Clinical Protocol AI447-029
A Phase 3, Open-Label Study with Asunaprevir and Daclatasvir Plus Peginterferon Alfa-2a (Pegasys) and Ribavirin (Copegus) (P/R) (QUAD) for Subjects Who Are Null or Partial Responders to Peginterferon Alfa 2a or 2b Plus Ribavirin with Chronic Hepatitis C Genotypes 1 or 4 Infection

Approximately 170 million people worldwide are chronically infected with
hepatitis C virus (HCV). The majority of individuals infected progress to
chronic hepatitis, which can lead to cirrhosis, liver failure and
hepatocellular carcinoma (HCC). HCV is the leading indication for liver
transplantation in most countries and a major cause of HCC.

The standard of care therapy for patients with genotype 1 chronic HCV infection
is the combination of a direct acting antiviral (DAA) and peg-Interferon plus
ribavirin. The recently approved DAAs include the two NS3/4A protease
inhibitors boceprevir (BOC) and telaprevir (TVR). These drugs are administrated
for either 24 weeks (naive early responders) or 48 weeks (previous
peg-Interferon Alfa-2 and ribavirin (P/R) treatment failures and naive late
responders) achieving sustained virologic response (SVR) rates of ~60 - 80% in
naive patients and ~30% - 80% among previous treatment P/R failures. Despite
this improvement in SVR rates and the option of short treatment duration,
adverse events occurred more frequently in patients treated with DAA + P/R than
in those treated with P/R therapy alone.

Daclatasvir (DCV) and asunaprevir (ASV) are man-made experimental drugs, in
tablet and capsule form respectively, that work by inhibiting hepatitis C virus
(HCV) proteins called NS5a and NS3 respectively. The NS5a and NS3 proteins have
a key function in the replication of HCV and modulation of viral cellular
signalling/communication pathways and are also important in blocking the hosts
IFN or immune response to the infection. IFN, named after their ability to
"interfere" with viral replication also function to activate immune cells,
increase the recognition of infected cells and increase the ability of
uninfected host cells to resist new infection by virus. By inhibiting this IFN
signalling or communication pathways, the NS5a and NS3 proteins impair the
host*s immune response to infection. Thus, DCV and ASV work by interfering with
viral replication and preventing the virus from impairing the immune response
to infection a double benefit. It is hoped that NS5a and NS3 protein inhibitors
such as the study drugs, DCV and ASV, will result in improved response and also
shorter treatment times. DCV and ASV have been studied intensively in
laboratory and animal studies and its effectiveness against HCV has been
demonstrated. DCV and ASV are not currently licensed but clinical studies have
shown that they may be effective in treating hepatitis C virus infection.

The addition of ASV + DCV in combination with P/R will potentially have even
greater success in the treatment of null responders of both sub-types of
genotype 1 (1a & 1b). In a Phase 2 study (AI447-011) evaluating *QUAD* therapy
in prior null responders SVR rates of 90% have been achieved (n = 51). Although
this data has yet to be confirmed in larger studies, it suggests that ASV
combined with DCV plus P/R may provide significant benefit to prior null
responders, and potentially also for partial responders of P/R, compared to
single direct acting antivirals (DAA) plus P/R regimens in subjects infected
with genotype 1 or genotype 4.
The purpose of this study is to assess the efficacy and safety of ASV and DCV
in combination with P/R (QUAD therapy) in a larger patient population.

Research Hypothesis: In subjects who are prior null/partial responders to P/R,
co-administration of ASV and DCV with P/R for 24 weeks for the treatment of
chronic HCV genotype 1 infection is safe, tolerable and efficacious where
efficacy is based on SVR12, defined as HCV RNA < LOQ at post-treatment Week 12.

Primary Objective:
This research study is designed to assess the effectiveness of the combination
of study drugs (ASV + DCV) being used to treat the hepatitis C virus (HCV). The
best way to assess this aim is to measure the amount of virus in patients*
blood 12 weeks after ceasing study the study medication which is 24 weeks in
duration. If a patient has achieved undetectable HCV in their blood 12 weeks
after ceasing treatment they are said to have achieved a "Sustained Virological
Response" (Abbreviated as SVR-12).

Secondary Objectives:
* To assess the safety of the study medications. This will be assessed by
measuring the number of serious adverse events (SAEs) and study medication
discontinuations*
* To assess the relationship between the efficacy of the study drugs and
changes in the HCV genome responsible for drug resistance.
* To assess the efficacy of the study drugs as determined by:
* Undetectable HCV RNA at the following time points throughout the trial: weeks
1, 2, 4, 6, and 8 and 12; at both Weeks 4 and 12 [Extended rapid virological
response (eRVR) - which means that the virus is undetectable at treatment weeks
4 and 12.]; End-Of-Treatment (up to 24 weeks), post-treatment Week 12 or
post-treatment Week 24;
* To evaluate antiviral activity endpoints for HCV genotype 4 subjects.

