Myrcludex B Plus Pegylated Interferon-alpha-2a in Patients With HBeAg Negative HBV/HDV Co-infection

Randomized Open-label Substudy of Daily Myrcludex B Plus Pegylated Interferon-alpha-2a in Patients With HBeAg Negative Chronic Hepatitis B Co-infected With Hepatitis Delta

Randomized open-label substudy of daily Myrcludex B (MXB) plus pegylated interferon-alpha-2a (PEG-INF-a) in patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B virus (HBV) co-infected with hepatitis delta virus (HDV).

The study is designed to evaluate safety and efficacy of MXB in a subset of HBV infected patients who are co-infected with HDV. Hepatitis delta represents the most severe form of chronic viral hepatitis and there is no approved treatment option available for patients infected with both HBV and HDV.

24 patients will be randomised into 3 arms: pre-treatment with MXB followed by PEG-INF-a treatment versus a combination of both drugs versus PEG-INF-a.

Prolonged blockade of HBV entry into hepatocytes should also block infection with HDV particles (which uses hepatitis B surface antigen (HBsAg) as its envelope) and thus provide a therapeutic option for this otherwise hardly treatable disease. PEG-INF-a is used for the treatment of chronic hepatitis delta. The study endpoints are virological response (HBsAg, hepatitis delta virus ribonucleic acid (HDV RNA), hepatitis B virus deoxyribonucleic acid (HBV DNA)), as well as safety and tolerability and drug immunogenicity.

Inclusion Criteria:

• Chronic hepatitis B defined by the presence of HBsAg for at least 6 months prior to screening period. Co-infection with hepatitis D virus defined as positive anti-HDV antibodies for at least 3 months and positive for HDV-RNA within the screening period.

• Liver biopsy performed within one year prior to screening or during screening period.

• HBeAg negative

• All women of childbearing potential must have a negative urine pregnancy test prior to enrolment.

• Women must:

  1. Be menopausal for at least 2 years, or
  2. Be surgically sterile (total hysterectomy or bilateral ovariectomy or bilateral tubal ligation/clips or otherwise be incapable of pregnancy), or
  3. Not be heterosexually active during the study, or
  4. Agree to use a highly effective method of birth control (double barrier method or combination of barrier method with hormonal or intrauterine device) during the study and for 3 month after the last dosing of the investigational medicinal product.

• Men must agree to use a highly effective method of birth control (double barrier methods or combination of barrier method with hormonal or intrauterine device in their women-partner) and not to donate a sperm during the study and for 3 month after the last dosing of the investigational medicinal product.

• An understanding, ability and willingness to fully comply with study procedures and restrictions.

• An ability to provide the written informed consent to participate in the study

Exclusion Criteria:

• Decompensated liver disease (Child-Pugh-Score >6).
• Co-infected with hepatitis C virus (HCV), or HIV.
• Patients with presence of anti-HCV antibody and negative HCV RNA in two separate occasions within 12 months prior to screening could be enrolled into the study after sponsor written permission.
• ALT > 6 ULN.
• Creatinine clearance < 60 mL/min.
• Total bilirubin > 2 mg/dL.
• Confirmed contraindication for treatment with PEG-INF-a.
• History of hepatocellular carcinoma (HCC) or findings suggestive of possible HCC, such as suspicious foci on imaging studies or elevated serum alpha-fetoprotein (AFP) levels. In patients with such findings, HCC will be ruled-out prior to screening for the present study.
• One or more additional known primary or secondary causes of liver disease, other than hepatitis B (e.g., alcoholism, autoimmune hepatitis, malignancy with hepatic involvement, hemochromatosis, alpha-1 antitrypsin deficiency, Wilson's Disease, other congenital or metabolic conditions affecting the liver, e.g. congestive heart failure or other severe cardiopulmonary disease). Patients with Gilbert's syndrome and Dubin-Johnson syndrome, two benign disorders associated with low-grade hyperbilirubinemia can be enrolled into the trial.
• History of clinically evident pancreatitis.
• History of alcohol or drug abuse within the preceding two years. For the purposes of the present study, alcohol abuse is arbitrarily defined as frequent consumption of alcoholic beverages with an average daily intake of more than 40 g of ethanol.
• Participation in another study with an investigational drug within less than one month prior to this study or simultaneously to this study.
• Patients who are unable or unwilling to follow the protocol requirements.
• Patients with a history of seizures, central nervous system disorders or psychiatric disability thought to be clinically significant in the opinion of the investigator.
• Patients with limited mental capacity to the extent that she/he cannot provide informed consent or information regarding adverse events of the study drug.
• Clinically significant renal, respiratory or cardiovascular disease.
• Pregnancy and lactation.
• Patients who have previously participated in this study.