Combination Therapy for Chronic Hepatitis C Infection

Chronic hepatitis C virus (HCV) infection is a major public health problem with an estimated
180 million people infected worldwide. In the United States an estimated 4.1 million people
are infected, and HCV is the principal cause of death from liver disease and leading
indication for liver transplantation. While treatment with ribavirin (RBV) and pegylated
interferon (PEG) in combination with boceprevir/telaprevir is the currently recommended
therapy for chronic HCV infection and has superior cure rates compared to PEG+RBV alone in
HCV monoinfected patients, treatment is still associated with a high incidence of adverse
events (AEs), discontinuations, and poor cure rates in several populations. Recent studies
have demonstrated that the use of a combination of antivirals, which target HCV without
interferon (IFN), can cure HCV without additional toxicities. However, the determinants of
response to IFN-free regimens have not been established.

This is an open label study to assess the safety, tolerability, and efficacy of treatment
with GS-7977 with GS-5885, alone or in combination with GS-9669 and/or GS-9451 (selective
HCV nucleotide NS5B, NS5A, nonnucleotide NS5B and NS3 inhibitors, respectively) in HCV
infected treatment na(SqrRoot) ve and treatment experienced patients with early and advanced
liver disease. The findings from this study will aid in our understanding of determinants of
response to an IFN-free regimen in HCV infected patients for both patients with early and
advanced liver disease as well as in patients who are treatment na(SqrRoot) ve and those who
have been treated before for HCV.

- INCLUSION CRITERIA:

1. Eighteen years of age or older at screening.

2. Female study participants with childbearing potential (as defined below) and all
males must be willing to practice either:

- Abstinence from sexual intercourse or

- One or more forms of effective barrier contraception throughout dosing and
for 30 days following the last dose. This cannot include hormonal
contraception for female subjects.

Effective forms of barrier contraception include:

- a male condom with spermicide

- use by female sexual partner of a female condom with spermicide

Non-childbearing potential (i.e., physiologically incapable of becoming
pregnant) includes 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
greater than or equal to1 year)

- Has had a bilateral tubal ligation or fallopian tube inserts

3. Chronic HCV GT-1 or GT-4 infection as documented by greater than or equal to 1
measurement of serum HCV RNA greater than or equal to 2,000 international units
per milliliter during screening and at least one of the following:

- A positive anti-HCV antibody, HCV RNA, or HCV genotype test result greater
than or equal to 12 months prior to the baseline (day 0) visit together
with current positive HCV RNA and anti-HCV antibody test results or

- Positive HCV RNA test and anti-HCV antibody test results together with a
liver biopsy consistent with chronic HCV infection or a liver biopsy
performed before enrollment with evidence of chronic hepatitis C infection
disease, such as the presence of fibrosis.

4. Group A may include up to 20% of subjects with compensated cirrhosis.

Group B and C may only include subjects with absence of cirrhosis.

Group D & E may include subjects with compensated cirrhosis.

Group F may only include patients with advanced liver disease (historic Metavir
or HAI Stage 3 or 4 or ISHAK Stage 4, 5 or 6 or cirrhosis as defined below)

Group G and H may only include those with absence of cirrhosis and HAI Stage 0-2
or FibroTest as below.

Cirrhosis is defined as any one of the following:

1. Any biopsy showing cirrhosis.

2. A FibroTest(r) score of greater than or equal to 0.75 AND an AST: platelet
ratio (APRI) of > 2 performed within 12 months of screening.

Liver imaging within 6 months of Day 0 to exclude hepatocellular carcinoma (HCC)
is required in patients with cirrhosis.

Absence of cirrhosis is defined as one of the following:

1. A liver biopsy performed within 36 calendar months of screening showing
absence of cirrhosis.

2. A FibroTest(r) score of < 0.48 AND APRI of < 1 performed within 6 months of
screening. This would also qualify a subject for Group G and H as having
Stage 0-2 disease in the absence of a liver biopsy.

In the absence of a definitive diagnosis of presence or absence of cirrhosis by
the above criteria, a liver biopsy is required (for Groups B, C, G and H).

5. Ability to communicate effectively with the study investigator and other key
personnel.

6. Willing to give written informed consent and comply with the study restrictions
and requirements.

7. Opioid-dependent individuals must be participating in a supervised treatment
program.

8. Subjects must have an external primary care doctor (outside of the CC and the
NIH) for their medical management.

EXCLUSION CRITERIA:

1. Current or prior history of any of the following:

- Clinically-significant illness (other than HCV) or any other major medical
disorder that may interfere with subject treatment, assessment or compliance
with the protocol; subjects currently under evaluation for a potentially
clinically-significant illness (other than HCV) are also excluded.

