Merck's Oral HCV Treatment Awaits FDA Approval

Combination of grazoprevir and elbasvir has been studied in patients with genotype 1 hepatitis C who also have end-stage renal disease and are undergoing regular hemodialysis.

At the 2015 International Liver Conference in Vienna, Austria, Merck scientists presented phase 2 and 3 data of a new single-tablet treatment for hepatitis C virus infection (HCVI) that has received breakthrough therapy designation from the FDA.

The treatment, which contains 2 active ingredients—the NS3/4A protease inhibitor grazoprevir and the NS5A replication complex inhibitor elbasvir—has been studied in patients with genotype 4 HCVI and in patients with genotype 1 HCVI. Unlike other treatments, the 2-drug combination tablet has been studied in patients with genotype 1 HCVI who also have end-stage renal disease and are undergoing regular hemodialysis.

According to Dr Eliav Barr, vice president of infectious disease research at Merck Research Laboratories, the treatment is designed to be, “an efficacious, well-tolerated, once-daily therapy that can be used to treat multiple genotypes and a diverse population of chronic HCV patients.” Barr continued, “Our clinical program is among the largest and most comprehensive, with studies dedicated to patient populations where significant unmet medical need still exists, such as prior treatment failures, as well as those living with co-morbid conditions, including HIV infection, chronic kidney disease and individuals on opiate substitution therapy.”

In the C-EDGE phase 3 program, grazoprevir/elbasvir has been studied both with and without ribavirin in patients with genotypes 1, 4, and 6 HCVI. The duration of treatment is expected to be 12 weeks, much like other anti-HCV direct-acting antiviral regimens.

Interim results of the C-SURFER Phase 2/3 clinical trial program in patients with advanced CKD with or without liver cirrhosis in patients with genotype 1 HCVI indicate a high rate of cure with minimal adverse events. In this trial, 18% of patients had advanced chronic kidney disease, and a subgroup of patients had both chronic kidney disease and cirrhosis.

In a total of 116 evaluable patients with genotype 1 HCV who received treatment for 12 weeks, the combination led to a 99% cure rate (114 out of 116 patients were cured, as defined by a sustained viral response 12 weeks after the end of therapy [SVR12]). Discontinuations due to adverse events occurred in 4% of patients in the placebo arm, with none of the patients receiving active therapy due to adverse events. Serious adverse events occurred in 14% of patients receiving active treatment versus 17% of patients receiving placebo. The most frequent treatment-related adverse events were headache, nausea, and fatigue.

Other results support the value of grazoprevir/elbasvir in patients with HIV coinfection. In the phase 2 C-WORTHY trial, investigators tested different durations of treatment with grazoprevir/elbasvir with and without ribavirin in patients with genotype 1 hepatitis C, and in patients coinfected with genotype 1 hepatitis C and HIV. The 218-patient phase 2 trial netted cure rates of 93% to 98% in patients with genotype 1 HCVI without HIV, and 87% to 97% with genotype 1 HCVI coinfected with HIV.

Although 7 patients experienced virologic failure, including virologic failure associated with drug resistant mutations, none of the patients in the trial discontinued treatment as a result of adverse events or out-of-range blood chemistry values.

Merck’s investigational treatment initially received breakthrough designation from the FDA in October 2013. However, due to the development of other highly effective anti-HCVI therapies, the breakthrough status was nearly rescinded in January 2015. Owing to a clinical trial program showing data in patients with unmet needs in HCV, including patients with chronic kidney disease, Merck retained the breakthrough designation for the drug and filed a new drug application for the treatment with the FDA in late May 2015.

References

• Merck. Grazoprevir/Elbasvir, Merck’s Investigational Chronic Hepatitis C Therapy, Granted FDA Breakthrough Therapy Designations; New Phase 2 and 3 Data in Multiple HCV Patient Types to be Presented at The International Liver Congress™ 2015 [press release]. http://www.mercknewsroom.com/news-release/hepatitis-c-newsroom/grazoprevirelbasvir-mercks-investigational-chronic-hepatitis-c-the. Accessed July 2015.
• Merck. Merck Announces Results from Phase 2/3 Study of Investigational Chronic Hepatitis C Therapy Grazoprevir/Elbasvir in Patients with Advanced Chronic Kidney Disease [press release]. http://www.mercknewsroom.com/news-release/hepatitis-c-newsroom/merck-announces-results-phase-23-study-investigational-chronic-hep. Accessed July 2015.
• Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015;385(9973):1087-1097.
• Beckerman J. The Wall Street Journal. Merck Submits New Drug Application for Hepatitis Combination to FDA . http://www.wsj.com/articles/merck-submits-new-drug-application-for-hepatitis-combination-to-fda-1432849137. Accessed July 2015.