Regulatory Decision Summary for ZEPATIER

The clinical efficacy of Zepatier (elbasvir 50 milligram [mg]/grazoprevir 100 mg fixed-dose combination) has been sufficiently demonstrated in 8 core Phase II and Phase III clinical studies (3 Phase III and 5 Phase II) involving approximately 1,800 genotype 1, 3, or 4 chronic hepatitis C adult patients who were treatment-naïve or prior treatment failures to regimens including peginterferon and ribavirin or a protease inhibitor, peginterferon and ribavirin.

The efficacy of Zepatier was assessed by measuring the sustained virologic response (SVR) rate at 12 weeks after completion of therapy. Treatment with Zepatier for 12 weeks showed 95% SVR among treatment-naive patients and 100% SVR in patients who had relapsed after treatment with peginterferon and ribavirin and who were infected with chronic hepatitis genotype 1 or 4. The SVR was 95% in genotype 1 patients who had previously failed a regimen that included a protease inhibitor, peginterferon and ribavirin. Treatment with Zepatier for 8 weeks was sufficient to yield 94% SVR in genotype 1b treatment-naïve non-cirrhotic patients whereas 12 weeks of therapy was required in patients who previously failed treatment with peginterferon and ribavirin or a protease inhibitor, peginterferon and ribavirin (95% SVR).

For genotype 1a or 4 patients who previously failed peginterferon and ribavirin therapy, including patients with compensated cirrhosis, Zepatier was efficacious when combined with ribavirin for 16 weeks of treatment (97% SVR). The clinical efficacy of Zepatier in genotype 3 treatment-naïve patients with or without cirrhosis was also demonstrated with a 12-week regimen in combination with sofosbuvir (92% SVR).

Comparable clinical efficacy of Zepatier has also been demonstrated among genotype 1 or genotype 4 chronic hepatitis C and HIV-1 co-infected patients with similar regimens. The clinical efficacy of a 12-week regimen of Zepatier has also been demonstrated in genotype 1, treatment-experienced, patients with severe renal impairment and end-stage renal disease including those on regular hemodialysis.

With respect to patients with genotype 6 infection, there was a lack of sufficient clinical data (efficacy and safety) to support treatment with Zepatier.

In the Zepatier trials, relapse at follow-up was the most common reason among a limited number of treatment failures that were reported, regardless of patient treatment experience or cirrhosis status. A greater than five time shift in anti-viral activity from baseline resistance-associated-variants or on-treatment resistance-emergent-associated-variants found in the viral non-structural 5A protein were likely associated with these failures.

Zepatier is generally well tolerated among the diverse patient populations and different treatment regimens with or without ribavirin. The most commonly reported adverse drug reactions of Zepatier when used alone were fatigue, headache and nausea. When combined with ribavirin, mostly in treatment-experienced patients, the most commonly reported adverse drug reactions were fatigue, headache, anemia and nausea. Most of these adverse drug reactions were mild in severity. A low rate of severe adverse events or discontinuations in patients treated with Zepatier, with or without ribavirin, was reported.

Risks of elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), especially ALT/AST elevations reported after 4 weeks of dosing, have been identified during early stages of clinical trials (especially those with grazoprevir). Patients with moderate or severe hepatic impairment (Child-Pugh B or C) were excluded from Phase II and III studies. With these hepatic risk mitigation measures, on-treatment ALT /AST elevations to greater than 5 times above the upper limit of normal as hepatic adverse drug reactions was observed in less than 1% of patients. The Zepatier Product Monograph has been revised to highlight Zepatier dosing-related hepatic risks in the Warnings and Precautions and the Adverse Drug Reactions sections. Furthermore, Zepatier use in moderate or severe hepatic impairment patients is contraindicated and other precautionary wording was incorporated into the Zepatier Product Monograph to advise healthcare professionals to closely monitor liver function prior to and during Zepatier treatment.

Co-administration with some human immunodeficiency virus (HIV) drugs (such as the HIV protease inhibitors atazanavir, darunavir, lopinavir, saquinavir or tipranavir) that inhibit the organic anion transporting polypeptide 1B transporter may significantly increase Zepatier serum exposure. These drugs are therefore contraindicated with the use of Zepatier. In addition, the concomitant use of Zepatier with some potent or moderate cytochrome P450 3A inducers such as efavirenz and etravirine may significantly decrease grazoprevir and elbasvir plasma concentrations leading to a reduced effect of Zepatier. Therefore, the use of Zepatier is contraindicated with efavirenz and is not recommended with etravirine.

A Risk Management Plan was included as part of this submission, and found to be acceptable with revisions recommended by Health Canada.

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