A Study to Evaluate the Safety and Efficacy of AHB-137 in Healthy Participants and Chronic Hepatitis B Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the tolerability, and pharmacokinetics of AHB-137 subcutaneous injection in healthy participants after single and multiple doses. In addition, the study will evaluate the antiviral efficacy of AHB-137 in chronic hepatitis B (CHB) patients following a multiple dosing regimen.

Detailed Description
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This study is a two-part study of AHB-137, including Part Ia and Part Ib. Part Ia evaluates the tolerability, pharmacokinetics of AHB-137 following subcutaneous single-ascending doses (SAD) or multiple-ascending doses (MAD) in healthy volunteers. Part Ib is a multiple dose study to assess the safety, tolerability, pharmacokinetics, and antiviral efficacy of AHB-137 in chronic hepatitis B (CHB) patients.

Official Title
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A Phase I, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Tolerability, Pharmacokinetics of AHB-137 With Single Ascending Doses and Multiple Ascending Doses in Healthy Volunteers and Initial Efficacy With Multiple Ascending Doses in Chronic Hepatitis B Patients

Conditions
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Hepatitis B, Chronic

Intervention / Treatment
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* Drug: AHB-137 injection
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy participants are required to meet all the following inclusion criteria in order to be enrolled in the study: The participants voluntarily participate in the study, and sign the Informed Consent Form (ICF) prior to screening; The participants are able to comply with all the protocol requirements; The participants (and partners) are willing to take effective contraceptive measures from the screening until at least 6 months after the last dosing; Male or female aged 18-55 when signing ICF; Body Mass Index (BMI) between 18 to 28 kg/m2 (inclusive) and body weight equal to or over 50 kg for male and 45 kg for female; Vital signs and physical examination are normal, or abnormal values are not clinically significant. CHB patients are required to meet all the following inclusion criteria in order to be enrolled in the study: The participants voluntarily participate in the study, and sign the Informed Consent Form (ICF) prior to screening; The participants are able to comply with all the protocol requirements; The participants (and partners) are willing to take effective contraceptive measures from the screening until at least 6 months after the last dosing; Male or female aged 18-65 when signing ICF; Body Mass Index (BMI) between 18 to 32 kg/m2 (inclusive) and body weight equal to or over 45 kg for male and 40 kg for female; CHB patients who have documented chronic HBV infection equal to or above 6 months prior to screening. Otherwise, CHB patients need to be HBsAg positive and IgM HBcAb negative. HBeAg content is negative. Exclusion Criteria: Healthy participants are required to not meet any of the exclusion criteria in order to be enrolled in the study: Any suspicion of drug component allergy, or allergic constitution (various drug and food allergy, and judged by the investigator to be clinically significant) in participants; Blood donation or blood loss not less than 400 mL within 12 weeks before screening; Drug administration that change the activity of liver enzymes within 28 days prior to screening; Receipt of another investigational drug or device within 3 months before first dosing (interventional treatment); Clinically significant electrocardiogram (ECG) abnormalities on screening ECG; TdP high-risk factors (hypokalemia, hypomagnesemia, decompensated heart failure and acute myocardial infarction), and QTc interval above 450 msec in participants (judged by investigator based on actual screening conditions); Pregnant (positive pregnancy test), recently ready to conceive, or lactating female; Clinically significant lab examination abnormalities, or other clinically significant diseases discovered within 12 months before screening, including but not limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrinological, tumor, pulmonary, immune, mental, or cardiovascular and cerebrovascular diseases; Any acute disease or concomitant medication occurred during screening to the first dosing; Alcohol consumption, or positive alcohol test 24 hours before drug dosing; Positive test for urinalysis (including Morphine, Cannabis) in participants; Other factors resulting in participant becoming unsuitable for the study, determined by the investigator. CHB patients are required to not meet any of the exclusion criteria in order to be enrolled in the study: Any suspicion of drug component allergy, or allergic constitution (various drug and food allergy, and judged by the investigator to be clinically significant) in participants; Blood donation or blood loss more than 400 mL within 12 weeks before screening; Blood transfusion; Blood donation or blood loss not less than 200 mL within 1 month before screening; Any oligonucleotide or siRNA treatments within 12 months before first dosing; Any immunosuppressing, immunomodulator (e.g. Thymosin) or cytotoxic drug administrations within 6 months before first dosing; Vaccination within 1 month in prior of screening, or plan to take any vaccines during the study; Receiving anticoagulant therapy (e.g., Warfarin, Factor Xa Inhibitors or antiplatelet drugs such as Clopidogrel); Any clinically significant liver diseases, including but not limited to hepatitis caused by other pathogenic infections, hemochromatosis, Wilson disease, primary