CS-121 APOC3 Base Editing in Severe Hypertriglyceridemia

A Clinical Study to the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of CS-121, an In Vivo Base Editing Therapy Delivered by Lipid Nanoparticles Targeting APOC3 for the Treatment of Severe Hypertriglyceridemia in Adults

This is an open-label, single-arm, dose-escalation IIT clinical trial to evaluate the safety, tolerability, pharmacodynamics (PD), and pharmacokinetics (PK) of CS-121, an in vivo base editing therapy delivered by lipid nanoparticles targeting APOC3, in adult participants (18-65 years) with Severe Hypertriglyceridemia(sHTG).

CS-121 is an investigational, in vivo base editing therapy delivered by lipid nanoparticles (LNPs) targeting the APOC3 gene in the liver. By introducing precise base edits at specific APOC3 loci, CS-121 is intended to mimic naturally occurring protective mutations that reduce ApoC3 expression, thereby restoring triglyceride clearance pathways and lowering pancreatitis risk. Preclinical studies in transgenic mouse and non-human primate models demonstrated dose-dependent APOC3 editing, reductions in serum ApoC3 protein and triglyceride levels, and acceptable safety profiles, supporting advancement into human evaluation.

This open-label, single-arm, dose-escalation early exploratory trial designed to evaluate the safety, tolerability, PK/PD characteristics and preliminary efficacy of CS-121 in patients with sHTG. Based on the properties of gene editing therapy, the primary focus of the study is to identify the optimal biological dose (OBD) rather than the traditional maximum tolerated dose (MTD).

Inclusion Criteria:

• Male or female participants aged 18 years ≤ age < 65 years.
• The serum triglyceride levels of the participants failed to be effectively controlled under the standard treatment regimen (or the medication that is available and tolerable as recommended by clinical practice) and were defined as having at least 3 records of different fasting triglyceride levels ≥ 5.65 mmol/L (500 mg/dL) within 2 years..
• The screening period should include at least two different days with a TG level of ≥ 5.65 mmol/L (500 mg/dL), with an interval of at least 7 days.
• Able to sign informed consent and comply with the requirements and restrictions specified in the informed consent form and the protocol.
• Female participants must meet one of the following: be not of childbearing potential (e.g., documented hysterectomy, bilateral salpingectomy/sterilization, or ≥1 year postmenopausal); or, if of childbearing potential, have a negative pregnancy test at screening and be willing to use strict and effective contraception (e.g., abstinence, pharmacologic, or barrier methods) during the study. Male participants with reproductive potential must agree to use strict and effective contraception (e.g., abstinence, pharmacologic, or barrier methods) throughout the entire post-dose observation period; males without reproductive potential must provide supporting medical history (e.g., post-vasectomy).

Exclusion Criteria:

• Currently participating in other interventional clinical studies, or having an insufficient washout period of less than 5 half-lives or 30 days (whichever is longer) since the last administration of other investigational drugs.
• Used antisense oligonucleotide (ASO)-based or small interfering RNA (siRNA)-based lipid-lowering drugs targeting APOC3 within 3 months prior to study drug administration.
• Requires long-term use of systemic corticosteroids and steroid drugs and cannot discontinue the medication.
• Patients who experienced acute pancreatitis within 4 weeks prior dosing.
• History of acute coronary syndrome (ACS) within 6 months before dosing, such as myocardial infarction or unstable angina, or prior coronary revascularization (such as coronary artery bypass grafting), angioplasty or stent implantation.
• In the investigator's judgment to be unsuitable for the study drug due to receipt of major surgery within 3 months before dosing.
• Any of the following laboratory abnormalities at screening:.
• ALT or AST ≥2 × ULN;
• Total bilirubin ≥2 × ULN;
• eGFR <30 mL/min/1.73 m²
• HbA1c ≥9%;
• Absolute neutrophil count < 1.0 × 109/L
• Hemoglobin (female)< 100 g/L, Hemoglobin (male) < 110 g/L
• Platelet count < 100 × 109/L
• Coagulation function abnormalities judged by the investigator as unsuitable for CS-121 administration.
• Positive results for HBsAg, dual positivity for HCV antibody and RNA, positive for HIV, or positive for Treponema pallidum infection.
• Known major organ diseases, mental disorders, Cushing's syndrome, hypothyroidism, history of lymphoproliferative disorders, or malignant tumors in any organ system, which are judged by the investigator as unsuitable for study participation due to potential intolerance to adverse events such as cytokine-Release-Storm.
• Concomitant medications/treatments judged by the investigator to affect lipid metabolism, liver and kidney function, coagulation function, or interfere with the efficacy evaluation of the study drug.
• Patients of childbearing potential who are planning pregnancy, breastfeeding, or have fertility plans.