847 ACH-2684 DEMONSTRATES POTENT VIRAL SUPPRESSION IN GENOTYPE 1 HEPATITIS C PATIENTS WITH AND WITHOUT CIRRHOSIS: SAFETY, PHARMACOKINETIC, AND VIRAL KINETIC ANALYSIS

Abstract

Background: ACH-2684 is a second-generation HCV NS3 protease inhibitor in Phase Ib development for the treatment of chronic HCV infection. ACH-2684 demonstrates potent activity in vitro against genotype-1 (GT1) HCV and, as compared to other protease inhibitors, has improved activity against multiple viral variants. Presented here are phase I study results in cirrhotic and non-cirrhotic patients with chronic HCV GT1 infection. Methods: ACH-2684 or placebo was administered to non-cirrhotic (n = 30) and cirrhotic (n = 8) patients with chronic HCV GT1 infection. Pharmacokinetic, (PK) viral load and safety assessments were collected on Days 1 through 35. Serial blood samples were collected on Day 1 and Day 3, and plasma non-compartmental pharmacokinetic parameters were determined. Drug efficiency was estimated by applying a single population viral dynamics model (Neumann et al, Science 1998, 282,103). Results: ACH-2684 was safe and well tolerated in non-cirrhotic and cirrhotic patients. There were no serious adverse events, and no discontinuations for safety concerns. Mean maximum reductions in plasma HCV RNA were 3.36, 3.73 and 4.16 log10 (IU/ml) at doses of 100 mg daily, 400 mg daily and 400 mg twice daily, respectively. In cirrhotic patients administered 400 mg daily, mean maximum reduction was 3.67 log10 (IU/ml). The systemic exposures were generally greater than doseproportional for the dose range studied in non-cirrhotics, and approximately 2-fold higher in cirrhotic versus non-cirrhotic patients. The drug efficiency of the 400 mg daily dose in non-cirrhotic and cirrhotic subjects was similar at 0.9993 ± 0.0005 and 0.9991 ± 0.0007, respectively. Conclusions: ACH-2684 was safe and well-tolerated, and produced more than a 3 log10 (IU/ml) mean maximum reduction in plasma HCV RNA levels in all groups. A 400 mg dose of ACH-2684 yielded approximately a 2-fold higher exposure in cirrhotics than non-cirrhotics, but was still safe and well-tolerated, and was equally effective in reducing HCV RNA levels. Viral kinetics parameters were robust and demonstrated high drug efficiency. These data provide evidence that ACH-2684 is a safe and well-tolerated protease inhibitor with potent anti-viral activity in both cirrhotic and non-cirrhotic patients with chronic GT-1 HCV infection, making it a promising candidate for future treatment of chronic HCV infection.