Phase 2b Study of Bulevirtide (With Peginterferon Alfa-2a) in Patients With CHD
Phase 2b Study of Bulevirtide (With Peginterferon Alfa-2a) in Patients With CHD
This is Phase 2b Clinical Study to Assess Efficacy and Safety of Bulevirtide in Combination
 with Pegylated Interferon alfa-2a in Patients with Chronic Hepatitis Delta
A Multicenter, Open-label, Randomized Phase 2b Clinical Study. Approximately 20 study sites
 in 4 countries globally: Russia, France, Moldova, Romania.

 There is currently no approved drug for treatment of chronic hepatitis Delta (CHD). Pegylated
 interferon alfa -2a (PEG-IFN alfa) is approved for treatment of chronic hepatitis B virus
 (HBV) infection which is required for the propagation of hepatitis Delta virus (HDV), and
 used to treat patients with HDV infection with evidence of some virologic efficacy.
 Interferon has a complex mode of action, whereas direct antiviral effects and
 immunomodulatory mechanisms have been described. Bulevirtide as an entry inhibitor has
 demonstrated significant virologic and biochemical activity in patients with HDV infection
 during the Phase 2 clinical trials. A combination of the both drugs demonstrated significant
 synergistic effects in the 201 clinical trial. It is therefore warranted to further
 investigate the combination therapy with the aim of improvement of sustained virologic
 response rates.
Inclusion Criteria:

 1. Provision of signed and dated informed consent form.

 2. Male or female, aged 18-65 years (inclusive).

 3. Positive serum HDV antibody results or PCR results for serum/ plasma HDV RNA for at
 least 6 months before Screening.

 4. Positive PCR results for serum/ plasma HDV RNA at Screening.

 5. Alanine transaminase level >1 x ULN, but less than 10 x ULN.

 6. Serum albumin >28 g/L.

 7. Thyroid stimulating hormone (TSH) within normal ranges (including on medication for
 control of thyroid function)

 8. Negative urine pregnancy test for females of childbearing potential.

 9. Inclusion criteria for female subjects:

 -  Postmenopausal for at least 2 years, or

 -  Surgically sterile (total hysterectomy or bilateral oophorectomy, bilateral tubal
 ligation, staples, or another type of sterilization), or

 -  Abstinence from heterosexual intercourse throughout the treatment period, or

 -  Willingness to use highly effective contraception (double barrier method or
 barrier contraception in combination with hormonal or intrauterine contraceptive)
 throughout the treatment period and for 6 months after the last dose of the study
 medication.

 10. Male subjects must agree to use a highly effective contraception (double barrier
 method or barrier contraception in combination with hormonal or intrauterine
 contraceptive used by female partners) and not to donate sperm throughout the
 treatment period and for 6 months after the last dose of the study medication.

 Exclusion Criteria:

 1. 1. Child-Pugh hepatic insufficiency score of B-C or over 6 points. NOTE: Child-Pugh
 hepatic insufficiency score of 6 points is allowed. Only patients with compensated
 cirrhosis are allowed. Uncomplicated oesophageal varices allowed; Subjects with
 current bleeding or ligation, or history of bleeding or ligation within the last 2
 years are excluded.

 2. HCV or HIV coinfection. Subjects with HCV antibodies can be enrolled, if screening HCV
 RNA test is negative.

 3. Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula.

 4. Total bilirubin ≥ 34.2 µmol/L. [Patients with higher total bilirubin values may be
 included after the consultation with the Study Medical Monitor, if such elevation can
 be clearly attributed to Gilbert's syndrome associated with low-grade
 hyperbilirubinemia.]

 5. Evidence of an active or suspected malignancy, or an untreated pre-malignancy
 disorder, or a history of malignancy within the last 5 years (with the exception of
 successfully treated carcinoma of the cervix in situ and successfully treated basal
 cell carcinoma and squamous cell carcinoma not less than 1 year prior to screening
 [and no more than 3 excised skin cancer within the last 5 years prior to screening])
 or history of hepatic carcinoma.

 6. Systemic connective tissue disorders.

 7. NYHA (New York Heart Association) class III-IV congestive heart failure.

 8. Patients with uncontrolled arterial hypertension: systolic blood pressure > 150 mm Hg
 and/ or diastolic blood pressure > 100 mm Hg at Screening.

 9. Previous or unstable concurrent diseases or conditions that prevent subject's
 enrolment into the study.

 10. Patients with mental disorders or social circumstances that preclude them from
 following protocol requirements.

 11. Current or previous decompensated liver disease, including coagulopathy, hepatic
 encephalopathy and esophageal varices hemorrhage.

 12. 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, congestive heart failure or
 other severe cardiopulmonary disease, etc.). Gilbert's syndrome, a benign disorder
 associated with low-grade hyperbilirubinemia, will not exclude patients from
 participation in this trial. Autoimmune hepatitis stigmata attributed to HDV infection
 in the opinion of the investigator are allowed.

 13. White blood cells (WBC) count < 3000 cells/mm3 (<1500 if African patients).

 14. Absolute neutrophil count < 1500 cells/mm3 (<1000 if African patients).

 15. Platelet count < 90,000 cells/mm3.

 16. Haemoglobin < 12 g/dL.

 17. Use of prohibited psychotropic agents at Screening.

 18. Use of interferons within 6 months before Screening.

 19. History of solid organ transplantation.

 20. Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this
 study; current drug addict or history of drug use within 2 years prior to Screening.

 21. History of disease requiring regular use of systemic glucocorticosteroids (inhalative
 glucocorticosteroids are allowed) or other immunosuppressants.

 22. Pregnant or breast-feeding females.

 23. Participation in another clinical study with investigational drugs within 30 days
 prior to randomization.

 24. Receipt of bulevirtide previously, e.g. in clinical trials.

 25. Inability to follow protocol requirements and undergo all protocol procedures. NOTE:
 Patients with medical contraindication for liver biopsy are allowed to participate in
 this study. Such patients will exempt from liver biopsy requirements in this study.

 Patients receiving prohibited treatment at Screening cannot be included into the study
 unless this treatment is withdrawn prior to randomization.

 26. Contraindications, intolerance or hypersensitivity to interferons alfa, genetically
 engineered E.coli medications, polyethylene glycol or other components of
 peginterferon alfa-2а.

 27. Presence or history of severe retinopathy, significant diabetic or hypertensive
 retinopathy.

 28. Uncontrolled diabetes mellitus.

 29. Uncontrolled cardiovascular disorders within 6 months before screening.

 30. History of autoimmune disorder (e.g. myositis, hepatitis, thrombotic thrombocytopenic
 purpura, idiopathic thrombocytopenic purpura, severe psoriasis, rheumatoid arthritis,
 interstitial nephritis, thyroiditis, and systemic lupus erythematosus)

 31. Presence or history of significant psychiatric disorder (e.g. severe depression,
 suicide attempt, severe neurosis or cognitive disorder).

 32. Presence or history of chronic lung disease with respiratory malfunction.