A Dose-exploration Study of EDP167 in HoFH

Angiopoietin-like 3 protein (ANGPTL3) is a key regulator of lipid metabolism. Clinical studies have shown that inhibition of ANGPTL3 could exert lipid-lowering effects in patients with dyslipidemia. EDP167 is a novel N-Acetylgalactosamine (GalNAc)-conjugated siRNA therapeutic that selectively silences hepatic ANGPTL3 mRNA expression, offering a promising strategy for lipid lowering. This trial includes two phase, main study phase (including screening period and 24 weeks treatment period) and extension phase (including 6 months treatment period). In main study phase, patients with HoFH will be randomized into two dose cohorts (200mg and 300mg, 10 subjects each), receiving EDP167 injections on Day 1 and at Week 12. At Week 24 of the main study phase, subjects will be evaluated and enter the extension phase, receiving EDP167 injections at Month 0 and at Month 3. The follow-up will last till Month 6 in extension phase to evaluate the efficacy, safety, PK profile and PD effects (ANGPTL3, low-density lipoprotein cholesterol [LDL-C], triglyceride [TG], and other lipid parameters) in HoFH patients after multiple EDP167 injections.

Inclusion criteria

• Age ≥18 years old, male or female, and weight ≥40 kg.
• Genetic diagnosis or clinical diagnosis of HoFH.
• Fasting serum LDL-C ≥2.6 mmol/L.
• Follow a daily low-fat diet during the study.
• Receiving stable and tolerable lipid-lowering treatment or other drugs for chronic diseases treatments for certain periods before the study, and maintain the stable treatments throughout the study.
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and a negative pregnancy test prior to receiving EDP167 at baseline.
• Agree to use contraceptive measures that comply with regulations and the protocol requirements during the study, and until 6 months after the last dose.
• Understand the study procedures, voluntarily participate, and sign the informed consent form.

Exclusion criteria

• Allergic to the drug in this study, its components or similar drugs.
• Used any antisense oligonucleotide (ASO) or small interfering nucleic acid (siRNA) drugs within 12 months prior to randomization.
• Received treatment targeting ANGPTL3 or Apolipoprotein C3 (ApoC3), or have participated in other clinical trials within 6 months or 5 half-life (whichever longer) prior to screening.
• Received health supplements or other medications that have been used for lipid-lowering purposes within 4 weeks prior to screening.
• Received Lipoprotein apheresis within 8 weeks prior to screening.
• A weight change of >10% within 4 weeks prior to randomization, or planning to undergo weight-loss surgery or weight intervention treatment during the study period.
• Starting a new diet plan or having significant differences from the previous diet within 4 weeks prior to randomization.
• Presence of diseases that would affect lipid or lipoprotein levels, such as nephrotic syndrome, severe liver diseases, Cushing's syndrome, hypothyroidism or hyperthyroidism, etc., which are poorly controlled, and in the opinion of the Investigator will interfere with the accurate assessment of the study results.
• Had New York Heart Association (NYHA) grade III-IV heart failure within 12 months prior to randomization, or acute coronary syndrome or stroke within 6 months prior to randomization.
• Performed coronary intervention within 6 months prior to randomization, or plan to perform coronary intervention during the study.
• Have a history of major surgery within 3 months prior to screening, or plan to undergo major surgery during the study.
• History of malignancy, unless considered cured by adequate treatment with no evidence of recurrence for ≥3 years prior to the first dose of EDP167; excluding adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, carcinoma in situ of the breast, or incidental histological findings of prostate cancer (TNM stage T1a or T1b).
• Clinical evidence of active infections or other major or poorly controlled serious diseases, any other conditions that in the opinion of the Investigator may interfere with the study results or put the subjects at excessive risk.
• Have a history of current existence of alcohol or drug abuse per evaluation of the investigator.
• Uncontrolled hypertension at screening (blood pressure >160/100 mmHg).
• Subjects with any of the following laboratory abnormalities at screening: a) fasting serum TG≥5.6 mmol/L; b) Glycosylated hemoglobin A1C (HbA1c)>8.5%; c) alanine aminotransferase (ALT) or aspartate aminotransferase (AST) or gamma-glutamyl transpeptidase (GGT)>1.5×ULN (Upper Limit Of Normal), total bilirubin (TBIL)>2×ULN; d) prothrombin time (PT) or activated partial thromboplastin time (APTT) or International Normalized Ratio (INR) clinically significant abnormal; e) Hepatitis B surface antigen (HBsAg) or antibody to hepatitis C virus (HCVAb) or human immunodeficiency virus (HIV) positive; f) estimated glomerular filtration rate (eGFR)<30 mL/min/1.73m2.
• Donated or lost blood ≥400 mL within 3 months prior to screening.
• Women who are pregnant, breastfeeding or planning for pregnancy.
• Other conditions that the Investigator would consider the subject is not suitable to participate in this study.