Study to Assess Efficacy and Safety of Bulevirtide in Participants With Chronic Hepatitis Delta (CHD)

A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess Efficacy and Safety of Bulevirtide in Patients With Chronic Hepatitis Delta

The primary objective of this study is to evaluate the efficacy of bulevirtide administered subcutaneously (SC) for 48 weeks at a dose of 2 mg or 10 mg once daily for treatment of chronic hepatitis delta (CHD) in comparison to delayed treatment.

The main goal of this study is to determine the effectiveness of bulevirtide in participants randomized to bulevirtide 2 mg or 10 mg once daily SC as compared to participants randomized to delayed treatment for 48 weeks. Treatment will continue through Week 144 (participants randomized to delayed treatment will change to bulevirtide 10 mg once daily SC after Week 48 through Week 144). All participants will be followed off-treatment for an additional 96 weeks.

Inclusion Criteria:

1. Provision of signed and dated informed consent form.

2. Positive serum anti-hepatitis delta virus (HDV) antibody results or polymerase chain reaction (PCR) results for serum/ plasma HDV ribonucleic acid (RNA) for at least 6 months before screening.

3. Positive PCR results for serum/plasma HDV RNA at screening.

4. Alanine transaminase level > 1 x upper limit of normal (ULN), but less than 10 x ULN.

5. Serum albumin > 28 g/L.

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

7. Inclusion criteria for females:

   • 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 study, or
   • Willingness to use highly effective contraception (double barrier method or barrier contraception in combination with hormonal or intrauterine contraceptive) throughout the study and for 3 months after the last dose of the study medication for individuals discontinued during the treatment period.

8. Individuals 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 study and for 3 months after the last dose of the study medication for individuals discontinued during the treatment period.

Exclusion Criteria:

1. Child-Pugh hepatic insufficiency score over 7 points. Uncomplicated oesophageal varices allowed; Individuals with current bleeding or ligation, or history of bleeding or ligation within the last 2 years are excluded.
2. Hepatitis C virus (HCV) or uncontrolled human immunodeficiency virus (HIV) coinfection. Individuals with HCV antibodies can be enrolled, if screening HCV RNA test is negative. Individuals with HIV infection can be enrolled if cluster of differentiation (CD4+) cell counts are >500/mL and HIV RNA is below limit of detection for at least 12 months.
3. Creatinine clearance < 60 mL/min as estimated using Cockcroft-Gault formula.
4. Total bilirubin ≥ 34.2 µmol/L. (Individuals 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 a history of malignancy, or an untreated pre-malignancy disorder 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. New York Heart Association (NYHA) class III-IV congestive heart failure.
8. Individuals 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 individual's enrolment into the study.
10. Individuals with mental disorders or social circumstances that preclude them from following protocol requirements.
11. Current or previous (within last 2 years) 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 individuals 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/mm^3 (<1500 if African individuals).
14. Neutrophil count < 1500 cells/mm^3 (<1000 if African individuals).
15. Platelet count < 60,000 cells/mm^3.
16. Use of prohibited psychotropic agents at Screening.
17. Use of interferons within 6 months before Screening.
18. History of solid organ transplantation.
19. Current alcohol abuse or alcohol abuse within 6 months prior to enrolment in this study; past or current drug addict.
20. History of disease requiring regular use of systemic glucocorticosteroids (inhalative glucocorticosteroids are allowed) or other immunosuppressants.
21. Pregnant or breast-feeding females.
22. Participation in another clinical study with investigational drugs within 30 days prior to randomization.
23. Receipt of bulevirtide previously, e.g. in clinical trials.
24. Inability to follow protocol requirements and undergo all protocol procedures. NOTE: Individuals with medical contraindication for liver biopsy are allowed to participate in this study. Such individuals will exempt from liver biopsy requirements in this study.

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