1 research outputs found
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.
Background: Ruzasvir (RZR, MKâ8408, an NS5A inhibitor) plus uprifosbuvir (UPR, MKâ3682, an NS5B uridine nucleotide polymerase inhibitor) in combination with grazoâ previr (GZR, an NS3/4A inhibitor) as a threeâdrug regimen has demonstrated promising efficacy in people with HCV GT1, 2, 3, 4, or 6 infection. Given the high efficacy of the threeâdrug regimen, the aim of this trial was to evaluate the safety and efficacy of a twoâdrug regimen of RZR 60 mg + UPR 450 mg without ribavirin for 12 weeks. Methods: A Phase 2, openâlabel, multiâarm clinical trial was conducted in adults with GT1â6 chronic HCV infection who were treatmentânaive or treatmentâexperienced 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 \u3c15 IU/mL]), and safety and tolerability. Resistanceâassociated substitutions (RASs) were assessed using nextâgeneration 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 \u3c15 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 postâtherapy followâup (Table) One cirrhotic treatment naĂŻve participant with GT1a infection and baseline NS5A Q30H and Y93H RASs relapsed with detectable treatmentâemergent Q30L and M28G. Nine treatment naĂŻve participants with GT3 infection relapsed, two of whom had baseline NS5A S62T and/or A30L RASs; all nine developed treatmentâemergent Y93H. Treatment was generally well tolerated. The most frequent drugârelated adverse events in all participants were fatigue (6.3%), diarrhea (5.6%), nausea (4.3%), and headache (3.8%). Conclusions: The twoâdrug 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). Viroâ logic failure in participants with GT3 infection was not clearly associated with presence of baseline RASs, but was associated with treatmentâemergent NS5A RASs. Higher doses of RZR in a twoâdrug combination with UPR may be needed to optimize efficacy against some HCV genotypes. Complete SVR12 results will be presented