A Phase 2b Open-Label Study of 200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 HCV-Infected Subjects with Renal Insufficiency

(Protocol Am2 dd. 20-Feb-2014, p13/93)

Hepatitis C virus (HCV) is responsible for a large proportion of chronic liver
disease worldwide and accounts for 70% of cases of chronic hepatitis in
industrialized countries. The global prevalence of chronic hepatitis C is
estimated to average 3% {19705}. The most common genotype worldwide is genotype
1 followed by genotypes 2 and 3 {19705}. Although there is evidence that the
incidence of viral infection may be decreasing, the
prevalence of liver disease caused by HCV is on the rise, primarily due to the
lag between the onset of infection and the clinical manifestation of liver
disease {19705}. The prevalence of chronic HCV is significantly higher among
patients with chronic renal failure, and HCV itself is associated with impaired
renal function. Treatment of these individuals is therefore recommended but is
often complicated by the substantial increase in hematologic toxicities
associated with the use of ribavirin in the setting of low creatinine clearance
{23275}. Standard of care for genotype 1 HCV infection involves 24-48 weeks of
an HCV protease inhibitor in combination with pegylated interferon-alfa
(PEG)+ribavirin (RBV). The recommended first-line treatment for subjects with
genotype 2 or genotype 3 chronic hepatitis C is PEG+ RBV for 24 weeks {13693},
{17940}. There are minimal data regarding the optimal regimen for patients with
severe renal disease (e.g., Cr clearance<30 mL/min) or end stage renal disease
on maintenance hemodialysis. Interferon monotherapy for 48 weeks which provides
an SVR rate of approximately 40% in clinical trials is often deemed the
treatment of choice. Due to the side effects and lengthy duration of current
treatment, there is substantial need for a short, simple, interferon-free
regimen, particularly in patients who are more susceptible to drug toxicities,
such as those with renal insufficiency.

(Protocol Am2 dd. 20-Feb-2014, p17/93)

The primary objectives of this study are:
- To evaluate the safety of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin (RBV)
for 24 weeks as assessed by review of the accumulated safety data in each
treatment arm
- To evaluate the efficacy of sofosbuvir (SOF) 200 mg or 400 mg + ribavirin
(RBV) for 24 weeks measured by the proportion of subjects with renal
insufficiency who have achieved a sustained viral response 12 weeks after
treatment discontinuation (SVR12) in each treatment arm
- To evaluate the steady state pharmacokinetics of SOF and its metabolites upon
dosing SOF 200 mg or 400 mg in subjects with renal insufficiency

The secondary objectives of this study are:
- To evaluate the proportion of subjects with renal insufficiency who attain
SVR at 4 and 24 weeks after discontinuation of treatment (SVR4 and SVR24)
- To evaluate the kinetics of plasma HCV RNA during and after treatment
discontinuation
- To evaluate the emergence of viral resistance to SOF during and after
treatment discontinuation

The exploratory objective of this study is:
- To identify or validate genetic markers that may be predictive of the natural
history of disease, response to therapy and/or tolerability of medical
therapies through genetic discovery research (e.g., pharmacogenomics), in
subjects who provide their separate and specific consent

(Protocol Am2 dd. 20-Feb-2014, p18/93)

This is a multicenter, open label study that will evaluate the safety,
tolerability and antiviral efficacy of SOF with RBV in chronic renal
insufficiency and HCV infection subjects with genotype 1 or genotype 3 HCV
infection, including those with compensated cirrhosis.

This study will have 2 parts.

Part 1 will enroll approximately 20 subjects with severe renal insufficiency.
- 10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.
- Following review of safety, efficacy and PK data through post-treatment Week
4 of the Part 1 SOF 200 mg group, 10 additional subjects will receive SOF 400
mg QD + RBV 200 mg QD for 24 weeks.

Part 2 will enroll approximately 20 subjects on dialysis following review of
safety, efficacy and PK data through post-treatment Week 4 of Part 1 SOF 400 mg
group.
- 10 subjects will receive SOF 200 mg QD + RBV 200 mg QD for 24 weeks.
- Following review of safety, efficacy and PK data through post-treatment Week
4 of the Part 2 SOF 200 mg group, 10

(Protocol Am2 dd. 20-Feb-2014, p18/93)

In Part 1, following screening procedures and Day 1 assessments, eligible
subjects will receive either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24
weeks.

In Part 2, following screening procedures and Day 1 assessments, eligible
subjects receive either SOF 200 mg or 400 mg QD + RBV 200 mg QD for 24 weeks.

RISK:
Adverse events of the study medication (Also, see E9.)

BURDEN: (As in E4)
Maximum study duration: ca. 1 year, 16 visits, duration: 0.5-3h
15x physical examn (Vital Signs, blood pressure, pulse, temperature. Height
and weight at screening only
11x 12-lead ECG
11x serum pregnancy tests (if applicable)
3x Echocardiogram
33x blood tests for a total of 546ml of blood

BENEFIT: (As in E1a)
The potential benefit of successful treatment of HCV in these subjects is
substantial. Few patients with severe renal insufficiency can tolerate
combination therapy with PEG+RBV due to profound anemia. SVR rates to
interferon monotherapy administered for 48 weeks are less than 50%.
Interferon-free treatment for 24 weeks could provide substantial improvements
in safety, tolerability and efficacy for individuals with chronic HCV infection
and end stage renal disease.

Also: (Protocol Am2 dd. 20-Feb-2014, p16/93, Risk/benefit ration)
To date there has been no safety signal identified that is attributable to SOF
when administered as part of a combination regimen. Furthermore, SOF does not
exacerbate the toxicities associated with RBV, most notably hemolytic anemia.
Clinical data with SOF in severe renal insufficiency and in subjects requiring
hemodialysis is limited to a single dose study in non-HCV infected subjects. No
specific safety signals were identified. The current study is designed to
assess the safety and efficacy of therapeutic treatment with SOF+RBV in a small
number of subjects with severe renal insufficiency. The 2-part stepwise design
will allow a full review of the risk/benefit of both doses and treatment arms
in patients with Cr clearance <30 mL/min before proceeding to the cohort of
patients on dialysis who are predicted to have higher SOF and GS-331007
exposures.