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

J Viral Hepat. 2019;26(6):675-684. 

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) 16 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.^[25]

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,^[79] 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 inhibitorcontaining 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.

Discussion

The combination of RZR 60 mg and UPR 450 mg once daily for 12 weeks was generally well tolerated. Data from the present study indicate that the combination showed high efficacy in participants with HCV GT1b, GT2 and GT4 infections, with SVR12 rates of 100%, 100% and 90%, respectively, in the PP analysis. No virologic failures occurred among participants with GT1b or GT2 infection, and only one virologic failure occurred within the GT4 cohort. In those with GT1a infection, 52 of 54 (96%) had SVR12, with two participants experiencing virologic relapse. The efficacy was lower in participants with GT3 infection: SVR12 was 77%, with 9 of 39 participants experiencing virologic relapse. Among the three participants with GT6 infection enrolled in this study, two achieved SVR12 and one experienced virologic relapse.

Efficacy did not appear to be impacted by treatment history across all genotypes, although there were relatively few treatment-experienced participants enrolled, and the number of HCV GT6-infected participants was very small. In participants with GT1b, GT2 and GT4 infections, SVR12 was similar in those with cirrhosis and without cirrhosis. However, cirrhosis may be associated with lower efficacy rates after treatment with this regimen. Both of the GT1a-infected participants who experienced virologic relapse were cirrhotic; one participant had no baseline NS5A RAS, while the other had baseline Q30H and Y93H RASs. It is difficult to evaluate whether there may be a potential impact of baseline Y93 RASs on SVR in HCV GT1a infection after treatment with this two-drug regimen because the clinical data are limited to a small number of participants. In addition, among participants with GT3 infection, relapse was more common in cirrhotic participants, as 67% (6/9) of GT3-infected participants with virologic failure were cirrhotic. Of note, of the nine GT3-infected participants with relapse, only two had baseline NS5A RASs: one cirrhotic participant with S62T and another noncirrhotic participant with A30L and S62T; none had Y93 RASs. Of the two GT4-infected participants who experienced relapse, one was cirrhotic and one was noncirrhotic. The one GT6-infected participant with relapse was cirrhotic. These data suggest that infection with certain HCV genotypes (such as GT1a, GT3 and GT6) combined with the presence of cirrhosis and/or baseline RASs are associated with lower SVR rates after treatment with RZR plus UPR at the doses evaluated in this study.

The results from this study also allowed a deeper understanding of the contribution of GZR within a three-drug regimen with RZR and UPR. This three-drug regimen was evaluated in the phase II C-CREST-1 and -2 studies, which included 676 participants with GT1, GT2 or GT3 infection.^[9] The plasma exposures of RZR and UPR and their metabolites were comparable when administered as part of a three-drug or two-drug regimen. Among participants receiving the once-daily combination of RZR 60 mg plus UPR 450 mg plus GZR 100 mg for 12 weeks, SVR12 was achieved by 98% (47 of 48), 100% (40 of 40) and 98% (45 of 46) of those with GT1a, GT1b and GT2 infection, respectively.^[9] These rates are similar to those in the present study, where SVR12 was achieved by 96% (52 of 54), 100% (15 of 15) and 97% (28 of 29) of GT1a-, GT1b- and GT2-infected participants receiving RZR 60 mg plus UPR 450 mg for 12 weeks in the FAS population. These data indicate that the two-drug combination of RZR 60 mg plus UPR 450 mg is sufficient to achieve SVR12 rates >95% in participants with GT1 and GT2 infection and that adding a third antiviral agent, such as GZR, may not offer clear benefit in these participants. However, SVR12 rates among participants with GT3 infection were 96% (76 of 79) in the C-CREST studies after treatment with GZR/RZR/UPR^[9] and 77% (30 of 39) after treatment with RZR plus UPR. Notably, SVR12 rates in noncirrhotic participants with GT3 infection were 96% (49 of 51) and 90% (26 of 29) with GZR/RZR/UPR and RZR plus UPR, respectively, whereas SVR12 rates in cirrhotic GT3-infected participants were 96% (27 of 28) and 40% (4 of 10), respectively. Similarly, the SVR12 rate in participants with GT4 infection receiving the three-drug regimen for 8 weeks was 100% (7 of 7) compared with 90% (18 of 20) in those receiving RZR plus UPR for 12 weeks. Although limited by small sample sizes, in GT6-infected participants in the C-CREST studies, the SVR12 rates were 100% (4 of 4) after treatment with GZR/RZR/UPR and 67% (2 of 3) after treatment with RZR plus UPR. These indirect comparisons suggest that the two-drug combination of RZR plus UPR is adequate for easier-to-cure genotypes and/or patient populations that have more favourable characteristics, but the addition of GZR may result in higher efficacy in harder-to-cure populations.

