TG4040 in Patients With Chronic HCV

The purpose of this study is to assess the safety, immunogenicity, and efficacy of the
hepatitis C virus (HCV) vaccine, TG4040, in outpatients with chronic hepatitis C. The study
will be conducted in two parts at two DMID Vaccine Treatment and Evaluation Unit (VTEU)
Centers: Saint Louis University and Cincinnati Children's Hospital. Up to 85 subjects with
chronic hepatitis C will receive the test vaccine via subcutaneous injection into the thigh.
In Part I of this study, 18 subjects will be randomized to 1 of 3 groups. At the initial
dosing time point, Group One will receive 10 to the 6th power particle-forming units (PFU)
and Groups Two & Three will receive saline placebo in 3 doses on Days 0, 7, and 14. After
Safety Monitoring Committee (SMC) review, Group Two will receive a higher dose of TG4040 (10
to the 7th power PFU) and Groups One & Three will receive saline placebo. After a further SMC
review, Group Three will receive a higher dose of TG4040 (10 to the 8th power PFU) and Groups
One & Two will receive saline placebo. (Each subject will therefore be treated with one
course of TG4040 and receive two courses of placebo). In Part II of this study, 60 subjects
(30 non-responders or relapse subjects-Part IIa, and 30 treatment naïve, Part IIb) will be
randomized into two groups to receive either 10 to the 8th power PFU (or the highest
tolerated dose) of TG4040 or saline placebo at two dosing time points with a crossover
design. (Each subject will therefore be vaccinated with the same dose of TG4040 and also
receive a course of placebo.) Subjects enrolled in either Part I or Part II of the study will
participate for 8 months. The primary objective for Part I of the study is to assess the
safety of escalating doses of TG4040 versus placebo administered to non-responders or relapse
subjects with chronic hepatitis C. The secondary objective for Part I of the study is to
assess immunogenicity of escalating doses of TG4040 versus placebo administered to
non-responders or relapse subjects with chronic hepatitis C. The primary safety objective for
Part II of the study is to assess the safety of the dose of TG4040 selected from Part I
versus placebo when administered to subjects with chronic hepatitis C, either non-responders
or relapse subjects or treatment- naïve subjects. The primary efficacy objective for Part II
of the study is to assess antiviral activity against HCV of TG4040 versus placebo in subjects
with chronic hepatitis C, non-responders or relapse subjects or treatment-naïve subjects,
assessed as a 1 log reduction in serum level of HCV RNA. The secondary objective for Part II
of the study is to assess immunogenicity of TG4040 versus placebo in subjects with chronic
hepatitis C, non-responders or relapse subjects or treatment-naïve subjects, and correlate
this with reductions in serum levels of HCV RNA. For Part I, the primary outcome measures are
related to safety and include measures of reactogenicity, changes in blood counts and hepatic
panel. For Part II, the primary outcome variable is a change in serum levels of HCV RNA
compared to baseline. A decrease in more than 1 log from baseline will be considered a
significant effect. In addition to this, other primary outcome measures will also include
safety and include measures of reactogenicity, changes in blood counts and hepatic panel.
Secondary outcomes measures include those tests aimed at assessing immunogenicity of the
vaccine candidate and include, but are not limited to, development of anti-HCV using standard
commercial assays and research assays, developed of enhanced in vitro T cell reactivity when
stimulated with HCV antigens.

Inclusion Criteria:

Part I and Part II:

1. Informed consent obtained and signed;

2. Male or female patients, age 18-65 years old (inclusive)

3. Female patients will be menopausal for at least 12 months, surgically sterile or agree
not to become pregnant from the time of study enrollment until at least 28 days after
the administration of vaccine or placebo. A woman is considered of childbearing
potential unless post-menopausal or surgically sterilized.

If the volunteer is female, of childbearing potential, and sexually active, she agrees
to use acceptable contraception. (Acceptable contraception methods are restricted to
effective intrauterine devices (IUDs) or licensed hormonal products with use of method
for a minimum of 30 days prior to vaccination and for the entire study period
post-vaccination).

Note: A woman is eligible if she is monogamous with a vasectomized male or abstinent,
without the additional need for hormonal or barrier birth control methods upon review
of a reproductive history.

4. With chronic hepatitis C evidenced by:

- HCV RNA detectable in blood, and

- A liver biopsy compatible with chronic hepatitis C;

5. Infected with HCV genotype 1;

6. Non-cirrhotic patients, i.e. liver biopsy available within one year prior to baseline,
excluding stage 4 fibrosis; otherwise, if no liver biopsy of less than one year is
available, it will be performed at baseline;

7. Patients participating in:

- Part I will be non-responder patients: patients having received at least 3 months
of pegylated IFN-alpha (IFN-alpha) plus ribavirin, with currently detectable HCV
RNA (whether or not they reach, Early Virologic Response (EVR, defined as a
reduction of HCV RNA by at least 2 logs from baseline or negative at 12 weeks)
and/or SVR) with > 6 months between the end of PEG IFN-alpha treatment and the
first TG4040 injection;

- Part IIa will be either non-responder or relapser patients. Part IIb will be
treatment-naïve patients: patients who have never received IFN-based treatment

8. Patients must have compensated liver disease, defined through use of the Child-Pugh
scoring system with:

- Features of low serum albumin, prolonged prothrombin time, raised bilirubin,
ascites and hepatic encephalopathy are scored and patients assigned to Child-Pugh
class A, B or C, the later two being decompensated. Only patients with
compensated liver disease will be enrolled.

