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

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. Drugrelated 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.

Cell Culture Studies of the Efficacy and Barrier to Resistance of Sofosbuvir-Velpatasvir and Glecaprevir-Pibrentasvir against Hepatitis C Virus Genotypes 2a, 2b, and 2c

“…found to be highly effective, but only for certain genotypes (32). Unfortunately, at the onset of this study, we did not have access to ruzasvir, so we instead tested the combination of uprifosbuvir with the NS5A inhibitor elbasvir.…”

Efficacy and safety of a two‐drug direct‐acting antiviral agent regimen ruzasvir 180 mg and uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis C virus genotype 1, 2, 3, 4, 5 or 6

“…In the current trial, we hypothesized that an increased dose of ruzasvir would overcome the lower efficacy in individuals with HCV GT3 infection observed in C‐BREEZE‐1 . However, we observed that the ruzasvir 180 mg dose used in the present study did not result in higher efficacy in participants with GT3 infection compared with the 60‐mg dose of ruzasvir used in C‐BREEZE‐1 (SVR12 rates of 77% and 73.8%, respectively) . It is possible that a plateau was reached on the dose‐response curve such that increasing the dose of ruzasvir did not result in any increase in efficacy for GT3 infection.…”

“…The C‐BREEZE‐1 trial of ruzasvir 60 mg plus uprifosbuvir 450 mg did not show pangenotypic activity; SVR12 rates were high among those with HCV GT1a (96%; 52/54), GT1b (100%; 15/15), GT2 (97% 28/29) and GT4 infection (90%; 18/20), with lower efficacy in those with GT3 (77%; 33/39) and GT6 infection (67%; 2/3) . In the phase II C‐CREST trials, the three‐drug regimen of ruzasvir 60 mg and uprifosbuvir 450 mg in combination with grazoprevir 100 mg, with or without ribavirin, resulted in SVR12 rates of >90% in a broad patient population with HCV GT1, GT2, GT3, GT4 or GT6 infection .…”

“…Removal of grazoprevir would eliminate drug‐drug interactions caused by the NS3/4A protease inhibitor drug class and would also eliminate concerns regarding hepatic transaminase elevations with the protease inhibitor, thus potentially enabling use of the two‐drug regimen in a broader range of populations. In the C‐BREEZE 1 study (NCT02759315), ruzasvir 60 mg and uprifosbuvir 450 mg were well tolerated but demonstrated lower efficacy for those infected with GT3 and GT6 infection compared with those with GT1, GT2 or GT4 infection . It was hypothesized that a higher dose of ruzasvir might improve the efficacy of this regimen and support a pangenotypic profile.…”

Interplay of Amino Acid Residues at Positions 28 and 31 in NS5A Defines Resistance Pathways in Hepatitis C Virus Genotype 2

“…In part A of the phase 2 C-CREST-1 and C-CREST-2 trials that investigated a 3-drug combination over an 8-week treatment duration, the combination of grazoprevir (100 mg), uprifosbuvir (450 mg), and ruzasvir (60 mg) was selected for further testing over the combination of grazoprevir, uprifosbuvir, and elbasvir (50 mg), as the former consistently resulted in higher 12-week SVR (SVR12) rates in HCV genotypes, including GT2 (27). In the phase 2 C-BREEZE trial, the combination of ruzasvir (60 mg) and uprifosbuvir, an NS5B polymerase prodrug (450 mg), administered once daily for 12 weeks resulted in a 100% SVR among GT2-infected patients (28). It seems reasonable to conclude that the success of the trial was, in part, due to the activity of ruzasvir in GT2.…”