Approximately 390 HCV subjects (approximately 350 genotype 1 and up to
approximately 40 genotype 4), who failed prior P/R treatment, will be treated
in this single arm, open-label study. Genotype 4 subjects will be capped at 10%
(maximum up to approximately 40 subjects will be enrolled). Enrollment in this
study may be closed once approximately 350 genotype 1 subjects are treated. The
study will enroll a minimum of 40% of genotype 1 subjects for each HCV Subtype:
1a and non-1a (ie, subtype will be capped at 60%).
All subjects will be treated for 24 weeks and will receive 100 mg BID of ASV
soft capsule, 60 mg QD of DCV, and P/R for 24 weeks and subjects will then be
followed-up for 24 weeks after completion of treatment or early
discontinuation. It is expected that all subjects who are in the study will
complete the protocol-defined durations for treatment and follow-up.
If alternative HCV therapy is initiated in the post treatment period for any
reason, the subject must withdraw from the study once the post-treatment Week 4
visit has occurred.
The last visit will be considered the date of the last post-treatment visit.
The end of the study will be considered the last subject*s last visit date or
when the last data point required for statistical analysis is received from the
last subject, whichever is later.
Following completion of the post-treatment period of the study, subjects will
then be asked to enroll into a separate observational study (AI444-046) for an
additional 3-year follow-up to assess long-term SVR, natural history of the HCV
resistance and liver-related complications.
The primary analysis will occur when all subjects complete post-treatment Week
12, and a final analysis will occur once all subjects complete post-treatment
Week 24.

All subjects will be treated with QUAD therapy (DCV + ASV + pegIFN*-2a + RBV)
for 24 weeks and will receive 24 weeks of follow-up after treatment or early
discontinuation.

Subjects will receive the following doses:
* pegIFN*-2a: Subjects will self-administer 180 *g pegIFN*-2a injection
subcutaneously once weekly throughout the entire dosing period.
* RBV: Subjects will take RBV twice daily with food. For subjects weighing < 75
kg the total dose is 1000 mg per day and for those weighing * 75 kg the dose is
1200 mg per day. Therefore, subjects should take either 400 mg (2 tablets for
subjects < 75 kg) or 600 mg (3 tablets for subjects * 75 kg) in the morning
with food and 600 mg (3 tablets) in the evening with food.
* ASV: ASV soft capsules should be taken twice daily (1 capsule per dose) for
the duration of assigned treatment.
* DCV: DCV tablets should be taken once daily (1 tablet) for the duration of
assigned treatment. DCV may be taken with or without a meal, and may be taken
with RBV.

Subjects who do not tolerate therapy with P/R during the study may continue on
ASV and DCV alone (DUAL) for a total treatment duration of 24 weeks. Any
subject with genotype non-1a is permitted to continue on DUAL therapy alone;
however, subjects with genotype 1a or genotype 4 must have HCV RNA < LOQ at the
last assessment before proceeding to DUAL therapy.

It is expected that all subjects who are on study will complete the protocol
defined durations for treatment and follow-up. If alternative HCV therapy is
initiated in the post-treatment period for any reason, subject must withdraw
from the study once the post treatment Week 4 visit has occurred.

RISKS:
As for any relatively new drug or new drug combination, there might be unknown
side effects. Based on what we have learned up to this point, the following
adverse drug reactions are known:

a) Side effects seen for the combination of DCV and ASV (alone or with P/R):
In clinical trials with HCV infected subjects receiving the combination of DCV
and ASV alone or with P/R:
AI447-011 is an ongoing Phase 2a, parallel, open label, randomized,
multiple-dose study to evaluate the safety, pharmacokinetics and
pharmacodynamics of DCV and ASV in combination alone or with P/R in chronically
infected subjects with HCV genotype 1 who were previous null responders to P/R.
Subjects received this *QUAD* therapy for 24 weeks. Based on preliminary safety
data, there were no deaths, SAEs or discontinuation due to AE/SAEs. The most
frequently reported AEs were diarrhea in 15/21 (71.4%), fatigue in 13/21 (62%),
headache 11/21 (52.4%), nausea 7/21 (33%), and cough 5/21 (23.8%). Six (6/21)
subjects were identified with elevations in ALT above 3x upper limit of normal
(ULN) (47 U/L). Two (2) of the subjects received DCV and ASV alone, and 4
received DCV and ASV in addition to P/R.
ALT values in all subjects showed improvement without intervention, dose
reduction or drug discontinuation. The etiology of these findings is not
understood: however, they appear similar to observations made from data as part
of a 12 week on-treatment database lock performed in study AI447-016. Continued
close monitoring of liver function tests during treatment is justified.
In addition to potential risks based on pre-clinical and early clinical
studies, the possibility of drug-induced liver injury (DILI) may be increased
with DAAs, which are concentrated and metabolized by the liver, and
administered to a population (chronic HCV) at increased risk for DILI. The type
of liver injury that leads to severe DILI is predominantly hepatocellular, and
is therefore associated with a rise in ALT and AST, but is extensive enough to
affect the liver*s functional ability to clear bilirubin or to synthesize
coagulation factors. Therefore increased total bilirubin and/or INR associated
with marked ALT/AST elevation should warrant consideration of DILI, and subject
interventions should include discontinuation of study drugs.

