Daclatasvir+GS-7977 achieves SVR4 in genotype I, II and III HCV patients

Bristol-Myers Squibb has dislcosed interim results from a Phase II open-label study of daclatasvir, the company's NS5A replication complex inhibitor, and GS-7977, a nucleotide NS5B polymerase inhibitor, in treatment-naïve patients with hepatitis C (HCV) genotypes I, II and III. In this interim analysis, a combination of the two oral, once-daily investigational compounds taken for 24 weeks, with or without ribavirin, achieved a rapid and sustained viral response.

The Phase II study (AI444-040) was designed to evaluate the potential to achieve sustained virologic response with an oral, pan-genotypic, once-daily treatment regimen combining daclatasvir (DCV) and Gilead Sciences' GS-7977, with or without ribavirin, in patients chronically infected with HCV genotypes I, II and III. In the initial phase of this study, patients were randomised into six groups, evaluating three different dosing schedules in patients with HCV genotype I (n=44) and in patients with HCV genotype II or III (n=44): GS-7977 400mg QD for seven days then DCV 60mg QD+GS-7977 400mg QD for 23 weeks; DCV 60mg QD+GS-7977 400mg QD for 24 weeks; and DCV 60mg QD+GS-7977 400mg QD+ribavirin for 24 weeks.

The study was subsequently expanded to include four new treatment arms that evaluate HCV genotype I patients who have previously failed telaprevir or boceprevir treatment, and shorter duration of therapy in treatment-naïve HCV genotype I patients. These treatment groups are currently under study. The primary endpoint is sustained virologic response 12 weeks post-treatment (SVR12). An interim analysis for safety and antiviral activity was conducted at 12 weeks on-treatment. An additional interim analysis for antiviral efficacy was conducted four weeks post-treatment. All of patients with genotype I, II or III HCV achieved viral load below the lower limit of quantification at week four on treatment. In the genotype I HCV treatment groups, 100 per cent of patients achieved sustained virologic response to four weeks off-treatment (SVR4). In the genotypes II and III treatment groups, 91 per cent (40/44) of patients achieved SVR4.

In the study, 88 treatment-naïve patients were divided into six treatment groups. The proportions of patients achieving viral load below the lower limit of quantification (HCV RNA <25 IU/mL) were:

DoseHCV GenotypeWeek four on-treatmentWeek 12 on-treatmentWeek 24 on-treatmentWeek four post-treatment (SVR)
GT I100% (15/15)100% (15/15)87% (13/15)100% (15/15)
Seven-day lead-in dose of GS-7977, then DCV+GS-7977 for 23 weeksGT II/III100% (16/16)88% (14/16)94% (15/16)88% (14/16*)
GT I100% (14/14)93% (13/14)86% (12/14)100% (14/14)
DVC+GS-7977 for 24 weeksGT II/III100% (14/14)93% (13/14)100% (14/14)100% (14/14)
GT I100% (15/15)100% (15/15)93% (14/15)100% (15/15)
DCV+GS7977+ribavirin for 24 weeksGT II/III100% (14/14)100% (14/14)86% (12/14)86% (12/14**)

*One patient experienced viral relapse and one patient experienced viral breakthrough.

**Two patients were lost to follow-up.

Safety data from this ongoing study are available up to 12 weeks on-treatment. No patients discontinued therapy due to treatment-related AEs. Of the 88 patients treated, one patient with genotype III HCV who received GS-7977 and daclatasvir without ribavirin experienced viral relapse, and one patient met the protocol definition of viral breakthrough - HCV RNA below the lower limit of quantification on or after week eight, confirmed by immediate retesting. However, this definition of viral breakthrough is not widely accepted and has since been removed from the protocol.

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Sector: Medical Devices
Geography: Spain

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