Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Characteristics of ACT500 in Participants With Metabolic Dysfunction-Associated Steatotic Liver Disease Complicated With Chronic Hepatitis B

A Multicenter, Randomized, Double-blind, Multiple Ascending Dose, Placebo-controlled Phase Ib Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic Characteristics of ACT500 in Participants With Metabolic Dysfunction-associated Steatotic Liver Disease Complicated With Chronic Hepatitis B.

This study is a Phase Ib, multicenter randomized, double-blind, dose-escalation, placebo-controlled trial designed to evaluate the safety, tolerability, PK, and PD profiles of multiple-dose ACT500 in participants with metabolic dysfunction-associated steatotic liver disease (MASLD) complicated with chronic hepatitis B (CHB). The trial plans to enroll 24 participants with MASLD complicated with CHB across three dose cohorts initially, each consisting of 8 participants who will receive oral ACT500 tablets once daily.

Inclusion Criteria:

• The participant fully understands the purpose, nature, methods of the trial, and the potential adverse reactions, voluntarily agrees to participate in this study, and signs the informed consent form.
• Male or female participants aged between 18 and 60 years (inclusive) at the time of signing the informed consent form.
• Liver fat content ≥10% as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) during the screening period.
• Liver stiffness measurement (LSM) by FibroScan during the screening period meets 8 kPa ≤ LSM < 12 kPa, or liver biopsy results within 6 months prior to screening show stage F2/F3 liver fibrosis.
• Hepatitis B surface antigen (HBsAg) positive for >6 months at screening, or other evidence of chronic hepatitis B (CHB), with HBV DNA < 20 IU/mL.
• Serum alanine aminotransferase (ALT) < 5×ULN at screening.
• Received nucleos(t)ide analog (NAs) therapy for at least 1 year prior to screening and are currently on stable NA therapy (including entecavir, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, and tenofovir amibufenamide). Stable NAs therapy is defined as receiving the same treatment regimen within 3 months prior to screening.
• Have at least one of the following metabolic disease risk factors:

BMI ≥24.0 kg/m^2, or waist circumference ≥90 cm (male) and ≥85 cm (female); Prediabetes: fasting blood glucose ≥6.1 mmol/L, or glycated hemoglobin (HbA1c) ≥5.7%; History of type 2 diabetes mellitus; 1.70 mmol/L ≤ fasting serum triglycerides < 5.6 mmol/L; Fasting serum high-density lipoprotein cholesterol ≤1.0 mmol/L (male) and ≤1.3 mmol/L (female), or receiving stable-dose lipid-lowering therapy; Systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥85 mmHg, with systolic blood pressure ≤160 mmHg and diastolic blood pressure ≤100 mmHg; or receiving stable-dose antihypertensive therapy with systolic blood pressure ≤160 mmHg and diastolic blood pressure ≤100 mmHg.

• Both male and female participants must agree to use adequate contraceptive methods, where:

Male participants: agree to use reliable contraceptive measures from the time of signing the informed consent form until 3 months after the last dose, and have no sperm donation plans; Female participants: women of non-childbearing potential; or women of childbearing potential who are not pregnant or breastfeeding, must have a negative serum pregnancy test result at screening and within 1 day prior to the first dose, agree to use reliable contraceptive measures from the time of signing the informed consent form until 3 months after the last dose, and have no oocyte donation plans.

Exclusion Criteria:

• Concurrent other liver diseases, including but not limited to hepatitis C, hepatitis D, drug-induced liver disease, alcoholic liver disease, autoimmune liver disease, suspected or confirmed liver cancer, etc.
• Participants with a previous or current history of other malignant tumors, liver cirrhosis (including imaging-confirmed or suspected cirrhosis, and liver biopsy-confirmed cirrhosis), or evidence of decompensated liver disease (such as ascites, esophagogastric variceal bleeding, hepatic encephalopathy), or with a history of liver transplantation.
• Participants with a history or current symptoms of severe cardiovascular and cerebrovascular diseases, including but not limited to uncontrolled or severe arrhythmia (ventricular fibrillation, atrial fibrillation, etc.), myocardial infarction, coronary heart disease, uncontrolled hypertension (systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg).
• Participants with persistent and clinically significant medical history of respiratory, nervous, gastrointestinal, immune, hematological or psychiatric diseases, which, in the opinion of the investigator, may impose additional risks on the participant.
• Participants with type 1 diabetes or poorly controlled type 2 diabetes (fasting blood glucose >9 mmol/L within 3 months prior to screening or glycated hemoglobin >9.5% at screening), or diabetic patients using hypoglycemic drugs other than metformin and insulin.
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (calculated by the CKD-EPI formula) at screening, or with a history of severe renal impairment.
• Known hemoglobinopathy, hemolytic anemia, sickle cell anemia; or hemoglobin <115 g/L in female participants and <130 g/L in male participants at screening; or any other conditions judged by the investigator to interfere with hemoglobin detection.
• Any of the following laboratory abnormalities at screening: alkaline phosphatase (ALP) >2 times the upper limit of normal (ULN), total bilirubin (TBIL) >1.5 times the ULN, international normalized ratio (INR) >1.3, albumin <35 g/L, platelet count <125×10⁹/L, and serum triglycerides >5.6 mmol/L.
• Participants with body weight gain or loss >5% within 3 months prior to screening, or those receiving diet control, bariatric surgery, or using approved anti-obesity medications for weight loss indications.
• Participants with a history of major trauma or surgery within 3 months prior to screening, or those scheduled to undergo surgery during the study period.
• Excessive alcohol consumption for 3 consecutive months or more within 1 year prior to screening. Excessive drinking is defined as weekly ethanol intake ≥210 g for males and ≥140 g for females; or with a history of drug abuse/dependence or drug inhalation/injection within 1 year prior to screening.
• Use of drugs with potential therapeutic effects on MASLD/MASH within 3 months prior to screening (e.g., GLP-1 receptor agonists, DPP4 inhibitors, SGLT2 inhibitors, FGF21 analogues, resmetirom, etc.), or drugs that may induce MASLD/MASH (e.g., amiodarone, methotrexate, tetracyclines, tamoxifen, estrogen at doses exceeding hormone replacement therapy, anabolic steroids, valproic acid, and other known hepatotoxic drugs); use of drugs that may affect the efficacy of hepatitis B treatment within 6 months prior to screening (e.g., anti-HBV drugs other than NAs, interferons, systemic immunomodulators, hepatitis B vaccines, etc.), or any other medications deemed by the investigator to interfere with the study.
• Participation in other clinical drug trials within 6 months prior to screening.
• Any positive result for human immunodeficiency virus antibody (HIV-Ab), hepatitis C virus antibody (HCV RNA test is required if positive, with the value below the quantitative lower limit of the local study center), hepatitis D virus antibody, or treponema pallidum antibody during the screening period.
• Participants with allergic reactions to excipients of ACT500 or drugs with similar chemical structures to ACT500, or other drug allergies deemed ineligible for study participation by the investigator.
• Any other conditions that render the participant unsuitable for this study as determined by the investigator, or participants who are unable to complete the trial due to personal reasons after signing the informed consent form (ICF).