Study of SCY-635, Pegasys and Copegus in Hepatitis C

• Undetectable HCV RNA [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
• Partial early virologic response [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  Proportion of subjects with detectable HCV RNA that achieve a > or = 2 log reduction in HCV RNA from baseline to Week 12
• Undetectable HCV RNA [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
• Incidence and severity of treatment emergent adverse events and changes in laboratory values as measures of Safety and tolerability [ Time Frame: through Week 24 of the study ] [ Designated as safety issue: Yes ]
  Assessed by determining incidence and severity of adverse events, changes in physical examinations, vital signs, 12 lead electrocardiograms (ECGs), and laboratory assessments (serum chemistry, hematology, and urinalysis)
• Pharmacokinetic assessment of SCY-635 [ Time Frame: throughout first 8 weeks of treatment ] [ Designated as safety issue: No ]
  On Day 1 and Day 28, serial blood samples for assessing the pharmacokinetics of SCY 635 will be collected prior to the morning dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Primary PK parameters include AUC(0-12), Cmax, Tmax, and Cavg. Trough concentrations of SCY-635 will be measured on Days 7, 14, and 21 and at Week 8.
• Pharmacokinetics of peginterferon alfa 2a and Ribavirin (trough concentrations) [ Time Frame: throughout first 8 weeks of treatment ] [ Designated as safety issue: No ]
  Trough concentrations of PegIFN alfa 2a and RBV will be measured on Days 7, 14, 21 and 28 and at Week 8. No other pharmacokinetic parameters will be determined.

• Undetectable HCV RNA [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
• Partial early virologic response [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
  Proportion of subjects with detectable HCV RNA that achieve a > or = 2 log reduction in HCV RNA from baseline to Week 12
• Undetectable HCV RNA [ Time Frame: Week 48 ] [ Designated as safety issue: No ]
• Undetectable HCV RNA [ Time Frame: Week 72 ] [ Designated as safety issue: No ]
  Proportion of subjects achieving sustained virologic response defined as an undetectable serum HCV RNA level 24 weeks after the end of treatment.
• Incidence and severity of treatment emergent adverse events and changes in laboratory values as measures of Safety and tolerability [ Time Frame: through Week 72 of the study ] [ Designated as safety issue: Yes ]
  Assessed by determining incidence and severity of adverse events, changes in physical examinations, vital signs, 12 lead electrocardiograms (ECGs), and laboratory assessments (serum chemistry, hematology, and urinalysis)
• Pharmacokinetic assessment of SCY-635 [ Time Frame: throughout first 8 weeks of treatment ] [ Designated as safety issue: No ]
  On Day 1 and Day 28, serial blood samples for assessing the pharmacokinetics of SCY 635 will be collected prior to the morning dose and at 0.5, 1, 2, 3, 4, 6, 8, and 12 hours after the morning dose. Primary PK parameters include AUC(0-12), Cmax, Tmax, and Cavg. Trough concentrations of SCY-635 will be measured on Days 7, 14, and 21 and at Week 8.
• Pharmacokinetics of peginterferon alfa 2a and Ribavirin (trough concentrations) [ Time Frame: throughout first 8 weeks of treatment ] [ Designated as safety issue: No ]
  Trough concentrations of PegIFN alfa 2a and RBV will be measured on Days 7, 14, 21 and 28 and at Week 8. No other pharmacokinetic parameters will be determined.

This study will examine the effectiveness of 28 days of triple combination therapy including SCY-635 with peginterferon alfa 2a and ribavirin in reducing serum HCV RNA levels. An additional 20 weeks of treatment with the currently approved standard of care will be offered to all participants. The Week 24 visit will be the last on-study visit. After the Week 24 visit, all subjects with undetectable HCV RNA will be given the option to continue treatment with standard of care for an additional 24 weeks (out to Week 48) under the care of their Principal Investigator.