biliary cirrhosis, autoimmune liver diseases, alcoholic liver disease, severe non-alcoholic fatty liver disease, Drug-induced liver injury, etc.; Personal history of cirrhosis or progressive hepatic fibrosis (e.g., the participant undergoes hepatic histopathological examination, which indicates cirrhosis, or undergoes endoscopic examination indicating esophagogastric varices); Confirmation or suspicion of decompensated hepatitis B cirrhosis, including but not limited to hepatic encephalopathy, hepatorenal syndrome, esophageal and gastric variceal bleeding, ascites, primary hepatocellular carcinoma, etc.; History of malignancy within the past 5 years, except for certain tumors that can be cured by surgical resection (e.g., non-melanoma skin cancer, cervical intraepithelial neoplasia, thyroid neoplasm, breast tumor, etc. that have been treated without signs of recurrence); Combined sever diseases of circulation, digestion, respiration, urinary, blood, metabolism, immune, nervous system, etc.; Acute infection within 2 weeks prior to screening; Receipt of another investigational drug or device within 3 months before first dosing (interventional treatment); Laboratorial examination: blood platelet counts<90 x 10^9/L, absolute neutrophil count<1.3 x 10^9/L, hemoglobin<90 g/L, serum total bilirubin ≥2 x ULN, albumin<30 g/L, creatinine clearance rate (calculated by MDRD formula) ≤60 mL/min, PT/INR>1.5; Alpha-fetoprotein (AFP) >70 ug/L, or imaging suspicion of malignant hepatic space-occupying; HCV antibody/HCcAg positive, AIDS antigen/antibody positive, or Treponema Pallidum antibody positive and Rapid Plasma Reagin (RPR) or Toluidine Red Unheated Serum Test (TRUST) positive, or Hepatitis D antibody positive; LSM≥12.4 kPa when screening; Pregnant (positive pregnancy test) or lactating female; Positive test for urinalysis (including Morphine, Cannabis) or alcohol test in participants; Other factors results in unsuitable for the study, determined by the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part Ia: dosing in healthy participants<br>Single ascending doses of 75 mg, 150 mg, 300 mg, 450 mg, and up to 600 mg (optional) AHB-137 and multiple ascending doses of 150 mg, 300 mg and up to 450 mg (optional) AHB-137 by 6 subcutaneous injections within a month in healthy participants | Drug: AHB-137 injection<br>* AHB-137 injection will be administered subcutaneously.<br>Drug: Placebo<br>* Placebo will be administered subcutaneously. CHB patients not receiving any NA therapy will not receive placebo.<br>|
| Experimental: Part Ib: dosing in CHB patients<br>Multiple ascending doses of 150 mg, 300 mg, and up to 450 mg (optional) AHB-137 by 6 subcutaneous injections within a month both in CHB patients who are under stable nucleos(t)ide analogue (NA) therapy and in CHB patients who have not received any nucleos(t)ide analogue (NA) therapy | Drug: AHB-137 injection<br>* AHB-137 injection will be administered subcutaneously.<br>Drug: Placebo<br>* Placebo will be administered subcutaneously. CHB patients not receiving any NA therapy will not receive placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of healthy participants with adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs |  | Up to 30 days for SAD; up to 113 days for MAD | 
| Number of healthy participants with clinically significant changes in laboratory parameters |  | Up to 30 days for SAD; up to 113 days for MAD | 
| Number of healthy participants with clinically significant changes in vital signs (blood pressure, pulse, body temperature) |  | Up to 30 days for SAD; up to 113 days for MAD | 
| Number of healthy participants with clinically significant changes in 12-lead electrocardiogram (ECG) |  | Up to 30 days for SAD; up to 113 days for MAD | 
| Number of CHB participants with adverse events (AEs), serious adverse events (SAEs), and withdrawals due to AEs |  | Up to 109 days | 
| Number of CHB participants with clinically significant changes in laboratory parameters |  | Up to 109 days | 
| Number of CHB participants with clinically significant changes in vital signs (blood pressure, pulse, body temperature) |  | Up to 109 days | 
| Number of CHB participants with clinically significant changes in 12-lead electrocardiogram (ECG) |  | Up to 109 days | 
| The pharmacokinetic profile of AHB-137 in healthy participants: the maximum observed plasma concentration (Cmax) of AHB-137 |  | Up to 30 days for SAD; up to 113 days for MAD | 
| The pharmacokinetic profile of AHB-137 in healthy participants: time of observed maximal concentration (Tmax) of AHB-137 |  | Up to 30 days for SAD; up to 113 days for MAD | 
| The pharmacokinetic profile of AHB-137 in healthy participants: areas under the concentration time curve (AUC) of AHB-137 |  | Up to 30 days for SAD; up to 113 days for MAD | 
| The pharmacokinetic profile of AHB-137 in healthy participants: terminal half-life (t1/2) of AHB-137 |  | Up to 30 days for SAD; up to 113 days for MAD | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The anti-HBV efficacy of AHB-137 in CHB participants: evaluate the the expression of HBV DNA, HBsAg, HBsAb, and HBeAb in serum |  | Up to 109 days | 
| The pharmacokinetic profile of AHB-137 in CHB participants: the maximum observed plasma concentration (Cmax) of AHB-137 |  | up to 109 days | 
| The pharmacokinetic profile of AHB-137 in CHB participants: time of observed maximal concentration (Tmax) of AHB-137 |  | up to 109 days | 
| The pharmacokinetic profile of AHB-137 in CHB participants: areas under the concentration time curve (AUC) of AHB-137 |  | up to 109 days | 
| The pharmacokinetic profile of AHB-137 in CHB participants: terminal half-life (t1/2) of AHB-137 |  | up to 109 days |