Immunotherapy With TG4040 in Treatment-naïve Patients Chronically Infected With Hepatitis C Virus

Open-label, Dose-escalating, Phase I Study of TG4040 (MVA-HCV) in Treatment-naïve Patients Chronically Infected With Hepatitis C Virus (HCV Genotype 1)

The primary objective is to determine the safety of sub-cutaneous (SC) injections of TG4040 in non-cirrhotic, treatment-naïve patients chronically infected with HCV (genotype 1).

Patients will be sequentially treated at an escalting dose of TG4040. All patients will be followed up to at least 6 months after his/her first injection. In addition, all patients treated at the highest dose will receive a TG4040 boost injection 6 months after the first injection, and will be followed up during an additional 6-month period.

The first nine patients will be sequentially treated in three cohorts of three patients, i.e. they will receive 3 SC injections of TG4040 on Days 1, 8 and 15, at the dose of 10e6 pfu (first cohort), 10e7 pfu (second cohort), or 10e8 pfu (third cohort).

There will be a one-week safety interval between the first injection of the patients of a given cohort, and a two-week safety interval between the last injection of the last patient of a given cohort and the first injection of the first patient of the next one. There will be also a two-week safety observation period after the last injection of the last patient of the third cohort. If the dose of 10e8 pfu does not raise safety problems, then 6 patients will be further enrolled, without safety intervals between patients. They will receive 3 SC injections of TG4040 at the dose of 10e8 pfu, on Days 1, 8 and 15.

All patients will be followed up to at least 6 months after his/her first injection. In addition, all patients treated at the dose of 10e8 pfu will receive a TG4040 boost injection 6 months after the first injection, and will be followed up during an additional 6-month period.

Three additional cohorts of 9 patients will receive a boost injection either at 2, 4 or 6 months.

Inclusion Criteria:

• Informed consent obtained and signed;

• Male or female patients;

• With chronic hepatitis C (genotype 1) evidenced by HCV positive serology detectable for more than 6 months;

• Patients with fibrosis status graded F0 or F1 according to the METAVIR grading system; patients with a F2 fibrosis stage could be enrolled on a case-by-case basis after being sure that they have a contraindication to be treated with an IFN-based standard HCV treatment; patients with F3 or F4 fibrosis stage will not be enrolled; this will be assessed either on the liver biopsy performed less than 18 months prior to baseline or on a FibroTest® and a FibroScan® performed within 2 months prior to first TG4040 injection; in case of discordant results, a liver biopsy will be performed prior to TG4040 treatment;;

• Treatment-naïve patients: patients who have never received IFN-based treatment;

• Patients must have compensated liver disease, with:

  • No history of ascites, hepatic encephalopathy or bleeding from esophageal varices;

  • Laboratory tests values:

    • Serum alanine aminotransferase (ALT)less then 2 folds the Upper Limit of Normal (ULN);
    • Serum bilirubin and international normalized ratio (INR) values within normal range (except in patients with Gilbert syndrome where serum bilirubin may be as high as 3.0 mg/dL); and
    • Other laboratory parameters of grade 0 or 1 (CTC criteria);

• For women of child-bearing potential, i.e. with no history of hysterectomy or tubal ligation, a negative pregnancy test at study entry and adequate protection against pregnancy during the conduct of the study and until 3 months after last TG4040 injection.

Additionnal cohorts:

• Patients with high ALT level (2 folds ULN<ALT<5 folds ULN in the 2 months before inclusion) and fibrosis not higher than F2.

Exclusion Criteria:

Patients will be excluded from the study for any of the following reasons:

• Co-infection with HBV (indicated by the presence of Hepatitis B Surface Antigen (HBsAg) in serum; patients with anti-hepatitis B core antibody response (anti-HBc) will not be excluded) or HIV (anti-HIV antibodies in serum); patients with HIV positive sexual partner (by history) will not be included;

• Current HCV therapies;

• Active IV drug or alcohol abuse;

• Serious, concomitant disorder, including:

  • primary biliary cirrhosis or sclerosing cholangitis;
  • auto-immune disease such as symptomatic cryoglobulinemia, polyarthritis, multiple sclerosis; a broad auto-immune testing will be performed at baseline;
  • proven or suspected immunosuppressive disorder;
  • active systemic infection; if the patient has acute febrile illness ( > 38°C) on the day of vaccination, it will be delayed by at least one week after complete recovery;

• Malignancy within the last 5 years; patients with history of squamous cell skin cancer or basal cell skin cancer will be enrolled, unless the history of skin cancer is at the vaccination site;

• Systemic corticosteroid therapy or other immunosuppressive/immunomodulating drugs (e.g. Cyclosporine) within 2 months prior to first study drug injection; corticosteroid nasal sprays, inhaled steroids for asthma and/or topical steroids are permissible;

• Participation in another experimental protocol during the study period (last intake of investigational drug within 6 months prior to baseline);

• Breast-feeding women;

• Receipt of any inactivated vaccine 14 days prior to vaccination or for the duration of the study; receipt of any live attenuated vaccine within 30 days prior to vaccination or for the duration of the study;

• Allergy to eggs;

• Patient unable to comply with the protocol requirements;

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