Clinical Study to Evaluate the Efficacy and Safety of HH-006 in Patients With Chronic Hepatitis B Virus Infection

This is a multicenter, open-label Phase II clinical study, It aims to evaluate the efficacy, safety, and tolerability of HH-006 in untreated HBeAg-positive/negative chronic HBV infected individuals and those with HBeAg-negative chronic HBV infection who have been treated with NAs for more than one year.

Study participants will undergo various screening examinations as per the protocol before enrollment. Eligible participants will be assigned to Cohort 1, Cohort 2, or Cohort 3 according to different inclusion and exclusion criteria (see Inclusion/Exclusion Criteria for details). Upon entering the study, participants in all cohorts will start a 4-week loading dose period of HH-006 480 mg QW, followed by HH-006 240 mg QW for 44 weeks. Participants in Cohort 3 will continue their pre-existing NAs therapy after enrollment. Evaluations will include changes in HBsAg/HBV DNA/ALT and safety.

Inclusion criteria

• Sex: male or female; Age: 18 to 45 years old (inclusive);
• Male body weight ≥ 50 kg, female body weight ≥ 45 kg, and body mass index (BMI): 18 kg/m² ≤ BMI ≤ 28 kg/m²;
• HBsAg and/or HBV DNA positivity for more than 6 months (including 6 months), or previous liver biopsy results indicating chronic hepatitis B, or negative for anti-HBc IgM;
• Virological and liver function indicators at screening:

Cohort 1: HBeAg-positive, 2000 IU/mL ≤ HBsAg ≤ 100,000 IU/mL, HBV DNA > 105 IU/mL, 2 × upper limit of normal (ULN) ≤ ALT ≤ 8 × ULN; Cohort 2: HBeAg-negative, 100 IU/mL ≤ HBsAg ≤ 3000 IU/mL, 20 IU/mL < HBV DNA ≤ 2000 IU/mL, ALT ≤ 5 × ULN; Cohort 3: HBeAg-negative, 100 IU/mL ≤ HBsAg ≤ 3000 IU/mL, HBV DNA ≤ 100 IU/mL, ALT ≤ 2 × ULN;

• Previous antiviral treatment:

Cohort 1 and Cohort 2: No interferon antiviral treatment within the past 1 year, and no nucleos(t)ide analogue (NA) treatment within the 6 months prior to screening; Cohort 3: No interferon antiviral treatment within the past 1 year; received only nucleos(t)ide analogue monotherapy for at least one year;

• Fully understand the study content, procedures, and possible adverse reactions, and sign the written informed consent form (ICF);
• Able to communicate effectively with the investigator and complete the study in accordance with the study requirements;
• Male subjects who have not undergone sterilization and female subjects who have been postmenopausal for less than two years must agree to take adequate and effective contraceptive measure from screening until the last follow-up visit.

Exclusion criteria

• Co-infected with hepatitis C, syphilis, or human immunodeficiency virus (HIV);
• At screening: total bilirubin ≥ 3 × ULN and direct bilirubin (DBil) > 1 × ULN; hemoglobin < 100 g/L; platelet count < 100,000/mm³ (100 × 109/L); absolute neutrophil count < 1,500/mm³ (1.5 × 109/L); serum albumin < 35 g/L; prothrombin time international normalized ratio (INR) > 1.3; glycated hemoglobin (HbA1c) ≥ 7%; estimated glomerular filtration rate (eGFR) (MDRD formula) < 60 mL/min/1.73 m² (Appendix 2 MDRD calculation formula);
• Clinically significant electrocardiogram (ECG) abnormalities (e.g., QTcF > 450 ms in males, > 470 ms in females, severe arrhythmias such as torsade de pointes, paroxysmal ventricular tachycardia, symptomatic atrial fibrillation/flutter requiring emergency treatment, complete atrioventricular block); poorly controlled or refractory hypertension (e.g., systolic blood pressure ≥ 160 mmHg and/or diastolic blood pressure ≥ 100 mmHg after medication use, etc.);
• Concurrent clinically significant other liver diseases, including but not limited to: moderate or severe fatty liver, alcoholic liver disease, autoimmune liver disease, hereditary metabolic liver disease, drug-induced liver injury, etc.;
• History of progressive hepatic fibrosis or cirrhosis at any time prior to or during screening;
• Current or prior history of hepatic decompensation manifestations, including but not limited to: ascites, hepatic encephalopathy, esophageal and gastric variceal bleeding, hepatorenal syndrome, etc.;
• Previous history of hepatocellular carcinoma, or at screening: serum alpha-fetoprotein (AFP) ≥ 50 ng/mL; or liver ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) findings suggestive of possible hepatocellular carcinoma;
• Concurrent severe diseases or clinical conditions in other systems that, in the investigator's judgment, make the participant unsuitable for inclusion in this study:

• Circulatory system diseases: e.g., unstable angina, myocardial infarction, congestive heart failure, etc.;
• Respiratory system diseases: e.g., severe chronic obstructive pulmonary disease, etc.;
• Primary or secondary kidney diseases (e.g., chronic renal decompensation, renal diseases secondary to diabetes, hypertension, vascular diseases, etc.);
• Endocrine system diseases: e.g., poorly controlled diabetes or thyroid diseases, etc.;
• Autoimmune diseases: e.g., systemic lupus erythematosus, primary immune thrombocytopenia, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, autoimmune hemolytic anemia, severe psoriasis, etc.;
• Neuropsychiatric disorders: e.g., epilepsy, schizophrenia, depression, etc.;
• Malignant tumors;
• Lactating women or those with a positive pregnancy test;
• Persistent alcohol consumption (average daily intake > 40 g alcohol for males, > 20 g alcohol for females) or illicit drug abuse within 6 months prior to screening (including the screening period);
• Participation in any clinical trial of a drug (except for those who did not receive the investigational product) or medical device (except for non-invasive medical devices) within 3 months prior to screening;
• Major trauma or major surgery within the past three months;
• History of allergy to HH-003, HH-006, or polysorbate 80;
• In the investigator's judgment, unsuitability for participation in this study, or close relationship with the study site: e.g., immediate family members of the investigator, or affiliated personnel (e.g., site staff or students).