CS-121 APOC3 base-edit gene therapy for familial chylomicronemia (FCS)

A Clinical Study to Evaluate the Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of CS-121, an In Vivo Base Editing Therapy Delivered by Lipid Nanoparticles Targeting APOC3, in Adults With Familial Chylomicronemia Syndrome

This trial will try a single-course, dose-escalation APOC3 base-editing treatment (CS-121) delivered by lipid nanoparticles in adults 18–55 with genetically confirmed FCS and very high triglycerides to see if it lowers ApoC3 and triglycerides and is safe.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 15 (estimated)
• Ages: 18 Years to 55 Years
• Sex: All
• Sponsor: CorrectSequence Therapeutics Co., Ltd (Industry-sponsored)
• Locations: 1 site (Hefei, Anhui)
• Trial ID: NCT07176923 on ClinicalTrials.gov

What this trial studies

This open-label, single-arm, adaptive Phase I dose-escalation protocol gives escalating doses of CS-121, an in vivo base-editing therapy delivered in lipid nanoparticles, to adults with genetically and clinically confirmed familial chylomicronemia syndrome. The treatment targets the APOC3 gene in the liver to introduce precise base edits intended to mimic protective loss-of-function variants and reduce ApoC3 protein levels. Primary data collection focuses on safety, tolerability, pharmacokinetics, and pharmacodynamics with close monitoring for adverse events and laboratory changes; dose adjustments are made based on emerging safety and PK/PD signals. Preclinical work in transgenic mice and non-human primates showed dose-dependent APOC3 editing, lower ApoC3 protein and triglyceride levels, and an acceptable safety profile, which supported first-in-human testing.

Who should consider this trial

Good fit: Adults aged 18–55 with genetically and clinically confirmed FCS who have persistent fasting triglycerides >10 mmol/L (880 mg/dL) despite standard therapy (or intolerance to therapy), a NAFCS score ≥45, and who can comply with protocol requirements are the intended participants.

Not a fit: People without genetically confirmed FCS (for example, other causes of high triglycerides), those outside the 18–55 age range, or those with contraindications to lipid nanoparticle or gene-editing approaches are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, CS-121 could durably reduce ApoC3 and triglyceride levels and thereby lower the risk of recurrent acute pancreatitis in people with FCS.

How similar studies have performed: Preclinical animal studies showed promising dose-dependent APOC3 editing and triglyceride reductions, but first-in-human in vivo base editing for APOC3 remains novel and unproven in people.

Eligibility criteria

Inclusion Criteria:

* Male or female aged 18 to 55 years (inclusive) at the time of signing informed consent.
* On regular standard therapy with good compliance, but fasting triglyceride (TG) levels have not been consistently reduced below 10 mmol/L (880 mg/dL); i.e., before screening, there must be records of at least three separate fasting TG values \>10 mmol/L (880 mg/dL), or the participant is intolerant to standard therapy.
* North American Familial Chylomicronemia Syndrome (NAFCS) score ≥45
* Able to sign informed consent and comply with the requirements and restrictions specified in the informed consent form and the protocol, such as dietary guidance and intake restrictions.
* 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 another interventional clinical study, or last use of another investigational product with a washout period of less than 5 half-lives or 30 days (whichever is longer).
* Use of APOC3-targeted antisense oligonucleotides (ASO) or siRNA lipid-lowering agents within 6 months prior to dosing.
* History of acute pancreatitis within 3 months before dosing.
* History of acute coronary syndrome (ACS) within 6 months before dosing, such as myocardial infarction or unstable angina, or prior coronary revascularization (e.g., coronary artery bypass grafting, angioplasty, or stent implantation).
* In the investigator's judgment, receipt of major surgery within 3 months before dosing that would make the participant unsuitable for this study drug or unable to tolerate possible cytokine-release events.
* Any of the following laboratory abnormalities at screening:

ALT or AST ≥3 × ULN Total bilirubin ≥1.5 × ULN eGFR \<30 mL/min/1.73 m² Random urine albumin-to-creatinine ratio (UACR) \>30 mg/g LDL-C \>130 mg/dL (3.4 mmol/L) HbA1c ≥9%

* Coagulation abnormalities deemed by the investigator to make CS-121 administration unsuitable.
* Positive at screening for HBsAg, HCV antibody and RNA, HIV, or Treponema pallidum (syphilis).
* Known major organ disease, psychiatric disorders, Cushing's syndrome, or malignancy that, in the investigator's judgment, would make the participant unsuitable for the study or unable to tolerate possible cytokine-release-like events.
* Concomitant medications or treatments judged by the investigator to affect lipid metabolism, hepatic or renal function, or coagulation, or to interfere with the evaluation of study drug efficacy, including but not limited to: systemic glucocorticoids, anabolic steroids, antiretroviral agents used within 4 weeks prior to dosing, plasma exchange, blood donation, or blood loss \>200 mL.
* Planning pregnancy, currently pregnant, or breastfeeding.

Where this trial is running

Hefei, Anhui

• The First Affiliated Hospital of Anhui Medical University — Hefei, Anhui, China (Recruiting)

Study contacts

• Study coordinator: Yaliang Li

Conditions Familial Chylomicronemia Syndrome; Severe Hypertriglyceridemia; Acute Pancreatitis; Apolipoprotein C3; In Vivo Base Editing; Lipid Nanoparticles; Gene Editing Therapy; First-in-Human Study