Cirrhotic individuals with HCV GT3 infection are known to be a difficult-to-cure population, and treatment-emergent NS5A Y93H variants are frequently associated with virologic failure in these individuals. In the SURVEYOR-II study,^[10] five of 131 participants with GT3 infection receiving glecaprevir/pibrentasvir for 1216 weeks experienced virologic failure and treatment-emergent Y93H variants were detected at the time of virologic failure in all five. Y93H was detected at the time of virologic failure in 19 of 20 patients who failed daclatasvir plus SOF with or without RBV for 12 or 16 weeks in the ALLY-3 and ALLY-3+ studies.^[11,12] Y93H was also detected at the time of virologic failure in all ten patients with GT3 infection who relapsed after receiving SOF/VEL for 12 weeks in the ASTRAL-3 study,^[13] in both of the cirrhotic patients who relapsed after receiving SOF/VEL for 12 weeks in the POLARIS-3 study,^[14] in four of five cirrhotic patients with GT3 infection and successful NS5A sequencing who relapsed following SOF/VEL for 12 weeks in the Spanish GT3 compensated cirrhosis study^[15] and in both cirrhotic patients with GT3 infection who relapsed following SOF/VEL plus RBV for 12 weeks in the same study.^[15] In the present study, nine of 39 participants with GT3 infection experienced virologic relapse: six were cirrhotic, and all nine had the Y93H variant at the time of failure. In the C-ISLE study, SVR12 was achieved by 98% (40 of 41) of cirrhotic participants with GT3 infection receiving elbasvir (EBR)/GZR plus SOF for 12 weeks, with one participant experiencing nonvirologic failure and no virologic relapses.^[16] In that study, nine participants had detectable baseline Y93H variants; eight of these nine participants achieved SVR12, and one who received EBR/GZR plus SOF plus RBV for 8 weeks experienced virologic relapse. These data suggest that the Y93H effect in people with HCV GT3 infection can be overcome with a potent protease inhibitor.

Limitations of the present study include the relatively small sample size and size of certain participant populations. Most participants were treatment-naive, white and male, and therefore certain subgroups, such as black participants and those with HIV coinfection, are not well represented. In addition, because participants who had been treated previously with a DAA-containing regimen or who had decompensated liver disease were excluded from the study, the data from this study cannot be extrapolated to these populations. No participants with GT5 infection were enrolled, so the efficacy of RZR plus UPR in this population also remains to be established. The number of GT6-infected participants was limited, so the efficacy data in this population should be interpreted with caution. Finally, this was a nonrandomized phase II study without a comparator treatment group, and therefore a direct comparison with other treatments for HCV infection is not possible.

In conclusion, 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. Uprifosbuvir 450 mg plus RZR at the higher dose of 180 mg once daily for 12 weeks is undergoing investigation in participants with HCV GT1, GT2, GT3, GT4 or GT6 infection to evaluate whether a higher dose of RZR can achieve higher efficacy rates, particularly in GT1a-, GT3- and GT6-infected people.^[17]