Safety, Tolerability, Pharmacokinetics and Antiviral Activity of GS-9669 in Subjects With Chronic Hepatitis C Virus Infection

• Safety and Tolerability [ Time Frame: through 24 weeks of off-treatment follow-up ]

  To evaluate safety and tolerability of escalating multiple oral doses of GS 9669.

  Safety will be assessed during the study through the reporting of adverse events, clinical laboratory tests, physical examinations, vital signs, and 12-lead ECGs at various time points during the study.

• Antiviral Activity [ Time Frame: through 24 weeks of off-treatment follow-up ]
  To evaluate antiviral activity of GS-9669 against HCV in genotype-1a and 1b (GT1a/b) subjects. This will be evaluated using change from baseline in plasma HCV RNA. Reduction in HCV RNA will be summarized as categorical (as < 1, ≥ 1 to <2, ≥ 2 to <3, or ≥ 3 log10 IU/mL) reduction from baseline.

• Viral Dynamics and Pharmacodynamics [ Time Frame: Through 17 days of therapy ]
  To characterize the viral dynamics of GS-9669. The median change from baseline in HCV RNA and time-weighted average change from baseline through Day 3 will be assessed based on plasma HCV RNA sampling times to characterize the viral dynamics of GS-9669.
• composite of Pharmacokinetics [ Time Frame: Through 17 days of therapy ]
  To characterize the plasma PK parameters of GS-9669. The secondary PK endpoints will be evaluated using standard non-compartmental methods. Relevant PK parameters will be determined using standard non-compartmental methods with the linear-logarithmic trapezoidal rule utilizing a PK data analysis program (e.g., WinNonlin®) for GS-9669 as appropriate: Cmax, Tmax, Clast, Tlast, Ctau, λz, AUC0-last, AUCtau, , CL/F, and T½.
• Genotypic Changes [ Time Frame: through 24 weeks of off-treatment follow-up ]
  To characterize genotypic changes from baseline in the NS5B coding region of HCV following multiple dose administration of GS-9669 and for up to 24 weeks thereafter

This is a research study to evaluate the safety, tolerability and anti-viral activity of GS-9669 in patients with Hepatitis C infection.

• Drug: GS-9669 tablets
  Other Names:

  • Cohort 1 (N = 10, genotype 1a): 100 mg GS-9669 or placebo BID with
  • food [total daily dose (TDD) = 200 mg] for 3 days;
  • Cohort 2 (N = 10, genotype 1a): 400 mg GS-9669 or placebo BID with
  • food (TDD = 800 mg) for 3 days;
  • Cohorts 1 and 2 may be conducted in parallel. Additional adaptive BID
  • and/or QD cohorts (Cohorts 3-5) in genotype 1a subjects may be
  • conducted depending on the safety, virology, and available
  • pharmacokinetics from the first two cohorts. Cohorts 3 -5 may be
  • conducted in parallel if the total daily dose is lower than the highest total
  • daily dose previously tested and determined to be safe and well tolerated.
  • Cohort 3 (N = 10, genotype 1a): up to 400 mg GS-9669 or placebo BID
  • with food (TDD = up to 800 mg) for 3 days;
  • Cohort 4 (N = 10, genotype 1a): up to 400 mg GS-9669 or placebo BID
  • Cohort 5 (N=10, genotype 1a): up to 800 mg GS-9669 or placebo QD in
  • the morning with food (TDD = up to 800 mg) for 3 days;
  • Based on the results of Cohorts 1 to 5, one or more regimens will be
  • selected for an evaluation in genotype 1b subjects to enable comparison
  • between genotypes. Cohorts 6 and 7 may proceed in parallel with other
  • Cohorts if the total daily dose is the same or lower than the highest total
  • Cohort 6 (N = 10, genotype 1b): up to 400 mg GS-9669 or placebo BID
  • with food (TDD = up to 800 mg) for 3 days
  • Cohort 7 (N = 10, genotype 1b): up to 800 mg GS-9669 or placebo QD in
  • the morning with food (TDD = up to 800 mg) for 3 days.
• Drug: Placebo to Match GS-9669 tablet

Inclusion Criteria:

• Adult subjects 18-65 years of old, inclusive
• Documented chronic HCV infection to be of at least 6 months duration and plasma HCV RNA ≥ 5 log10 IU/mL at screening.
• HCV treatment naïve or PEG-IFN, IFN, and/or RBV experienced (treatment must have ceased at least 3 months prior to screening). Treatment experienced subjects should not exceed 40% of the subjects enrolled in each cohort
• Mono-infection with HCV genotype 1a for Cohorts 1, 2, 3, 4, and 5 and mono-infection with HCV genotype 1b for Cohort 6 and 7.
• Estimated creatinine clearance ≥ 70 mL/min,
• QTcF interval ≤ 450 msec for males and ≤ 470 msec for females, QRS duration < 120 msec, PR interval < 220 msec,
• Body mass index (BMI) of 19.0 to 34.0 kg/m^2, inclusive.

Exclusion Criteria:

• Urine drug screen positive for illicit/illegal drugs
• ALT and AST levels > 5 times the upper limit of the normal range (ULN)
• Direct bilirubin > ULN, clinical or other laboratory evidence of hepatic decompensation (i.e., platelets < 90,000/mm^3, prothrombin time ≥ 1.5 × ULN and albumin < 3.5 g/dL) are not eligible for study participation.
• Subjects with an absolute neutrophil count (ANC) < 1,000 cells/mm^3 (< 750 cells/mm^3 for black or African-American subjects), hemoglobin (Hb) < 11 g/dL,
• Coinfected with hepatitis B virus (HBV), human immunodeficiency virus (HIV), or another HCV genotype other than genotype 1a/b are not eligible for study participation.
• Evidence of hepatocellular carcinoma (e.g., a-fetoprotein > 50 ng/mL or as indicated by recent ultrasound or other standard of care measure)
• History of significant cardiac disease. The following ECG abnormalities at screening are exclusionary: QTcF (QT corrected using Fridericia's formula=QT/RR^0.333) > 450 msec for males and > 470 for females; QRS > 120 msec (left or right hemiblock is not exclusionary); PR interval > 220 msec; bradycardia (< 45 beats per minute); second or third degree heart block.
• History of clinically-significant illness or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol
• History of a primary gastrointestinal disorder that could interfere with the absorption of the study drug or that could interfere with normal gastrointestinal anatomy or motility