Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic(PK/PD) Profile of ACT500 in Metabolic Dysfunction-Associated Steatotic Liver Disease(MASLD)

Official title

A Multicenter, Open-label, Multiple-dose Escalation Phase Ⅰb Clinical Study to Evaluate the Safety, Tolerability, and Pharmacokinetic/Pharmacodynamic Profile of ACT500 in Participants With Metabolic Dysfunction-associated Steatotic Liver Disease

Overview

This study is a multicenter, open-label, dose-escalation trial designed to evaluate the safety, tolerability, PK, and PD profiles of ACT500 in participants with metabolic dysfunction-associated steatotic liver disease (MASLD). The trial plans to enroll approximately 24 MASLD participants across four dose cohorts, each consisting of 6 participants who will receive oral ACT500 once daily.

Interventions

• Drug ACT500 tablets
  Once daily, orally

Primary outcome measures

• Adverse Event#AE# [Time frame: Day1-112]
• Serious Adverse Event [Time frame: Day1-112]
• body temperature [Time frame: Day 1,14,29,56,84,112]
• Number of participants with treatment-related adverse events as assessed by NCI-CTCAE v6.0 [Time frame: Day 1,14,29,56,84,112]
• pulse [Time frame: Day 1,14,29,56,84,112]
• heart rate [Time frame: Day 1,14,29,56,84,112]
• blood pressure [Time frame: Day 1,14,29,56,84,112]
• Number of Participants with Abnormal Laboratory Parameters Findings [Time frame: Day 1,14,29,56,84,112]
• Number of participants with clinically significant change from baseline in physical examination [Time frame: Day 1,14,29,56,84,112]
• Heart Rate [Time frame: Day 14,29,56,84,112,]

Secondary outcome measures (12)

• Area Under Curve（0-t） [Time frame: Day 1,2,14,28,29]
• Area Under the Concentration-time curve from time zero to τ at steady state [Time frame: Day 1,2,14,28,29]
• Area Under Curve（0-∞） [Time frame: Day 1,2,14,28,29]
• Maximum Plasma Concentration [Time frame: Day 1,2,14,28,29]
• Time to Maximum (plasma) Concentration [Time frame: Day 1,2,14,28,29]
• Elimination Half-Life [Time frame: Day 1,2,14,28,29]
• CL/F [Time frame: Day 1,2,14,28,29]
• Apparent Volume of Distribution [Time frame: Day 1,2,14,28,29]
• Cmin,ss [Time frame: Day 1,2,14,28,29]
• Cav,ss [Time frame: Day 1,2,14,28,29]
• Rac_Cmax [Time frame: Day 1,2,14,28,29]
• Rac_AUC0-tau [Time frame: Day 1,2,14,28,29]

Eligibility criteria

Inclusion criteria

• The participant fully understands the purpose, nature, methods, and possible adverse reactions of the study, voluntarily participates in this study, and has signed the informed consent form.
• Male or female participants aged between 18 and 69 years (inclusive of 18 and 69 years) at the time of signing the informed consent form.
• Liver fat content (LFC) ≥10% as assessed by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) during the screening period.
• Liver stiffness measurement (LSM) assessed by FibroScan during the screening period meets the criteria of 8 kPa ≤ LSM ≤ 15 kPa, OR a liver biopsy pathological result of F2/F3 fibrosis within 6 months prior to screening.
• Serum alanine aminotransferase (ALT) levels meeting 2×ULN ≤ ALT ≤ 5×ULN at screening.
• Presence of at least one of the following metabolic risk factors:

• BMI ≥ 24.0 kg/m\^2, or waist circumference ≥ 90 cm (males) and ≥ 85 cm (females);
• Presence of prediabetes: fasting blood glucose ≥ 6.1 mmol/L, or glycated hemoglobin (HbA1c) ≥ 5.7%;
• History of type 2 diabetes mellitus;
• Fasting serum triglycerides (TG) ≥ 1.70 mmol/L but < 5.6 mmol/L;
• Fasting serum high-density lipoprotein cholesterol (HDL-C) ≤ 1.0 mmol/L (males) and ≤ 1.3 mmol/L (females), OR currently receiving a stable dose of lipid-lowering medication;
• Systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure (DBP) ≥ 85 mmHg, while simultaneously meeting SBP ≤ 160 mmHg and DBP ≤ 100 mmHg, OR currently receiving a stable dose of antihypertensive medication and meeting SBP ≤ 160 mmHg and DBP ≤ 100 mmHg.
• Both male and female participants must agree to use appropriate contraceptive methods, as follows:

• For male participants: Agreement to use reliable contraceptive measures and refrain from sperm donation from signing the informed consent form until 3 months after the last dose.
• For female participants: Female participants of non-childbearing potential; OR female participants of childbearing potential who are not pregnant or breastfeeding, have a negative serum pregnancy test at screening and within 1 day prior to the first dose, and agree to use reliable contraceptive measures and refrain from egg donation from signing the informed consent form until 3 months after the last dose.

