Elbasvir / Grazoprevir (1) – Zepatier®

• Clinical trials
  • The pharmaceutical manufacturer presents the results of the randomised, controlled, open-label Phase III C-EDGE H2H trial for patient groups with HCV genotype 1 infection.
  • The pharmaceutical manufacturer carries out a separate analysis for patients with chronic kidney disease (stage 4 to 5 renal insufficiency), taking into account the results of the direct comparison in the C-SURFER trial. This trial compared treatment with elbasvir/grazoprevir against best supportive care. Blinding was achieved by administering a placebo in the control arm.

a) Patients without cirrhosis or with compensated cirrhosis, genotype 1

• An additional benefit of elbasvir/grazoprevir over the appropriate comparator therapy is not proven for patients with HCV infection of genotype 1 or genotype 4, in each case without cirrhosis or with compensated cirrhosis.
• Overall, therefore, no hint of additional benefit can be derived.
• For this reason, the direct comparison in the C-EDGE H2H study is not suitable for establishing an additional benefit of elbasvir/grazoprevir.
• A comparison using individual arms from different studies (non-adjusted indirect comparison) is, in principle, subject to increased uncertainty regarding the results, meaning that conclusions regarding additional benefit can only be drawn if so-called dramatic effects are observed. In the present case, the comparison using individual arms from different studies does not reveal any effects that can be classified as dramatic.
• For example, for the primary endpoint SVR12 (sustained virological response 12 weeks after the end of treatment, which was the primary endpoint in all the studies mentioned), 92.2% for elbasvir/grazoprevir versus 93.1–98.4% for ledipasvir/sofosbuvir in patients with genotype 1a infection, 98.8% versus 97.6–97.8% for genotype 1b, and 95.9% for elbasvir/grazoprevir versus 96.0% for ombitasvir/paritaprevir/ritonavir plus dasabuvir plus ribavirin in patients with genotype 1a and a high baseline viral load.
• Furthermore, the pharmaceutical manufacturer does not claim any additional benefit based on a comparison of the study arms, i.e. compared with the appropriate comparator therapy.
• Overall assessment
  • No additional benefit is proven for patients with genotype 1 HCV infection. No direct comparisons with the appropriate comparator therapy were presented; no additional benefit can be inferred from the comparison of individual study arms in the sense of unadjusted indirect comparisons.

b) Patients without cirrhosis or with compensated cirrhosis, genotype 4

• An additional benefit of elbasvir/grazoprevir over the appropriate comparator therapy is not proven for patients with HCV infection of genotype 1 or genotype 4, in each case without cirrhosis or with compensated cirrhosis.
• Overall, therefore, no hint of additional benefit can be derived.
• A comparison using individual arms from different studies (non-adjusted indirect comparison) is, in principle, subject to increased uncertainty regarding the results, meaning that conclusions regarding additional benefit can only be drawn if so-called dramatic effects are observed. In the present case, the comparison using individual arms from different studies does not reveal any effects that can be classified as dramatic.
• For example, for the primary endpoint SVR12 (sustained virological response 12 weeks after the end of treatment was the primary endpoint in all the studies mentioned) was 100% for elbasvir/grazoprevir versus 100% for ombitasvir/paritaprevir/ritonavir plus ribavirin.
• Furthermore, the pharmaceutical manufacturer does not claim any additional benefit based on indirect comparisons, i.e. compared with the appropriate comparator therapy.
• Overall assessment
  • No additional benefit is proven for patients with genotype 4 HCV infection. Only a comparison of individual study arms in the form of an unadjusted indirect comparison was presented, which is not suitable for deriving an additional benefit.

Courtesy translation only, please refer to the German original.