- Gastrointestinal disorder or post operative condition that could interfere with
the absorption of the study drug.

- Poor venous access interfering with required study blood collection.

- Clinical hepatic decompensation (i.e., ascites, encephalopathy or variceal
hemorrhage).

- Solid organ transplantation.

- Significant pulmonary disease, significant cardiac disease or porphyria.

- Unstable psychiatric disease (Subjects with psychiatric illness that is
well-controlled on a stable treatment regimen or currently not requiring
medication may be included).

- Any malignancy or its treatment that in the opinion of the PI may cause ongoing
interference with host immunity; subjects under evaluation for malignancy are
not eligible.

- Significant drug allergy (such as anaphylaxis or hepatotoxicity).

- Substance abuse, which in the opinion of the investigator is likely to interfere
with medication adherence or study compliance.

- Lactose allergy, patients with lactose intolerance will be evaluated on a
case-by-case basis.

2. Positive test results at screening for hepatitis B virus (HBV) surface antigen
(HBsAg), HBV DNA (if medically indicated) or anti-HIV antibody (unless previously
treated on 13-I-0159).

3. Prior exposure to any direct-acting antivirals for HCV infection, except for patients
who were previously treated studies 11-I-0258, 13-I-1059 or this study enrolling in
Group D.

4. History of clinically significant chronic liver disease due to other etiology (e.g.,
hemochromatosis, autoimmune hepatitis, Wilson s disease, alpha 1-antitrypsin
deficiency, alcoholic liver disease, > moderate non-alcoholic steatohepatitis and
toxin exposures).

5. Use of herbal/natural remedies for potential benefit to the liver within 21 Days of
Day 0.

6. History of ascites, variceal hemorrhage, hepatic encephalopathy, or conditions
consistent with decompensated liver disease.

7. Screening or baseline ECG with clinically significant ECG findings, or a
personal/first degree relative history of Torsade de pointes.

8. Abnormal hematological and biochemical parameters at screening, including:

- Neutrophil count less than 750 cells per cubic millimeter.

- Hemoglobin level < 9 g/dL. If Hgb < 11g/dL in women and < 12 g/dL in men other
causes of anemia should be excluded as medically indicated.

- Platelet count less than or equal to 50,000 cells per cubic millimeter.

- Estimated glomerular filtration rate less than 50 milliliter/min/1.73m(2).

- ALT or AST level greater than or equal to 10 times upper limit of normal (ULN).

- Serum lipase level greater than or equal to 1.5 times upper limit of normal
(ULN)at screening or during the screening period in a patient with symptoms
consistent with pancreatitis.

- Total bilirubin level greater than or equal to 2.0 times upper limit of normal
(ULN), except in subjects with Gilbert s syndrome.

- Albumin level less than or equal to 3.0 grams per deciliter in patients without
cirrhosis, albumin less than or equal to 2.8 g/dL in cirrhotic patients.

9. Poorly controlled diabetes mellitus indicated by hemoglobin A1C greater than 9% at
screening.

10. Donation or loss of blood of greater than 400 milliliter within 8 weeks prior to the
first dose of the study drugs.

11. Known hypersensitivity to GS-5885, GS-7977, GS-9669, GS-9451 or formulation
excipients.

12. Pregnant/Breastfeeding women.

13. Need for use of the following medications from 21 days prior to the start of study
drugs through the end of treatment (unless otherwise specified):

- Hematologic stimulating agents (e.g. erythropoiesis-stimulating agents (ESAs);
granulocyte colony stimulating factor (GCSF); thrombopoietin (TPO) mimetics).

- Chronic systemic immunosuppressants including, but not limited to,
corticosteroids (prednisone equivalent of greater than 10 milligrams per day for
greater than 2 weeks), azathioprine, or monoclonal antibodies (e.g.,
infliximab).

- Investigational agents or devices for any indication.

- Medications for disease conditions excluded from the protocol (e.g., active
cancer, transplantation) are not listed under this Concomitant Medication
section and are disallowed in the study.

- Concomitant use of certain medications or herbal/natural supplements per PI
discretion expected to result in pharmacokinetic interactions resulting in
increases or decreases in exposure of study drug(s).

14. Co-enrollment Guidelines: Co-enrollment in other clinical trials is restricted, other
than enrollment in observational studies. Study staff should be notified of
co-enrollment status, as it may require prior approval of the investigator.