Exclusion criteria

• \[1\] Combined with other liver diseases, including but not limited to hepatitis B, hepatitis C, drug-induced liver disease, alcoholic liver disease, autoimmune liver disease, suspected or confirmed hepatocellular carcinoma, etc.

\[2\] Have a history of or currently have other malignancies, liver cirrhosis (including confirmed or suspected liver cirrhosis by imaging examination, or liver cirrhosis confirmed by liver biopsy), or have evidence of decompensated liver disease (such as ascites, esophageal and gastric variceal bleeding, or hepatic encephalopathy, etc.), or have a history of liver transplantation.

\[3\] Have a history of or current symptoms of severe cardiovascular and cerebrovascular diseases, including but not limited to uncontrolled or severe arrhythmias (ventricular fibrillation, atrial fibrillation, etc.), myocardial infarction, coronary heart disease, etc.

\[4\] Have a history of persistent, clinically significant respiratory, neurological, gastrointestinal, immunological, hematological, or psychiatric diseases, which, in the investigator's judgment, would pose additional risk to the participant.

\[5\] Have type 1 diabetes or uncontrolled type 2 diabetes (fasting blood glucose >9 mmol/L within 3 months prior to screening, or HbA1c >9.5% at screening), or are diabetic patients using glucose-lowering medications other than metformin.

\[6\] Have an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² at screening or a history of severe renal impairment.

\[7\] Have known hemoglobinopathy, hemolytic anemia, or sickle cell anemia; or have hemoglobin <105 g/L for female participants or <115 g/L for male participants at screening; or any other condition known to interfere with hemoglobin measurement as judged by the investigator.

\[8\] Have any of the following laboratory abnormalities at screening: alkaline phosphatase (ALP) > 2 × upper limit of normal (ULN), serum total bilirubin (TBIL) > 1.5 × ULN, or international normalized ratio (INR) > 1.3.

\[9\] Have had a body weight change (increase or decrease) of >5% within 3 months prior to screening, or have undergone dieting, bariatric surgery, or used medications approved for weight loss indications.

\[10\] Have a history of major trauma or surgery within 3 months prior to screening, or plan to undergo surgery during the study period.

\[11\] Have a history of excessive alcohol consumption for 3 consecutive months or more within 1 year prior to screening, defined as a weekly ethanol intake of ≥210 g for males and ≥140 g for females; or have a history of drug abuse/dependence or a history of illicit drug inhalation/injection within 1 year prior to screening.

\[12\] Have used medications that may have a therapeutic effect on MASLD/MASH (e.g., GLP-1 receptor agonists, DPP-4 inhibitors, SGLT2 inhibitors, FGF21 analogs, resmetirom, etc.) or medications that may cause MASLD/MASH (e.g., amiodarone, methotrexate, tetracyclines, tamoxifen, estrogens at doses greater than hormone replacement therapy, anabolic steroids, valproic acid, other known hepatotoxic drugs, etc.) within 3 months prior to screening, or other medications that the investigator considers may affect the trial.

\[13\] Have participated in another drug clinical trial within 3 months prior to screening.

\[14\] Have a positive test for any of the following at screening: human immunodeficiency virus antibody (HIV-Ab) or Treponema pallidum antibody.

\[15\] Have a known allergy to the excipients of ACT500 or to drugs with a similar chemical structure to ACT500, or have other drug allergies that, in the investigator's judgment, preclude participation in the study.

\[16\] Have any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in this study, or are unable to participate in the trial due to the participant's own reasons after signing the informed consent form (ICF).

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Other

Study locations

China · 4 centers

• Beijing Tsinghua Changgeng Hospital — Beijing
• Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine — Shanghai
• The First Affiliated Hospital of Xi'an Jiaotong University — Xi'an
• The First Affiliated Hospital of Xiamen University — Xiamen

Identifiers

NCT: NCT07462455 · ACT500-4-1-002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