Myrcludex B in Combination With Peginterferon Alfa-2a Versus Peginterferon Alfa-2a Alone in Patients With Chronic Viral Hepatitis B With Delta-agent

A Multicenter, Open-label, Randomised, Comparative, Parallel-Arm, Phase II Study to Assess Efficacy and Safety of Myrcludex B in Combination With Peginterferon Alfa-2a Versus Peginterferon Alfa-2a Alone in Patients With Chronic Viral Hepatitis B With Delta-agent

Randomised, Comparative, Parallel-Arm Study to Assess Efficacy and Safety of Myrcludex B in Combination with Peginterferon Alfa-2a Versus Peginterferon Alfa-2a Alone in Patients with Chronic Viral Hepatitis B with Delta-agent

This is a multicenter, open-label, randomised, comparative, active-controlled parallel-arm phase II study.

The study will be conducted in Russia. The aim of this study is to explore the safety and efficacy of treatment with Myrcludex B used as a monotherapy and in combination with PEG-IFNα and Tenofovir compared to monotherapy with PEG-IFNα in patients with chronic viral hepatitis B with delta-agent, based on the achievement of undetectable viral load at the end of the follow-up period 6 months (24 weeks) after the end of treatment. The study is also aimed at investigating immunogenicity of Myrcludex B and the drug pharmacokinetics when used in combination with PEG IFN alfa-2a and with Tenofovir.

It is planned to screen 110 patients, and 90 patients will be randomised in equal numbers into six treatment arms.

• Arm A (n=15): PEG IFN alfa-2a 180 µg for 48 weeks
• Arm B (n=15): Myrcludex B 2 mg + PEG IFN alfa-2a 180 µg for 48 weeks
• Arm C (n=15): Myrcludex B 5 mg + PEG IFN alfa-2a 180 µg for 48 weeks
• Arm D (n=15): Myrcludex B 2 mg for 48 weeks
• Arm E (n=15): Myrcludex B 10 mg (10 mg once a day)+ PEG IFN alfa-2a 180 µg for 48 weeks
• Arm F (n=15): Myrcludex B 10 mg (5 mg twice a day)+ Tenofovir for 48 weeks

Inclusion Criteria:

1. Signed Informed Consent form.
2. Males and females 18 to 65 years of age (inclusively).
3. Patients with chronic hepatitis B (HBeAg-positive or negative) and HBsAg-positive for at least 6 months prior to Screening.
4. Positive for anti-HDV antibodies for at least 6 months prior to Screening.
5. HDV RNA-positive at Screening.
6. ALT ≥ 1 x ULN and < 10 x ULN.
7. The patient agreed to use adequate method of contraception during the study, starting from the time of Informed Consent signing and until completion of the Follow-up Period.

Exclusion Criteria:

1. Intolerance or hypersensitivity to the active ingredient or other components of the study drug Myrcludex B.

2. Intolerance or hypersensitivity to interferons alfa, genetically engineered E.coli medications, polyethylene glycol or other components of peginterferon alfa-2a.

3. Previous treatment with Myrcludex B (patients with previous exposure to interferon are eligible).

4. Therapy with antiviral drugs for chronic viral hepatitis B with delta-agent over the previous 6 months.

5. Therapy with anti-tumour agents (including radiotherapy) or immunomodulatory medications (including systemic glucocorticoids) over the previous 6 months.

6. The following laboratory test results at Screening:

   1. Hemoglobin < 100 g/L
   2. Leucocytes < 3000/µL
   3. Neutrophils < 1500/µL
   4. Platelets < 90000/µL
   5. Serum creatinine >1.5 x ULN.

7. Total bilirubin > 34.2 µM/L. Patients with higher total bilirubin may be enrolled upon consultation with the study Medical Monitor, if there is clear evidence that the elevated bilirubin is caused by Gilbert's syndrome.

8. Current or previous decompensated liver disease, including coagulopathy, hyperbilirubinemia, hepatic encephalopathy, hypoalbuminaemia, ascites, and oesophageal varices haemorrhage; Child-Pugh score of B/C or ≥6 points.

9. HCV or HIV coinfection (patients with anti-HCV antibodies and no HCV RNA at Screening are eligible).

10. Hepatocellular carcinoma.

11. Signs of drug- or alcohol-induced liver disease or any other medical conditions associated with chronic liver disease (e.g. autoimmune hepatitis, hemochromatosis, thalassaemia, alcoholic hepatitis, toxic liver disease).

12. Contraindications for liver biopsy.

13. Concurrent malignancy (current diagnosed or suspected malignancy; risk of a previous malignancy recurrence).

14. Severe decompensated cardiovascular diseases, including unstable and poorly controlled conditions, over 6 months before Screening.

15. History of poorly controlled thyroid conditions or clinically significant signs of thyroid dysfunction at Screening.

16. Previous or current severe renal failure or significant renal dysfunction at Screening.

17. Previous or current chronic pulmonary disease with respiratory distortion at Screening.

18. Previous or current severe retinopathy, significant ophthalmology disorders associated with diabetes mellitus or hypertension.

19. Previous or current severe psychiatric disorders at Screening (e.g. severe depressions, suicidal attempts, severe neuroses or cognitive disorders).

20. Previous or current endocrine disorders (hypoglycaemia, hyperglycaemia, diabetes mellitus) that are not adequately controlled at Screening.

21. History of visceral organ transplantation.

22. Signs of drug and/or alcohol dependence (80 g of alcohol/day for men and 40 g of alcohol/day for women) within 1 year before Screening.

23. History of immune disorders (e.g. idiopathic thrombocytopenic purpura, lupus erythematosus, sclerodermia, severe psoriasis, rheumatoid arthritis).

24. Need for concomitant use of glucocorticoids or myelotoxic agents.

25. Participation in another clinical study within 30 days prior to enrollment into this study.

26. Pregnant or breast-feeding females.

27. Any other condition that, in the opinion of Investigator, precludes the patient from taking part in this study.