Study Detail

The proportion of participants who achieve a composite endpoint of virologic response and ALT normalization at Week 24 in brelovitug arms will be compared to response at Week 12 of delayed-treatment arm:

• Virologic response is defined as HDV RNA ≥2 log10 IU/mL decrease from Baseline or undetectable HDV RNA (< lower limit of quantification [LLOQ], target not detected [TND]),
• ALT normalization is defined as a decrease in ALT from Baseline to ≤ULN

Safety endpoint will evaluate:

•  Incidence and severity of treatment-emergent adverse events (TEAE)
•  Proportion of participants who permanently discontinue treatment due to an adverse event

The proportion of participants who achieve the following at Week 24, 48, and 96 of treatment unless specified:

• Virologic response defined as ≥2 log10 IU/mL decline from baseline or undetectable HDV RNA
• HDV RNA <LLOQ
• HDV RNA <LLOQ, TND
• ALT normalization alone and in combination with: Virologic response defined as ≥2 log10 IU/mL decline from baseline or undetectable HDV RNA (Weeks 48 and 96), HDV RNA <LLOQ, HDV RNA <LLOQ,  TND

 Proportion of subjects who achieve HDV RNA <LLOQ, TND at post-treatment follow-up Weeks 24 and 48.

Change from Baseline in liver stiffness as determined by transient elastography (e.g., FibroScan) at Weeks 24, 48, and 96 of brelovitug treatment

Change from Baseline in AST-to-platelet ratio index (APRI) at Weeks 24, 48, and 96 of brelovitug treatment.

Change from Baseline in CTP score in cirrhotic participants at Weeks 24, 48, and 96 of brelovitug treatment.

Change from Baseline in Model for End-Stage Liver Disease (MELD) score in cirrhotic participants at Weeks 24, 48, and 96 of brelovitug treatment.

Proportion of participants with clinical disease progression from Baseline in HDV-associated liver disease at Weeks 24, 48 and 96 of brelovitug treatment. Progression will be determined by the Independent Data Monitoring Committee (IDMC).

Proportion of participants who experience virologic non-response, defined as a <1 log10 decline in HDV RNA from baseline after at least 24 weeks of treatment.

Proportion of participants who experience virologic breakthrough, defined as confirmed increase of >2 log10 from nadir.

Summarize brelovitug exposure using a population PK model.

The proportion of participants who achieve composite response by HBV and HDV genotype.

5.2 Inclusion Criteria

1. Willing and able to provide written informed consent.

2. Male or female, ≥18 years of age at Screening.

3. Confirmation of chronic HDV infection, defined as positive for anti-HDV antibody test

or HDV RNA for at least 6 months prior to Day 1. If prior documentation is not

available, then HDV RNA positivity along with evidence of fibrosis (liver stiffness of

≥7 kPa) is acceptable.

4. HDV RNA >500 IU/mL at Screening.

5. ALT >ULN at Screening.

6. Taking or willing to take tenofovir disoproxil fumarate (TDF), tenofovir alafenamide

fumarate (TAF), or entecavir (ETV) at baseline, and willing to remain on stable treatment

for the duration of the study.

7. Cirrhosis determination at Screening is defined as:

a) Absence of cirrhosis is transient elastography (e.g., FibroScan) <12.5 kPa

b) Presence of cirrhosis is transient elastography (e.g., FibroScan) ≥12.5 kPa

8. In countries where HDV treatment is approved and available, participants must be

documented as unwilling or unable to receive treatment.

5.3 Exclusion Criteria

1. Pregnant or nursing females.

2. Male or female participants of childbearing potential unwilling to comply with

contraception requirements during the study (Appendix 5).

3. Current, prior history, or is under evaluation for any of the following:

a) Difficulty with blood collection and/or poor venous access for the purposes of

phlebotomy,

b) Clinical hepatic decompensation (i.e., ascites, encephalopathy variceal hemorrhage).

Incidental small ascites on imaging without other clinical symptoms/signs of acute

decompensation would not exclude the participants,

c) Hepatocellular carcinoma; suspected HCC on ultrasound at Screening,

d) Vasculitis,

e) Extrahepatic disorders possibly related to HBV immune complexes

(e.g., glomerulonephritis, polyarteritis nodosa),

f) Solid organ or bone marrow transplantation,

g) Significant pulmonary disease (e.g., O2-dependent or forced expiratory volume

1 second (FEV1) ≤50% predicted value),

h) Significant cardiac disease (e.g., history of myocardial infarctions within 6 months,

any history of ventricular tachycardia, congestive heart failure, dilated

cardiomyopathy with left ventricular ejection fraction <40%),

i) Malignancy diagnosed or treated within 5 years (recent localized treatment of

squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in

situ is allowed if appropriately treated prior to Screening).

