Efficacy and Safety of Ruzasvir 60 mg and Uprifosbuvir 450 mg for 12 Weeks in Adults With Chronic Hepatitis C Virus Genotype 1, 2, 3, 4 or 6 Infection

Eric Lawitz; Fred Poordad; Leah J. Anderson; Michelle Vesay; Michelle M. Kelly; Hong Liu; Wei Gao; Doreen Fernsler; Ernest Asante-Appiah; Michael N. Robertson; George J. Hanna; Eliav Barr; Joan Butterton; Kris V. Kowdley; Tarek Hassanein; Amandeep Sahota; Stuart C. Gordon; Wendy W. Yeh

Disclosures

J Viral Hepat. 2019;26(6):675-684. 

In This Article

Abstract and Introduction

Abstract

In clinical trials, the three-drug regimen of ruzasvir (RZR) 60 mg, uprifosbuvir (UPR) 450 mg and grazoprevir 100 mg, with or without ribavirin, has demonstrated promising efficacy and excellent tolerability across a wide range of hepatitis C virus (HCV)-infected individuals. The present study assessed the efficacy and safety of the two-drug combination of RZR 60 mg plus UPR 450 mg administered for 12 weeks in participants with HCV genotype (GT) 1–6 infection. In this open-label clinical trial, treatment-naive or -experienced and cirrhotic or noncirrhotic participants with chronic HCV GT1-6 infection received RZR 60 mg plus UPR 450 mg orally once daily for 12 weeks (NCT02759315/protocol PN035). The primary efficacy endpoint was sustained virologic response at 12 weeks after the end of therapy (SVR12). One hundred and sixty participants were enrolled. SVR12 rates were 96% (52 of 54) in participants with GT1a infection; 100% (15 of 15) in those with GT1b infection; 97% (28 of 29) in those with GT2 infection; 77% (30 of 39) in those with GT3 infection; 90% (18 of 20) in those with GT4 infection; and 67% (2 of 3) in those with GT6 infection. Drug-related adverse events (AEs) reported by >5% of participants were fatigue (n = 10, 6.3%) and diarrhoea (n = 9, 5.6%). Five participants reported a total of 11 serious AEs, none considered drug-related. One participant experienced on-treatment alanine aminotransferase/aspartate aminotransferase elevations that resolved without intervention. Data from the present study indicate that the combination of RZR 60 mg plus UPR 450 mg once daily for 12 weeks was well tolerated overall but was effective only for certain genotypes.

Introduction

The introduction of direct-acting antiviral agents (DAAs) has transformed the treatment of hepatitis C virus (HCV) infection, and pangenotypic regimens are now available that deliver high rates of sustained virologic response (SVR) across all HCV genotypes (GTs).[1] Currently available treatment approaches may be further optimized through the development of a once-daily, short-duration, oral regimen suitable for use in most people with HCV infection without regard for cirrhosis status, prior treatment status or administration with food and that does not have complex drug interactions. Currently, several two-drug treatment regimens are available for the treatment of HCV infection. Glecaprevir/pibrentasvir[2] and sofosbuvir (SOF)/velpatasvir[3] are approved for the treatment of all six major HCV genotypes, SOF/ledipasvir[4] is approved for people with HCV GT1, GT4, GT5 or GT6 infection, and elbasvir/grazoprevir[5] is approved for those with GT1 or GT4 infection. With each of these regimens, the treatment duration and/or requirement for ribavirin coadministration can vary, depending on factors such as HCV genotype, prior treatments for HCV infection, presence of drug-resistant HCV variants or presence of cirrhosis.[2–5]

Ruzasvir (RZR, MK-8408) is a potent HCV nonstructural protein 5A (NS5A) complex inhibitor with pangenotypic activity in vitro against resistance-associated substitutions (RASs) selected by first-generation NS5A inhibitors in individuals with HCV GT1a infection.[6] Uprifosbuvir (UPR, MK-3682) is a potent HCV NS5B polymerase nucleotide inhibitor with pangenotypic activity in vitro and a high barrier to resistance. In the phase II C-CREST studies,[7–9] the three-drug regimen of RZR 60 mg plus UPR 450 mg combined with grazoprevir (GZR, an approved NS3/4A protease inhibitor) 100 mg, with or without ribavirin (RBV), demonstrated promising efficacy and excellent tolerability in approximately 800 participants. These studies enrolled a broad patient population that included treatment-naive and prior interferon (IFN)–experienced, cirrhotic and noncirrhotic participants with HCV GT1, GT2, GT3, GT4 or GT6 infection, and participants with virologic relapse after treatment with all-oral, DAA regimens. The RZR/UPR/GZR combination without RBV for 12 weeks was highly effective and well tolerated in cirrhotic and noncirrhotic, treatment-naive or interferon-experienced participants with HCV GT1, GT2, GT3, GT4 or GT6 infection.[8,9] Furthermore, RZR/UPR/GZR with RBV for 16 weeks or without RBV for 24 weeks was highly effective and well tolerated in GT1-infected participants with virologic relapse after prior treatment with an NS5A inhibitor–containing all-oral DAA regimen.[7] Given the high efficacy of RZR/UPR/GZR in the C-CREST studies and the availability of other effective two-drug treatment regimens, the aim of the present study was to assess the efficacy and safety of a two-drug regimen of RZR 60 mg plus UPR 450 mg without RBV administered for 12 weeks in participants with GT1-6 infection.

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