 rates reported in Phase III trials of patients infected with HCV only, without additional new side effects. The treatment response was sustainable because all patients had maintained their viral response 48 weeks post-treatment. Biological safety parameters reported in patients were generally not frequent and in the vast majority they were mild to moderate.

Study M12-999 was an open-label, single arm, Phase II study to evaluate the safety and efficacy of Holkira Pak, co-administered with ribavirin (RBV) in adult liver transplant recipients with genotype 1 HCV infection. The enrollment into this study was considered for subjects who had received liver transplantation as a consequence of HCV genotype 1 infection no less than 12 months before the study screening visit. Participants were required to have a liver biopsy showing evidence of fibrosis ≤ F2 (Metavir scale) and which was obtained within the 6 months prior to the screening period but not less than 9 months post-transplant or during the screening period.

Holkira Pak was very effective in liver transplant recipients with HCV genotype 1, although Holkira Pak should be used with RBV and for up to 24 weeks in this subpopulation in order to prevent potential relapses. However, there is a potential risk of drug-drug interactions when co-administering Holkira Pak with a series of medications, including specific HIV anti-retroviral drugs and selected immunosuppressant drugs given during the post-transplant period. In addition, Holkira Pak is contraindicated in patients who have moderate to severe hepatic impairment (Child-Pugh B and C) due to risk of potential toxicity.

Overall safety and efficacy of Holkira Pak was demonstrated as an all-oral treatment option for chronic HCV genotype 1 and HIV-1 co-infected subjects as well as for liver transplant recipients infected with HCV genotype 1. The benefit of Holkira Pak in these two subpopulations of HCV patients outweighs the potential risks under the conditions recommended in the Product Monograph.