Zepatier for the Treatment of Chronic Hepatitis C Genotype 1 and 4 Infection, United States of America
Zepatier (elbasvir and grazoprevir) is a once-daily oral selective NS5A replication complex inhibitor (elbasvir-50mg) and NS3/4A protease inhibitor (grazoprevir-100mg) for the treatment of patients with chronic hepatitis C virus (HCV) GT1 with end-stage renal disease and patients with chronic HCV GT4.
The new drug application (NDA) for Zepatier was submitted by Merck to US Food and Drug Administration (FDA) on 28 May 2015.
The FDA granted breakthrough therapy designation status for the drug in April 2015 and approved it for the treatment of patients with chronic HCV GT1 and GT4 infections on 28 January 2016.
Merck submitted the license application for Zepatier in Europe in July 2015.
Hepatitis C virus GT1 and GT4 infection
Hepatitis C infection is a liver disease caused by hepatitis C, a blood borne virus. The infection may range from an acute mild illness to a chronic lifelong illness.
HCV is a small enveloped, single-stranded, positive-sense RNA virus, which occurs in seven major genotypes classified as one to seven. It causes inflammation of the liver, leading to decreased liver function or liver failure.
The infection is an asymptomatic until the liver damage becomes evident in patients, which takes several years. The chronic viral infection is characterised by cirrhosis, associated with complications such as bleeding, jaundice, fluid accumulation in the abdomen, infections or liver cancer.
Approximately three million Americans are estimated to have HCV, of which genotype one is most common and genotype four is the least common.
Zepatier's (elbasvir and grazoprevir) mechanism of action
Zepatier is a combination of NS5A replication complex inhibitor and NS3 / 4A protease inhibitor, which functions by inhibiting the activity of NS5A protein and NS3 / 4A protease of the viral cells.
The NS5A replication complex inhibitor prevents replication of viral cells by interacting with NS5A protein on HCV replicon cells, which are responsible for reducing human interferon antiviral activity.
The NS3/4A protease inhibitor stops viral replication by binding to the NS3/4A protease, a serine protease domain that is essential for viral poly-protein maturation and neutralisation of the host's innate antiviral immunity for HCV.
The FDA approved Zepatier (elbasvir and grazoprevir) based on results obtained from the Phase II, Phase IIb / III and Phase III clinical trials namely C-SCAPE (Phase II), C-SALVAGE (Phase-II), C-SUFFER (Phase IIb / III), C-EDGE (Phase III), C-EDGE TN (Phase III), C-EDGE CO-INXFN (Phase III) and C-EDGE TE (Phase III).
The open-label, randomised, double-blind, placebo-controlled clinical trials enrolled 1,373 patients with chronic HCV GT1 or GT4 infection to demonstrate the safety and efficacy of Zepatier (elbasvir and grazoprevir) by assessing the rate of sustained virologic response 12 weeks after completion of treatment (SVR12).
The trials conducted on HCV genotype one infected patients were C-EDGE TN (double-blind, placebo-controlled), C-EDGE CO-INFXN (open-label, single arm), C-SUFFER (double blind, placebo-controlled) C-EDGE TE (open-label, comparative) and C-SALVAGE (open label, single arm).
The trials conducted on HCV genotype 4 infected patients were C-SCAPE (open label), C-EDGE TN, C-EDGE CO-INFXN and C-EDGE TE.
Merck also conducted three more Phase II trials namely C-CREAST 1, C-CREAST 2 and C-WORTHY on HCV GT1, GT2 and GT3 infected patients respectively.
The drug's safety and efficacy with or without ribavirin were evaluated in clinical trials on 1,373 chronic HCV genotype one or four infected patients with and without cirrhosis.
Subjects were administered Zepatier with or without ribavirin once daily for either 12 or 16 weeks. Overall SVR rates were observed to be from 94% to 97% in genotype one infected subjects, while the range in genotype four infected subjects was from 97% to 100%.
Fatigue, headache and nausea were the most common side effects of Zepatier without ribavirin, while those in Zepatier with ribavirin were anaemia and headache.