A Clinical Study of HH-006 in Untreated Chronic Hepatitis B Virus Infected Patients

A Randomized, Double-blind, Placebo-controlled Phase I Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic Profile, and Preliminary Antiviral Activity of Multiple Doses of HH-006 Injection in Untreated Chronic Hepatitis B Virus Infected Individuals

This is a randomized, double-blind, placebo-controlled Phase I dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and antiviral activity of multiple ascending doses (120 mg, 240 mg, 480 mg SC, QW×5) of HH-006 in untreated chronic HBV patients. Each cohort includes 12 participants (9 active, 3 placebo), with dose progression approved by a Safety Review Committee. Participants are monitored through 24 weeks post-dose. The study design allows for adjustments based on emerging data.

This is a randomized, double-blind, placebo-controlled, multiple-dose escalation Phase I clinical study. The study aims to evaluate the safety, tolerability, pharmacokinetic profile, and preliminary antiviral activity of multiple doses (120 mg QW, 240 mg QW, 480 mg QW, administered subcutaneously (S.C.) once weekly (QW) for 5 doses) in chronic hepatitis B virus (HBV) infected participants who are not receiving anti-HBV treatment, are HBeAg-negative or positive, have HBV DNA ≥ 100 IU/mL, 100 IU/mL < HBsAg < 5000 IU/mL, and ALT ≤ 5 × ULN.

Each dose cohort plans to enroll 12 participants, enrolled in batches according to the dose escalation principle. Participants will be randomized to receive either HH-006 (N=9) or placebo (N=3) for a repeated-dose (5 doses) tolerability and pharmacokinetic study.

Dosing for the next cohort will commence only after all 12 participants in the current dose cohort have completed the safety assessment up to 14 days post-last dose (Week 7, Day 43) and after review and approval by the Safety Review Committee. The currently planned maximum dose for escalation is 480 mg QW.

Each participant is planned to be followed up for 24 weeks after the last dose to assess the safety, tolerability, PK, immunogenicity, and preliminary antiviral activity of HH-006 in participants with chronic HBV infection. During the study, adjustments to the maximum dose, dosing regimen, blood sampling time points, and follow-up duration may be made based on the accumulating data obtained during the study.

Throughout the study, participants' safety indicators and virologic parameters will be closely monitored to evaluate the safety and antiviral activity of HH-006.

Inclusion Criteria:

• Male or female aged 18 to 60 years (inclusive);
• Male weight ≥ 45 kg, female weight ≥ 40 kg, and body mass index (BMI, BMI = weight/height²): 18 kg/m² ≤ BMI ≤ 32 kg/m²;
• HBsAg positive for more than 6 months (including 6 months), and with 100 IU/mL < HBsAg < 5000 IU/mL prior to randomization;
• HBV DNA ≥ 100 IU/mL prior to randomization;
• ALT ≤ 5 × ULN prior to randomization;
• No prior interferon antiviral therapy within 1 year before the screening period, and no prior treatment with nucleos(t)ide analogues within 6 months before the screening period;
• Males not having undergone sterilization surgery and females not postmenopausal for less than two years must agree to use adequate and effective contraceptive measures from screening until the last follow-up visit of the study (including hormonal contraceptives, intrauterine devices, cervical caps, or condoms);
• Subjects must understand and comply with the study procedures, participate voluntarily, and sign the informed consent form.

Exclusion Criteria:

• Females who are pregnant, breastfeeding, or have a positive pregnancy test at baseline with childbearing potential.
• Co-infection with hepatitis C, syphilis, or HIV.
• History of alcoholic liver disease, non-alcoholic steatohepatitis, autoimmune liver disease or other hereditary liver diseases, drug-induced liver disease, or other clinically significant chronic liver diseases not caused by HBV.
• History of or concurrent progressive liver fibrosis or cirrhosis;
• History of or concurrent hepatocellular carcinoma, or at screening: blood alpha-fetoprotein (AFP) ≥ 50 ng/mL; or imaging examinations such as liver ultrasound, CT, or MRI suggest possible hepatocellular carcinoma.
• Clinically significant ECG abnormalities;
• Concurrent severe diseases of other systems or clinical conditions that, in the investigator's judgment, make the subject unsuitable for participation 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 (COPD), etc.

Primary or secondary renal diseases: e.g., chronic renal decompensation and renal diseases secondary to diabetes, hypertension, vascular diseases, etc.

Endocrine system diseases: e.g., poorly controlled diabetes or thyroid disease, etc.

Autoimmune diseases: e.g., systemic lupus erythematosus, primary thrombocytopenic purpura, rheumatoid arthritis, inflammatory bowel disease, sarcoidosis, autoimmune hemolytic anemia, severe psoriasis, etc.

Neuropsychiatric diseases: e.g., epilepsy, schizophrenia, etc. Malignancies.

• At screening: total bilirubin > 1.1 × ULN or direct bilirubin > 1.1 × ULN; hemoglobin < 120 g/L (male) or < 110 g/L (female); platelets < 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; estimated glomerular filtration rate (eGFR, MDRD formula) < 60 mL/min/1.73 m².
• History of sustained alcohol consumption (average daily alcohol intake > 40 g for males, > 20 g 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 drug) or medical device (except for non-invasive medical devices) within 3 months prior to screening, or being within 5 half-lives of a prior drug at the time of screening.
• Significant trauma or major surgery within 3 months prior to screening.
• Known allergy to antibody-based drugs or to any component of the investigational drug.
• Individuals judged by the investigator to be unsuitable for participation in this study, or those with a close relationship to the study center: e.g., relatives of the investigator, affiliated personnel (e.g., staff or students of the study center).