A Phase 3, Randomized, Double-Blind, Controlled Study Evaluating the Efficacy and Safety of Peginterferon Lambda-1a, with and without Daclatasvir, Compared to Peginterferon Alfa-2a, Each in Combination with Ribavirin, in the Treatment of Naïve Genotype 2 and 3 Chronic Hepatitis C Subjects;+ Pharmacogenetics Blood Sample Amendment Number 01 - Site Specific (version 1.0, dated 30-Mar12)

Hepatitis C virus (HCV) is found in almost every region in the world.
Approximately 3% of the world*s population, 170 - 180 million people, are
infected with HCV. In industrialized countries, chronic HCV accounts for 40%
of cases of end-stage cirrhosis7, 60% of cases of hepatocellular carcinoma
(HCC) and 30% of liver transplantation.Quality of life is also impaired for
patients infected with the virus, even among those without cirrhosis. Although
the incidence of new infections has declined, the number of deaths may continue
to increase 2- to 4-fold over the next 20 years due to prevalent cases with
longstanding infection.

Treatment of Genotype 2 and 3 Chronic Hepatitis C Infection:
The current standard treatment for chronic HCV GT-2, -3 is peginterferon
alfa-2a (alfa-2a) and ribavirin (RBV) for 24 weeks. This treatment regimen has
sustained virological response (SVR) rates of between 74% - 83% for subjects
infected with chronic HCV GT-2 infection and, between 54% - 79% for subjects
infected with chronic HCV GT-3 infection. However, this treatment regimen is
associated with side effects that prevent initiation of therapy for a number
of HCV infected patients. Furthermore, dose modifications and early
discontinuations limit the effectiveness of this treatment. By substituting
alfa-2a with a more tolerable pegylated interferon (IFN) or shortening the
required duration of IFN/RBV exposure by the addition of a potent, well
tolerated antiviral, it is expected that more patients will be able to adhere
to their treatment regimens and will be more likely to achieve Sustained
Virological Response.

Given the limitations of current therapy, there remains a need for improved
treatments for all genotypes of HCV. An alternative approach to improving
outcomes in HCV is to develop novel interferon-like molecules that improve the
tolerability of treatment, leading to fewer dose reductions and treatment
discontinuations, and greater adherence to prescribed therapy, whether used in
combination with RBV or as part of a DAA-containing regimen.

Primary Objective:
The primary objective for this study is to evaluate, in treatment-naive
subjects with chronic HCV GT-2 or -3 infection:
* SVR12 following 24 weeks of treatment with Lambda/RBV and the SVR12 following
24 weeks of treatment with alfa-2a/RBV
* SVR12 following 12 weeks of treatment with Lambda/RBV/DCV and the SVR12
following 24 weeks of treatment with alfa-2a/RBV

Secondary Objectives
* Evaluate RVR by treatment group
* Evaluate the safety of 24 weeks of treatment with Lambda/RBV and 12 weeks of
treatment with Lambda/RBV/DCV compared to 24 weeks of treatment with
alfa-2a/RBV in reducing treatment emergent cytopenic abnormalities (anemia as
defined by Hb < 10 g/dL, and/or neutropenia as defined by ANC < 750 mm3 and/or
thrombocytopenia as defined by platelets < 50,000 mm3)
* Evaluate the following on-treatment IFN-associated symptoms following 24
weeks of treatment with Lambda/RBV and 12 weeks of treatment with
Lambda/RBV/DCV compared to 24 weeks of treatment with alfa-2a/RBV:
* Flu-like symptoms (as defined by pyrexia or chills or pain)
* Musculoskeletal symptoms (as defined by arthralgia or myalgia or back pain)
* Evaluate SVR24 by treatment group
* Evaluate, by treatment group, safety as measured by the frequency of dose
reductions, discontinuations due to adverse events (AEs), and serious adverse
events (SAEs)
* Evaluate SVR12, by treatment group, in subjects with GT-3 chronic HCV
infection
* Evaluate on-treatment IFN-associated constitutional symptoms (fatigue or
asthenia)

In AI452017, 875 treatment-naïve subjects with chronic HCV GT-2 or -3 infection
will be randomized 2:2:1 to 24 weeks of Lambda/RBV (n = 350) or 12 weeks of
Lambda/RBV/DCV (n = 350) or 24 weeks of alfa-2a/RBV (n = 175). This
randomization increases the likelihood of subjects receiving a potentially
better treatment regimen, consisting of Lambda/RBV or a shorter duration of
treatment with Lambda/RBV/DCV. Randomization will be stratified by host HCV
viral load (* 800,000 IU/mL or < 800,000 IU/mL), cirrhosis status, region
(Japan/ROW), and viral GT-2 or -3. Each genotype, 2 or 3, will be capped at 60%
of the total enrolled (e.g., if a particular genotype enrolls 60% of the total
study subjects, the enrollment of that genotype will be capped and the
remaining 40% of the subjects will be enrolled from the other genotype). The
number of subjects from Japan will be limited to approximately 60 of the total
enrolled subjects. In keeping with the alfa-2a registrational studies (Roche
Study 4 and 5 as described in the US Product Label) enrolling GT-2 and -3
subjects,29 the number of compensated cirrhotic subjects participating in this
study will be capped at approximately 20% of the total number of subjects in
each treatment group.

In this protocol, investigational products are:

Peginterferon Lambda 1-a - 180 *g/0.45 mL, prefilled syringe, blinded
Daclatasvir - 60 mg - tablets, blinded
Peginterferon alfa 2-a - 180 *g/0.5 mL, prefilled syringe, blinded
Ribavirin - 200 mg - tablets, open label

Overall Risk/Benefit Assessment

The burden and risks are summarised in Sections E4 and E9 above.

Based on data from the EMERGE and D-LITE studies, the key benefits observed
with the use of Lambda(180 *g)/RBV are:
* Improved early on-treatment (RVR and cEVR) virological responses
* Less cytopenic abnormalities
* Less interferon associated AEs
* Fewer Lambda and RBV dose reductions
* Better SVR


Potential Benefits with Daclatasvir
Potential benefits of DCV are attributable to its potent efficacy when combined
with alfa- 2a/RBV, its well-tolerated safety profile and its once daily
dosing. The study drug Daclatasvir will hopefully help research participants
to achieve a virologic response to treatment and hence prevent their HCV from
progressing to liver cirrhosis (scarring), liver cancer or end stage liver
disease which may require a liver transplant. However this cannot be
guaranteed.