EDP167 in Healthy Volunteers and Subjects With Mild Dyslipidemia

A Dose-escalation Phase I Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic and Pharmacodynamic of Single Dose of EDP167 Injection in Healthy Volunteers and Subjects With Mild Dyslipidemia

EDP167 is a double-stranded small interfering RNA (siRNA) drug targeting ANGPTL3, which may bring benefits for patients with dyslipidemia conditions. This is the first in human study of EDP167 in health volunteers and subjects with mild dyslipidemia to evaluate the safety and PK/PD profiles of EDP167.

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 GalNAc-conjugated siRNA therapeutic that selectively silences hepatic ANGPTL3 mRNA expression, offering a promising strategy for lipid lowering. In this trial, subjects will be sequentially enrolled into five cohorts (35, 100, 200, 300 or 400 mg), each consists of six subjects receiving EDP167 and two receiving matching placebos. The follow-up will last for 85 days to evaluate the PK profile and PD effects (ANGPTL3, LDL-C, TG, and other lipid parameters) following a single subcutaneous injection of EDP167.

Inclusion Criteria:

1. Subjects aged 18 to 60 years (inclusive) at the time of signing the informed consent form, male or female.
2. Male subjects weighing ≥50.0 kg, female subjects weighing ≥45.0 kg, and body mass index (BMI) between 18.0 and 35.0 kg/m² (inclusive).
3. Subjects with fasting serum TG ≥1.13 mmol/L and <5.6 mmol/L, and LDL-C ≥1.8 mmol/L and <4.9 mmol/L at screening.
4. Subjects with no abnormalities or only minor abnormalities judged by the investigator as clinically insignificant (excluding lipid laboratory tests) upon physical examination, vital signs, 12-lead ECG, posteroanterior and lateral chest X-rays, abdominal ultrasound, and laboratory tests at screening.
5. Subjects who have maintained a stable dietary habit for at least 4 weeks before dose administration, and have no plans to significantly change their diet or body weight during the study.
6. Female subjects of childbearing potential or male subjects with partners of childbearing potential must agree to use highly effective contraception from signing the informed consent form until 6 months after dosing and refrain from donating sperm or eggs.
7. Subjects who voluntarily sign the written informed consent form, understand the study procedures and content, are able to communicate well with the investigator, and are willing to comply with the relevant study regulations.

Exclusion Criteria:

1. Subjects with known allergy/hypersensitivity to the investigational drug, its components, or drugs of the same class.
2. Subjects with a history or current presence of serious or clinically significant diseases/abnormalities, including but not limited to cardiovascular, respiratory, endocrine, gastrointestinal, renal, hepatic, biliary, dermatologic, hematologic, immunologic, neurologic, or psychiatric diseases/abnormalities, , or any diseases (except for dyslipidemia) that the investigator considers to pose safety concerns or interfere with the pharmacokinetic evaluation.
3. Subjects who have undergone major surgery within 3 months prior to screening, or have undergone surgery that may significantly affect drug absorption, distribution, metabolism, or excretion, or who plan to undergo elective surgery during the study.
4. Subjects with any of the following laboratory abnormalities at screening: total bilirubin (TBIL), gamma-glutamyl transferase (GGT), or alkaline phosphatase (ALP) >1.5×ULN; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >ULN.
5. Subjects with any of the following 12-lead ECG findings: QTcF >450 ms or any other clinically significant abnormal ECG result.
6. Subjects with tattoos, scars, or birthmarks on the abdomen, upper arms, or thighs that may interfere with the assessment of injection site reactions.
7. Subjects who have used any prescription drugs, over-the-counter (OTC) medications, Chinese herbal medicines, or health supplements within 14 days prior to dosing; or for whom administration occurs within 5 half-lives of any prior medication (based on the longer period); or who have used any medication known to affect lipid metabolism within 90 days prior to screening.
8. Subjects who have received any live vaccine within 4 weeks prior to screening, or who plan to receive any live vaccine during the study.
9. Subjects who have used any antisense oligonucleotide (ASO) or small interfering RNA (siRNA) therapy within 12 months prior to screening.
10. Subjects with a history of drug abuse/substance abuse, or a positive result for the specified drugs (ketamine, marijuana, morphine, MDMA, methamphetamine, cocaine) in the urine drug screen at screening.
11. Subjects who regularly consumed alcohol within 3 months prior to screening (defined as >14 units of alcohol per week; 1 unit = 360 mL of beer, or 45 mL of spirits with 40% alcohol, or 150 mL of wine), or are unwilling to abstain from alcohol during the study, or have a breath alcohol test result >0 mg/100 mL.
12. Subjects who consumed excessive amounts of tea, coffee, or caffeinated beverages (defined as >8 cups per day; 1 cup = 250 mL) within 3 months prior to screening, or consumed any such beverages within 48 hours prior to dosing, or are unwilling to abstain from them during the study.
13. Current smokers, or subjects with a positive urine nicotine test at screening, or former smokers who have quit smoking for less than 6 months.
14. Subjects with positive test results for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (HCVAb), human immunodeficiency virus (HIV) antibody, or specific treponemal antibody (for syphilis) at screening.
15. Subjects with intolerance to venipuncture, difficulty in blood sampling, or a history of needle or blood syncope.
16. Subjects who have donated blood or experienced significant blood loss (≥400 mL) within 3 months prior to screening.
17. Subjects who have participated in, or are currently participating in, another clinical trial and have received the investigational product/device or placebo within 3 months prior to screening.
18. Female subjects with a positive pregnancy test at screening, or who are breastfeeding, or who plan to become pregnant during the study period.
19. Any other condition that the investigator deems inappropriate for the subject to participate in this clinical trial.