b). Side effects seen for the combination of P/R:
i). Side effects seen in 1 in 10 or more of subjects:
Anaemia (low red blood cell count), loss of appetite, feeling depressed
(feeling low, feeling bad about oneself or feeling hopeless), anxiety,
inability to sleep, headache, difficulty concentrating and dizziness, cough,
shortness of breath, Diarrhoea, nausea, abdominal pain, loss of hair, and skin
reactions (including itching, dermatitis and dry skin), pain in joints and
muscles, fever, weakness, tiredness, shaking, chills, pain, injection site
irritation and irritability (getting easily upset)
ii). Side effects seen in less than 1 in 10 but more than 1 in 100 patients:
Fungal, viral and bacterial infections. Upper respiratory infection,
bronchitis, fungal infection of the mouth and herpes (a common recurring viral
infection affecting the lips, mouth), low platelet count (affecting the
clotting ability) and enlarged lymph glands, overactive and underactive thyroid
gland, mood /emotion changes, aggression, nervousness, decreased sexual desire,
poor memory, fainting, decreased muscle strength, migraine, numbness, tingling,
burning sensation, tremor, changes in the sense of taste, nightmares,
sleepiness, blurry vision, eye pain, eye inflammation and dry eyes, sensation
of room spinning, ear pain, rapid heart rate, pulsation of the heart beats,
swelling in the extremities, flushing, shortness of breath with activity, nose
bleeds, nose and throat inflammation, infections of the nose and sinuses
(airfilled spaces found in the bones of the head and face), runny nose, sore
throat, vomiting,indigestion, difficulty swallowing, mouth ulceration, bleeding
gums, inflammation of tongue and mouth, flatulence (excess amount of air or
gases), dry mouth and loss of weight, rash, increased sweating, psoriasis,
hives, eczema, sensitivity to sunlight, night sweats, back pain, joint
inflammation, muscle weakness, bone pain, neck pain, muscle pain, muscle
cramps, impotence (inability to maintain an erection), chest pain, flu-like
illness, malaise (not feeling well), lethargy, hot flushes, thirst.
iii). Side effects seen in less than 1 in 100 but more than 1 in 1,000 patients:
Lower respiratory tract infections, urinary tract infection, skin infections,
liver tumour, sarcoidosis (areas of inflamed tissue occurring throughout the
body), inflammation of the thyroid, diabetes (high blood sugar), dehydration,
thoughts of suicide, hallucinations (abnormal perceptions), anger, hearing loss
, peripheral neuropathy (disorder of the nerves affecting the extremities),
bleeding in the retina (back of the eye), high blood pressure, wheezing,
gastrointestinal bleeding, inflammation of the lips, inflammation of the gums,
poor functioning of the liver.
This risk will be minimised by frequently monitoring the safety of the
participant during and after treatment, and providing a list of prohibited
medications to the subjects, and their GPs to prevent possible drug to drug
interactions.

Risks for patients if they are able to become pregnant: Participating patients
must not become pregnant or breastfeed whilst they are taking the study
treatments and for 6 months after stopping treatment. Patients who are woman of
child bearing potential must be using two adequate methods to avoid pregnancy
for the duration of this study and are advised to immediately contact their
study doctor if there is a change in the method to avoid pregnancy or if
patients start any prescription drug or other medication (including
over-the-counter drugs and herbal
supplements) not prescribed by the study doctor.
The reasons for these precautions are because taking peg-IFN* in combination
with ribavirin can cause death, serious birth defects or other harm to an
unborn child or breastfeeding infant.

BENEFITS:
The study drugs (ASV + DCV + P/R) 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.
The addition of two DAAs (ASV, DCV) to P/R will potentially have even greater
success than the addition of a single DAA in the treatment of genotypes 1 and 4
null responders and, by extension, all genotypes 1 and 4 non-responders.
Results from the Phase 2a study (AI447-011) evaluating *Quad* therapy in prior
null responders has achieved SVR rates approaching > 90% (n = 51). Although
this data has yet to be confirmed in larger studies, it suggests that DCV
combined with ASV plus P/R may provide significant benefit to prior null
responders of P/R compared to single direct-acting antiviral (DAA) plus P/R
regimens in subjects infected with genotype 1. It is anticipated that the
*Quad* regimen will be at least equally efficacious in other P/R non-null
responder groups (partials, relapsers, and breakthrough). Finally, DCV and ASV
not only have potent and selective activity against genotypes 1b and 1a, but
also have potent activity against genotype 4. Therefore the unprecedented
response in the re-treatment of genotype 1-infected subjects is anticipated to
translate into the genotype 4-infected population.

During the study, subjects will be monitored closely by the study doctor (who
is an experienced clinician) and his/her team. Subjects may benefit from being
seen more frequently by a experienced clinicians and nursing staff, and from
receiving increased emotional support from the research team.

Although not of direct benefit to research participants, the information
learned from this study may help other subjects with chronic HCV infection in
the future.