Safety Study to Investigate PSI-7977 in Combination With SOC in Treatment-Naïve HCV Patients With Chronic Hepatitis C Virus(HCV) Infection

Inclusion Criteria:

1. Males or females aged 18 to 70 years, inclusive, at Screening.

   A female is allowed to enter and participate in the study if she is either of:

   • Non-childbearing potential (i.e., physiologically incapable of becoming pregnant), including any female who:

     • Has had a hysterectomy or
     • Has had a bilateral oophorectomy (ovariectomy) or
     • Is post-menopausal (a demonstration of a total cessation of menses for ≥ 1 year). Follicle Stimulating Hormone will be performed to confirm post-menopausal status or
     • Has had a bilateral tubal ligation or fallopian tube inserts.

   • Childbearing potential, has a negative serum pregnancy test at Screening, and agrees to or has undergone one of the following:

     • Complete abstinence from sexual intercourse from 2 weeks prior to administration of the study drug until completion of the Follow-up procedures and at least 6 months after the last dose of ribavirin
     • Vasectomized partner
     • Use of an intrauterine device from 2 weeks prior to administration of study drug until completion of the Follow-up procedures and at least 6 months after the last dose of ribavirin
     • Double barrier method [condom or occlusive cap (diaphragm or cervical/vault caps) used with spermicidal foam/gel/film/cream/suppository]

   A male is allowed to enter and participate in the study if he either:

   • Is a sterile male or

   • Agrees to use from 2 weeks prior to administration of the study drug until completion of the follow up procedures and at least 6 months after the last dose of ribavirin at least one of the following approved methods of contraception:

     • a male condom with spermicide; a sterile sexual partner; use by female sexual partner of an IUD; a female condom with spermicide; an intravaginal system [e.g., NuvaRing®]; a diaphragm with spermicide; a cervical cap with spermicide; or oral, implantable, transdermal, or injectable contraceptives

2. Chronic Genotype 1, 2, or 3 Hepatitis C Virus (HCV)-infection documented by at least one measurement of serum HCV RNA ≥ 50,000 IU/mL measured during Screening by the COBAS AmpliPrep/COBAS TaqMan HCV and at least one of the following:

   • A positive anti-HCV antibody, HCV RNA, or an HCV genotype test at least 6 months prior to baseline (Day 1) visit together with positive HCV RNA test and anti-HCV antibody at the time of screening; or
   • A positive HCV RNA test and anti-HCV antibody test at the time of screening together with either a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of CHC disease, such as the presence of fibrosis)
3. Naïve to all HCV antiviral treatment(s), including but not limited to immunomodulatory and nucleoside/tide treatments for chronic HCV infection.
4. A body mass index (BMI) of greater than 18 kg/m2, but not exceeding 36 kg/m2.
5. Otherwise healthy as determined by the medical history, physical examination, ECG, and clinical laboratory measurements performed at Screening.
6. Liver biopsy obtained within 3 years (36 calendar months) prior to the Day 1 visit, with a fibrosis classification of non-cirrhotic as judged by a local pathologist (defined as Knodell ≤ 3, Metavir ≤ 2, Ishak ≤ 4, or Batts & Ludwig ≤ 2). Both incomplete and transition to cirrhosis (e.g., Metavir score 3) are considered as cirrhosis. If no recent (<36 months) liver biopsy is available, a study qualifying biopsy must be performed prior to the baseline (Day 1) visit.
7. Able to effectively communicate with the Investigator and other center personnel. Willing to give written informed consent and comply with the study restrictions and requirements.
8. Patient should be willing to refrain from beginning any new exercise regimens during the first 3 months of the study.
9. Fasting blood glucose ≤300 mg/dl and/or HbA1c≤ 8
10. Patients with a history of hypertension only if managed effectively on a stable regimen of two or fewer antihypertensives for at least three (3) months prior to Screening.

Exclusion Criteria:

1. Positive test at Screening for HBsAg, anti-HBc IgM Ab, or anti-HIV Ab.
2. History of any other clinically significant chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, Wilson's disease, 1-antitrypsin deficiency, alcoholic liver disease, > Grade 1 non-alcoholic steatohepatitis and toxin exposures).
3. Treatment with herbal/natural remedies with antiviral activity within 30 days of the baseline.
4. Any significant history of immunologically mediated disease, cardiac or pulmonary disease, seizure disorder or anticonvulsant use, in the opinion of the Investigator.
5. Patients with a history of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions consistent with decompensated liver disease.
6. Any patient who has used medications associated with QT prolongation within 30 days prior to dosing the protocol, including but not limited to macrolides, antiarrhythmic agents, azoles, fluoroquinolones, and tricyclic antidepressants.
7. Screening ECG QTc value greater than 450 ms and/or clinically significant ECG findings.
8. A personal or family history of Torsade de pointes.
9. Positive results on screen for drugs of abuse test at Screening (unless used as medical treatment, e.g., with a prescription).

10. Abnormal hematological and biochemical parameters, including:

    • neutrophil count <1500 cells/mm3 (or < 1250 cells/mm3 for African American/black subjects)
    • Hgb < 11 g/dL in females or 12 g/dL in males
    • creatinine ≥ 1.5 times upper limit of normal (ULN)
    • ALT, AST, or alkaline phosphatase ≥ 5 times ULN
    • total bilirubin ≥ 2.0 times ULN (except patients with Gilbert's syndrome)
    • albumin ≤ 3.0 g/dL
    • serum lipase ≥ 1.5 times ULN (at Screening or during the Screening period)
    • potassium or magnesium less than the lower limit of normal (LLN)
    • platelet count ≤ 90,000
11. History of major organ transplantation with an existing functional graft.
12. History of uncontrolled thyroid disease or abnormal TSH levels as defined < 0.8 x LLN or > 1.2 x ULN at Screening
13. Donation or loss of more than 400 mL blood within 2 months prior to first dose administration.
14. History of clinically significant drug allergy to nucleoside/nucleotide analogs.
15. History or current evidence of psychiatric illness, immunologic disorder, pulmonary, cardiac disease, seizure disorder, cancer or history of malignancy that in the opinion of the investigator makes the patient unsuitable for the study.
16. History of having received any systemic antineoplastic or immunomodulatory treatment (including supraphysiologic doses of steroids > 10 mg/day, and radiation) within 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.
17. Participation in a clinical study with an investigational drug, biologic, or device within 3 months prior to first dose administration.
18. Pregnant/Breastfeeding women.