4. CTP >6 (B or C) (see Section 6.7.7.2)

5. Presence of other liver disease(s) (non-HBV/HDV), such as metabolic dysfunctionassociated steatohepatitis (MASH), alcohol associated hepatitis, cholestatic liver disease,

other viral (e.g., HCV or HAV) or non-viral hepatitis that has the potential to impact

interpretation of data. Exceptions to this criterion include fatty liver without any signs of

steatohepatitis or past HCV infection that was successfully treated (HCV RNA negative)

≥6 months prior to Screening.

6. Uncontrolled human immunodeficiency virus (HIV) infection defined as having

quantifiable HIV RNA levels in the blood at Screening.

7. History of hypersensitivity to any of the components in the brelovitug formulation.

8. Screening laboratory results as follows, or any other clinically significant abnormalities

in Screening laboratory values that would render a participant unsuitable for inclusion:

a) Platelet count <50,000/mm3

b) Hemoglobin <10.0 g/dL

c) Creatinine clearance by Crockcroft-Gault (CrCl) <30 mL/min

d) Alpha fetoprotein (AFP) >100 ng/mL

9. Treatment with another investigational drug, a biological agent, or device within 4 weeks

or 5 half-lives, whichever is longer, of Baseline.

10. Use of any interferon or bulevirtide within 12 weeks of Screening.

11. Use of any prohibited concomitant medications as described in Section 7.7.

12. Regular alcohol misuse, defined as weekly intake of ≥14 alcoholic drinks per week

(average of ≥2 alcoholic drinks per day) within 12 months of Screening.

13. Clinically relevant drug abuse (not including cannabis) within 12 months of Screening.

14. Unwillingness to comply with study procedures as specified by this protocol, or

unwillingness to cooperate fully with the Investigator.

15. Have any other conditions (medical, social, psychiatric, or other), which in the opinion of

the Investigator would make the participant unsuitable for inclusion or could interfere

with the participant participating in or completing the study.

This is a Phase 3, randomized, open-label, multicenter trial in which eligible patients will either receive brelovitug immediately or start treatment later (delayed treatment group). The study population includes adult patients with confirmed chronic hepatitis D CHD infection who currently have very limited or no approved treatment options available.

The trial is designed to:

• Assess whether brelovitug can improve clinical health outcomes and reduce viral activity compared to delayed treatment. 
• Monitor the safety profile and tolerability of brelovitug during both treatment and follow-up periods. 
• Generate robust data that may support regulatory approval and future clinical use of brelovitug as a new treatment for chronic hepatitis D.

Study duration - 3 years 

Target population - Male and female participants aged ≥18 with chronic hepatitis delta (CHD) infection (hepatitis Delta virus [HDV] RNA >500 IU/mL), alanine transaminase (ALT) > upper limit of normal (ULN), and compensated liver disease, with or without the presence of cirrhosis (Child-Turcotte-Pugh [CTP] A).

Primary Objective - To evaluate the efficacy of brelovitug at Week 24 compared with delayed treatment on CHD at Week 12

The arms are defined as followed:

• Arm 1 - Brelovitug 300 mg (2 mL) subcutaneously once weekly for 96 weeks. Brelovitug will be administered on Day 1 by trained clinical staff and the first self-administered dose on Day 8 will be completed in-clinic under clinical staff oversight. Participants may then self-administer at home once approved by clinical staff.
• Arm 2 -  Brelovitug 900 mg (6 mL) subcutaneously once every 4 weeks for 96 weeks with a 900 mg (6 mL) loading dose at Week 2. Treatment will be administered in-clinic by trained clinical staff. Self-administration is not allowed in this arm.
• Arm 3 - Participants will attend study clinic visits and delay treatment for 12 weeks. At\Week 12, participants will receive brelovitug 300 mg (2 mL) subcutaneously once weekly for 96 weeks. The first brelovitug dose on Day 85 will be administered by trained clinical staff. The first self-administered brelovitug dose Day 92 will be completed in-clinic under clinical staff oversight. Participants may then self-administer at home once approved by clinical staff.

Randomization will be stratified by cirrhosis status (presence or absence) and HBsAg level (> or ≤4 log10 IU/mL) at Screening, and nucleot(s)ide analog (NUC) treatment (continuing or planning to initiate NUC at Baseline). Participants will continue to take NUC treatment from Screening through the end of the study. Participants not already on a NUC will initiate treatment upon enrollment on Baseline/Day 1 for chronic hepatitis B (CHB) management. Upon completion of the End of Treatment visit, participants who complete the treatment phase of the study and meet eligibility criteria will be offered enrollment into a rollover treatment study with brelovitug. Participants who do not enroll into the rollover long-term treatment study will complete 48 weeks of post-treatment follow up.