Regulatory Decision Summary for DAKLINZA

Health Canada considers that the benefit/risk profile of Daklinza is favourable for use in combination with other agents for the treatment of chronic hepatitis C in adult patients with HCV genotype 1, 2, or 3* (*qualified under NOC/c guidance) and compensated liver disease, including cirrhosis.

Benefits

This submission included an open-label Phase 2 study to evaluate results of the efficacy, safety and tolerability of Daklinza in combination with sofosbuvir, with or without ribavirin, in the treatment of infection with chronic HCV genotype 1, 2, or 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. The study demonstrated high SVR12 rates in treatment-naïve patients with HCV genotype 1, 2, or 3 and in genotype 1-infected patients who failed prior treatment with telaprevir and boceprevir.

The Daklinza and sofosbuvir [with or without ribavirin] treatment regimen produced consistently high SVR12 rates across all subgroups of patients and genotypes: 99.2% in genotype 1 treatment-naïve patients, 96.2% in genotype 2 treatment-naive patients, 88.9% in genotype 3 treatment-naïve patients, and 100% in genotype 1 telaprevir and boceprevir treatment-failure patients.

The response rates were consistently high in treatment-naïve non-cirrhotic patients with HCV genotype 1 regardless of Daklinza and sofosbuvir treatment duration (12 or 24 weeks): 98.8% (81/82 patients) for 12 weeks and 100.0% (44/44 patients) for 24 weeks. The high efficacy and safety data favored short treatment duration (12 weeks) in which the use of ribavirin was not required.  However, a longer treatment duration (24 weeks) is recommended for treatment-naïve patients with compensated cirrhosis.

The Daklinza and sofosbuvir SVR12 response rate was high in treatment-experienced (prior telaprevir and boceprevir failures) non-cirrhotic genotype 1 patients treated for 24 weeks, in the presence (100%, 20/20 patients) or absence (100%, 21/21 patients) of ribavirin. A 24-week treatment period without ribavirin is recommended for non-cirrhotic patients and consideration should be given for the use of ribavirin for patients with cirrhosis.

The addition of ribavirin to the Daklinza and sofosbuvir regimen was not necessary to achieve high SVR12 rates for genotype 2 and 3 patients in treatment-naïve non-cirrhotic patients. The clinical data provided sufficient evidence to permit a recommendation for treatment duration for genotype 2 and 3. Based on the data 24-weeks treatment duration is recommended for genotype 2 treatment-naïve patients with or without cirrhosis and treatment-experienced patients without cirrhosis. For genotype 3, the recommended treatment duration is 12 weeks for treatment-naïve or treatment-experienced patients without cirrhosis and 24 weeks for treatment-naïve or treatment-experienced patients with cirrhosis.

For genotype 3, the evidence presented for efficacy was considered promising with demonstrated safety and a NOC/c with requirements for additional efficacy data was recommended.

High SVR12 rates were observed across all subgroups including those with baseline characteristics that have been historically predictive of poor outcomes with other HCV treatment regimens such as genotype 1a/1b subtype, HCV genotype 3 Interleukin-28B non-CC genotype, black race, and high baseline HCV viral load.

The combination of Daklinza and sofosbuvir represents an advance in the treatment of HCV infection that does not appear limited by baseline demographic or disease characteristics, and represents a treatment option for patients intolerant/ineligible to receive peginterferon or ribavirin.

Risks

The Daklinza and sofosbuvir regimen showed a favourable safety profile. No deaths were reported in the study submitted, and there was also a low rate of serious adverse events (SAE), and a low rate of adverse events (AE) leading to discontinuation of study therapy. In general, AEs and laboratory abnormalities reported while on-treatment were mild to moderate in intensity and have been addressed in the product monograph with appropriate cautionary statements.

The major safety observation recorded in the study was the effect of ribavirin on rates of common AEs as well as on key hematologic parameters. Inclusion of ribavirin in the treatment regimen led to increased rates of AEs consistent with the safety profile of ribavirin, such as cough, anemia, rash, insomnia, anxiety, and dyspnea.

Based on the data submitted, the anticipated benefits of the Daklinza and sofosbuvir regimen are considered to outweigh the potential risks.

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