Merck, a global healthcare leader, announced the presentation of results from C-EDGE Head-to-Head, the company’s comparative, phase 3, open-label clinical trial evaluating the efficacy and safety of Zepatier (elbasvir and grazoprevir) 50mg/100mg tablets versus a regimen of sofosbuvir 400mg tablets plus peginterferon and ribavirin (pegIFN/RBV) in treatment-naïve and pegIFN/RBV treatment-experienced patients with chronic hepatitis C (HCV) genotype (GT) 1 or GT4 infection.

In this study, Zepatier demonstrated superiority on efficacy and safety endpoints compared to sofosbuvir plus pegIFN/RBV, based on pre-specified analyses. In the full analysis set (FAS) (n=255), the efficacy endpoint of sustained virologic response (SVR) 12 weeks after the completion of therapy (SVR12, considered virologic cure) was achieved in 99 per cent (128/129) of patients receiving Zepatier for 12 weeks versus 90 per cent (114/126) of patients receiving sofosbuvir plus pegIFN/RBV for 12 weeks. The study’s safety endpoint was the frequency of pre-specified (Tier 1) safety events focusing on tolerability, hematologic side effects, and liver-related laboratory abnormalities.

Zepatier – Merck’s once-daily, fixed-dose combination tablet indicated with or without RBV for the treatment of chronic HCV GT1 or GT4 infection in adults – was approved by the US Food and Drug Administration (FDA) on January 28, 2016, based in part on prior studies from the phase 3 programme. The results of C-EDGE Head-to-Head were featured in the official press programme at The International Liver Congress 2016.

“Overall in this study, the elbasvir and grazoprevir regimen showed superior SVR rates and improvement on pre-specified safety endpoints compared to the sofosbuvir plus peginterferon and ribavirin regimen in these genotype 1- or 4-infected patients,” said Dr. Jan Sperl, Department of Hepatogastroenterology, Institute for Clinical and Experimental Health, Prague, Czech Republic and lead study investigator.

“Sofosbuvir in combination with peginterferon and ribavirin continues to be a prescribed treatment regimen in many regions, and this comparative study versus combination treatment with elbasvir and grazoprevir provides interesting and important insights.”

C-EDGE Head-to-Head is a comparative phase 3, randomized, open-label, parallel-group trial conducted at multiple sites in the European Union, Norway and Turkey, and was designed to evaluate the efficacy and safety of 12 weeks of Zepatier (elbasvir and grazoprevir) versus a 12 week treatment regimen of sofosbuvir plus pegIFN/RBV. The trial enrolled treatment-naïve and pegIFN/RBV treatment-experienced patients, with or without cirrhosis, with chronic HCV GT1 or GT4 infection. Investigators were to enroll only patients whom, in their opinion, were appropriate candidates for 12 weeks of pegIFN/RBV-based therapy; this assessment included consideration of factors associated with lower response rates to interferon-based therapies (e.g., advanced fibrosis/cirrhosis, high baseline viral concentrations, black race, IL28B non-CC genotype, or prior null-response to pegIFN/RBV therapy). The study randomized 255 GT1- or GT4-infected patients to 12 weeks of treatment with either Zepatier (elbasvir and grazoprevir) 50mg/100mg tablets (n=129) or sofosbuvir 400mg tablets plus pegIFN/RBV (n=126). Overall, at baseline, 17 per cent of patients had compensated cirrhosis; 67 per cent had HCV RNA greater than 800,000 IU/ml; 99 percent were white; 78 per cent had IL28B non-CC genotype; and approximately 25 per cent had failed prior treatment with pegIFN/RBV (10 per cent prior null-responders, 5 per cent prior partial-responders, 10 per cent prior relapsers).

In the FAS (n=255), the efficacy analyses demonstrated superiority of Zepatier compared to sofosbuvir plus pegIFN/RBV, as measured by SVR12. 2 Higher SVR rates were observed among those receiving Zepatier (elbasvir and grazoprevir) in subgroups of patients who had previously experienced a non-response to pegIFN/RBV therapy and in those with cirrhosis, higher baseline viral load, or IL28B non-CC genotype. In the Zepatier group, one patient (1 per cent) discontinued from the trial after completing treatment. There were no virologic failures in the Zepatier group. In the sofosbuvir plus pegIFN/RBV group, virologic failure occurred in 11 patients (9 per cent) and one patient (1 per cent) discontinued from the trial after the first week of treatment.

The primary safety analysis compared the incidence of adverse events (AEs) of special relevance (Tier 1 AEs) between the Zepatier and sofosbuvir plus pegIFN/RBV treatment groups. Additional AEs (Tier 2 AEs) also were recorded. Overall, the incidence of tier 1 AEs, including those commonly associated with pegIFN and/or RBV such as hematological side effects of decreased hemoglobin and decreased neutrophil count, were lower in the Zepatier treatment group versus the sofosbuvir plus pegIFN/RBV treatment group. In the Zepatier (elbasvir and grazoprevir) treatment group, headache was the only AE reported at a frequency of greater than 10 per cent. In the sofosbuvir plus pegIFN/RBV treatment group, AEs reported in greater than 10 per cent of patients were pyrexia, headache, fatigue, asthenia, influenza-like illness, chills, myalgia, decreased appetite, anemia, nausea and cough. No grade three or four abnormalities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) or hemoglobin were observed in the  Zepatier group. In the sofosbuvir plus pegIFN/RBV group, one patient had a grade three ALT abnormality and five patients had grade three or four hemoglobin reduction.

“Treatment regimens containing peginterferon and ribavirin are associated with certain serious side effects,” said Dr. Jan Gerstoft, Clinic for Infectious Diseases and Rheumatology, Copenhagen, Denmark. “This study provides evidence for the clinical potential of elbasvir and grazoprevir in chronic HCV genotype 1- or 4-infection as compared with a regimen containing peginterferon and ribavirin along with sofosbuvir.”

In subjects receiving Zepatier for 12 weeks, the most commonly reported adverse reactions of all intensity (greater than or equal to 5 per cent in placebo-controlled trials) were fatigue, headache and nausea. In subjects receiving  Zepatier with RBV for 16 weeks, the most commonly reported adverse reactions of moderate or severe intensity (greater than or equal to 5 per cent) were anemia and headache.