- No history of ascites, hepatic encephalopathy or bleeding from esophageal varices
laboratory tests values:

- Serum bilirubin and international normalized ratio (INR) values <1.2 (except in
patients with Gilbert syndrome where serum bilirubin may be as high as 3.0 mg/dL)

- Serum alanine aminotransferase (ALT) < 5 fold the upper limits of normal (ULN)
and

- Other laboratory parameters of grade 0 or 1 (CTC criteria)

Exclusion Criteria:

Part I and Part II:

1. Co-infection with HBV (indicated by the presence of hepatitis B surface antigen
(HBsAg) in serum) or HIV (anti-HIV in serum); patients with HIV positive sexual
partner (by history) will not be included;

2. Current HCV therapies through out the trial period

3. Current alcohol abuse or drug addiction that in the opinion of the investigator may
interfere with the subject's ability to comply with trial procedures.

4. History of immunodeficiency

5. Known or suspected impairment of immunologic function including moderate to severe
kidney impairment

6. Malignancy within the last 5 years, not including squamous cell skin cancer or basal
cell skin cancer unless at the vaccination site or history of skin cancer at the
vaccination site

7. Significant cardiac disease, evidenced by:

- History of myocardial infarction, angina, congestive heart failure,
cardiomyopathy, stroke or transient ischemic attack, chest pain or shortness of
breath on activity, or other heart conditions under the care of a physician

- Baseline ECG showing clinically significant abnormalities (e.g., all kinds of
advanced atrioventricular block or intraventricular block with QRS >120msec, QTc
>460 msec, or frequent premature atrial contractions, atrial fibrillation or
other atrial arrhythmias, > ventricular couplets or ST-T wave abnormalities
diagnostic of myocardial ischemia or prior myocardial infarction. EKGs will be
interpreted by an identified cardiologist at Saint Louis University prior to
enrollment.

- Baseline echocardiogram showing clinically significant abnormalities including
valvular disease or contractile dysfunction.

- Ten percent or greater risk of developing a myocardial infarction or coronary
death within the next 10 years using the National Cholesterol Education Program's
risk assessment tool (http://hin.nhlbi.nih.gov/atpiii/calculator.asp)

NOTE: This criterion applies only to subjects 20 years of age and older AND only if at
least one of the following apply:

A) have smoked a cigarette in the past month, and/or B) have hypertension (defined as
systolic blood pressure >140 mm Hg) or are on antihypertensive medication, and/or C)
have a family history of coronary heart disease in male first-degree relative (father
or brother) < 55 years of age or a female first-degree relative (mother or sister) <
65 years of age.

8. Current use of immunosuppressive medication; Corticosteroid nasal sprays, Inhaled
steroids for asthma and/or topical steroids are permissible. Persons taking short
courses of oral steroids for conditions such as poison ivy will need to wait a period
of 2 weeks after completion of the steroids to begin vaccination.

9. History of any one of the following:

- Suicide attempt or hospitalization for depression within the past five years.

- Any current (within 6 months) severe or poorly-controlled psychiatric disorder
(e.g., depression, schizophrenia, bipolar illness, obsessive-compulsive disorder,
severe anxiety, personality disorder).

- The following patients must be excluded unless they are assessed and followed by
a psychiatrist or other mental health professional who pre-approves their study
participation:

- Patients who have had a suicide attempt and/or hospitalization for depression
more than 5 years ago.

- Patients who have had a severe or poorly-controlled psychiatric disorder (e.g.,
depression, schizophrenia, bipolar illness, obsessive-compulsive disorder, severe
anxiety, personality disorder) more than 6 months ago but less than 5 years ago.

10. Receipt of any inactivated vaccine 14 days prior to vaccination or for the duration of
the study

11. Receipt of any live attenuated vaccine within 30 days prior to vaccination or for the
duration of the study

12. Receipt of any MVA vaccine in the last five years

13. Use of any experimental agent within 30 days prior to vaccination or for the duration
of the study

14. Receipt of blood products or immunoglobulin within six months prior to vaccination

15. Donation of a unit of blood within 56 days prior to vaccination or for the duration of
the study following the first vaccination

16. Acute febrile illness (>100.5 degrees F) on the day of vaccination

17. Pregnant or lactating women

18. Any condition that, in the opinion of the investigator, might interfere with study
objectives

19. Known allergy to MVA vaccine

20. Receipt of antiviral drugs such as alpha interferon or ribavirin

21. Other laboratory parameters of grade 2 or more

22. Study personnel engaged in the blinding of this study