• Drug: Placebo
  Oral tablets given bid for 28 days
• Drug: SCY-635
  SCY-635 tablets, 300 mg bid for 28 days
• Drug: peginterferon alfa 2a
  180 ug prefilled syringe given once per week for up to 48 weeks
  Other Name: Pegasys, PegIFN
• Drug: Ribavirin
  tablets given bid for up to 48 weeks
  Other Name: Copegus, RBV

• Placebo Comparator: Placebo
  Placebo + PegIFN + RBV for 4 weeks followed by PegIFN + RBV for 20 weeks
  Interventions:

  • Drug: Placebo
  • Drug: peginterferon alfa 2a
  • Drug: Ribavirin
• Active Comparator: SCY-635 600 mg
  SCY-635 600 mg + PegIFN + RBV for 4 weeks followed by PegIFN + RBV for 20 weeks
  Interventions:

  • Drug: SCY-635
  • Drug: peginterferon alfa 2a
  • Drug: Ribavirin

Inclusion Criteria:

• Quantifiable serum levels of HCV-specific RNA in excess of 100,000 IU/mL
• Chronic HCV status
• HCV genotype 1 infection and IL28B genotype of C/T or T/T

• Liver biopsy results within 3 years prior to screening indicating the absence of cirrhosis

  *If no previous biopsy is available, a biopsy must be performed during the screening period to qualify for randomization

• Body mass index (BMI) between 18 and 38 kg/m2

• Laboratory variables within acceptable ranges:

  • ALT/AST < 3 × ULN;
  • HgB > 12g/dL for females, > 13 g/dL for males;
  • total WBC count > 3000/mm3 and ANC > 1500/mm3;
  • platelets > 100,000/mm3;
  • prothrombin time (or INR) ≤ 1.2 × ULN;
  • serum albumin ≥ 3.4 g/dL;
  • total bilirubin WNL;
  • serum creatinine WNL; if serum creatinine is > ULN, then calculated creatinine clearance must be > 100 mL/min (by Cockcroft-Gault formula) for subject to be eligible
• Subjects of childbearing potential (i.e., not surgically sterile or postmenopausal) must agree to use 2 forms of contraception from Screening until 24 weeks after completion of treatment with RBV
• Negative urine testing for amphetamines and cocaine at Screening.
• If female, the subject has a negative pregnancy test at Screening and on study Day 1

Exclusion Criteria:

• History of clinically significant gastrointestinal, renal, hepatic, neurologic, hematologic, endocrine, oncologic, pulmonary, immunologic, psychiatric, or cardiovascular disease
• Females who are pregnant or breastfeeding
• Males with partners who are pregnant or are planning to become pregnant
• HCV genotype other than genotype 1 and an IL28B genotype of C/C
• Seropositive for HIV-1 or HIV-2 or hepatitis B virus (HBV) surface antigen (HBsAg)
• Use of any investigational agent within 3 months prior to dosing
• Received any prior FDA-approved or investigational drug or drug regimen for the treatment of hepatitis C
• Evidence of cirrhosis on a previous liver biopsy
• Evidence of decompensated liver disease
• Recipient of an organ transplant
• Evidence of hepatocellular carcinoma
• Evidence of ongoing alcohol or substance abuse
• Poorly-controlled diabetes mellitus
• Congestive heart failure or unstable cardiopulmonary condition, renal disease, or hemoglobinopathy (sickle cell anemia or thalassemia
• History of seizure disorder
• History of severe psychiatric illness, including severe depression, history of suicidal ideation, suicidal attempts, related hospitalizations, bipolar disorder, or psychosis requiring medication
• Concurrent medical condition or laboratory abnormality that would constitute a contra-indication for interferon use
• History of unstable thyroid disease that would preclude administration of interferon-based therapy
• Medical condition that requires use of systemic corticosteroids
• Received warfarin or other anticoagulants during the 21 days immediately prior to Screening, or is expected to require warfarin or other anticoagulants during the study.
• One or more additional known primary or secondary causes of liver disease, other than hepatitis C
• Any other concurrent medical condition likely to preclude compliance with the schedule of evaluations, or likely to confound the efficacy or safety observations

• 12-lead ECG showing the following:

  • Corrected QTc interval ≥ 450 msec (Bazett's correction);
  • QRS > 120 msec;
  • Clinically significant abnormalities;
• Severe retinopathy or other significant ophthalmological disorder
• Use of any herbal supplements within 28 days prior to dosing.
• The use of CYP3A inducers or inhibitors for at least 2 weeks prior to initiation of treatment through Week 6