C-BREEZE 1: Efficacy and safety of ruzasvir 60 mg plus uprifosbuvir 450 mg for 12 weeks in adults with chronic hepatitis c virus (HCV) genotype (GT)1, 2, 3, 4, or 6 infection.

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Background: Ruzasvir (RZR, MK‐8408, an NS5A inhibitor) plus uprifosbuvir (UPR, MK‐3682, an NS5B uridine nucleotide polymerase inhibitor) in combination with grazo‐ previr (GZR, an NS3/4A inhibitor) as a three‐drug regimen has demonstrated promising efficacy in people with HCV GT1, 2, 3, 4, or 6 infection. Given the high efficacy of the three‐drug regimen, the aim of this trial was to evaluate the safety and efficacy of a two‐drug regimen of RZR 60 mg + UPR 450 mg without ribavirin for 12 weeks. Methods: A Phase 2, open‐label, multi‐arm clinical trial was conducted in adults with GT1‐6 chronic HCV infection who were treatment‐naive or treatment‐experienced with interferon ± RBV and either had no cirrhosis or compensated cirrhosis (NCT02759315). All participants received RZR 60 mg + UPR 450 mg once daily for 12 weeks. The primary objectives were the assessment of efficacy (sustained virologic response at 12 weeks after the end of study therapy [HCV RNA <15 IU/mL]), and safety and tolerability. Resistance‐associated substitutions (RASs) were assessed using next‐generation sequencing (15% sensitivity threshold). Results: One hundred sixty participants were enrolled (GT1a, n=54; GT1b, n=15; GT2, n=29; GT3, n=39; GT4, n=20; GT5, n=0; GT6 n=3), 50 (31%) of whom had cirrhosis. All participants had HCV RNA <15 IU/mL at the end of treatment. Results to date are based on 149 participants who received 12 weeks of therapy and have at least 8 weeks of post‐therapy follow‐up (Table) One cirrhotic treatment naïve participant with GT1a infection and baseline NS5A Q30H and Y93H RASs relapsed with detectable treatment‐emergent Q30L and M28G. Nine treatment naïve participants with GT3 infection relapsed, two of whom had baseline NS5A S62T and/or A30L RASs; all nine developed treatment‐emergent Y93H. Treatment was generally well tolerated. The most frequent drug‐related adverse events in all participants were fatigue (6.3%), diarrhea (5.6%), nausea (4.3%), and headache (3.8%). Conclusions: The two‐drug combination of RZR 60 mg + UPR 450 mg for 12 weeks was well tolerated and has promising efficacy in GT1, 2, and 4 infection. However, the efficacy in GT3 infection was lower, particularly in cirrhotic participants (6/9 GT3 failures had cirrhosis). Viro‐ logic failure in participants with GT3 infection was not clearly associated with presence of baseline RASs, but was associated with treatment‐emergent NS5A RASs. Higher doses of RZR in a two‐drug combination with UPR may be needed to optimize efficacy against some HCV genotypes. Complete SVR12 results will be presented.



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