Regulatory Decision Summary for Technivie

Health Canada considers that the benefit/risk profile of Technivie is favourable when used in combination with ribavirin for the treatment of genotype 4 (GT4) chronic hepatitis C (CHC) infection in adults who are either treatment naïve or previously treated with peginterferon and ribavirin (RBV).

Benefits

This submission included an open-label, single-arm, Phase II study to evaluate the efficacy, safety and tolerability of Technivie in combination with RBV in treatment-naïve (TN) or treatment-experienced (TE), CHC GT4-infected patients. The primary endpoint was sustained virologic response (SVR) defined as hepatitis C viral ribonucleic acid (RNA) below the lower limit of quantification (<LLOQ) 12 weeks after the end of treatment (SVR12).

Overall, high efficacy rates (SVR12) have been demonstrated for the combination therapy of Technivie for the treatment of infections caused by GT4. The SVR12 rates were 100% in adult TN and TE non-cirrhotic patients when given in combination with RBV for 12 weeks. In comparison, 90.9% of the TN patients who received Technivie without RBV for 12 weeks achieved SVR12, indicating that the addition of RBV to the treatment regimen contributes to maximizing SVR. The high SVR12 rates reported in TN non-cirrhotic patients in the absence of RBV indicate that the Technivie can also be used in patients who are intolerant/ineligible to receive RBV.

All non-cirrhotic CHC GT4-infected patients treated with Technivie + RBV (100%) achieved SVR12, and the SVR12 rate did not differ across subgroups.

Risks

Overall, Technivie therapy has been shown to be well tolerated with a limiting number of associated adverse events (AEs). No specific adverse drug reactions have been reported that could be considered associated with the Technivie regimen, in the presence and absence of RBV. No patients discontinued Technivie (± RBV) due to treatment-emergent AEs. The most common treatment-emergent AEs were headache, asthenia, fatigue, nausea, and insomnia.

Although the sample size was small for baseline factors known to impact efficacy [for example (e.g.) sex, race, interleukin-28B genotype, virologic failure, etc.], the overall efficacy data (SVR12, 100%) reported in the presence of RBV for these covariates did not differ.

The risks of Technivie occur mostly in the area of drug-drug interactions. Many drugs have been contraindicated with Technivie (e.g. moderate/strong inducers and substrates of cytochrome P450 3A4) because of safety concerns and the regimen has been contraindicated in severe hepatic impairment patients.

Post-baseline alanine transaminase increases of at least grade 3 severity have been reported with Technivie regimen when used in combination with ethinyl estradiol-containing regimens (contraceptives). The administration of these drugs is contraindicated with Technivie. In addition, a switch to progestin-only contraceptive has been recommended before initiating treatment with Technivie.

In non-cirrhotic TN and TE patients treated with Technivie for 12-weeks in the presence of RBV, the increases in indirect bilirubin, hemolysis of red blood cells, or decline of hemoglobin (Hb) during the treatment phase was much lower than other existing regimens that include RBV. The changes in Hb, anemia, or bilirubin were manageable by RBV dose reduction (no discontinuations due to RBV were reported in the study). 

No virologic failures during treatment or post-treatment relapses in the presence of RBV were reported in each of the treatment groups. In contrast, on-treatment virologic failures and relapses have been observed during the 12-weeks of treatment in the absence of RBV. All virologic failures reported in the absence of RBV were associated with the hepatitis C virus subtype 4d. As virologic failure was not seen in the presence of RBV, development of resistance with Technivie is expected to be low as confirmed by the clinical isolates which showed the appearance of infrequent resistance-associated variants.

In conclusion, the presented information and data indicate that the overall benefit-risk assessment is favorable for Technivie in the treatment of GT4CHC when used as prescribed, in combination with ribavirin.