This is an open-label, single-arm, dose-escalation Phase I 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 (18-55 years) with familial chylomicronemia syndrome (FCS).
Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive lipid metabolism disorder characterized by impaired clearance of triglyceride-rich lipoproteins due to deficiencies in lipoprotein lipase or its cofactors. Patients experience severe hypertriglyceridemia, recurrent episodes of acute pancreatitis, abdominal pain, and other complications that significantly reduce quality of life and may be life-threatening. Despite strict dietary restrictions and conventional lipid-lowering therapies, many patients fail to achieve adequate triglyceride control, highlighting a major unmet medical need. 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 first-in-human evaluation. This Phase I study uses an adaptive, dose-escalation design to investigate multiple dose levels of CS-121 in adults with genetically and clinically confirmed FCS. The design incorporates dynamic dose adjustment based on emerging safety, pharmacokinetic (PK), and pharmacodynamic (PD) data, consistent with regulatory guidance for rare disease trials. Participants will undergo screening to confirm eligibility, including fasting triglyceride measurements, North American FCS score (NAFCS), genetic and laboratory testing, and imaging studies. Eligible participants will receive a single intravenous infusion of CS-121 and will be observed in-clinic immediately post-dose for early safety monitoring. Extended follow-up visits will be conducted for up to 10 months, with evaluations of clinical safety parameters, ApoC3 protein and triglyceride levels, drug exposure (sgRNA/mRNA), and exploratory endpoints such as pancreatitis incidence and imaging of hepatic lipid accumulation. The study is designed to establish a dose range, identify an optimal biological dose (OBD), and provide first-in-human safety, tolerability, PK, and PD data for CS-121 in FCS. Findings from this trial will inform the future development of base editing therapies in severe hypertriglyceridemia and related rare metabolic disorders.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
15
CS-121 is a in vivo base editing therapy formulated in lipid nanoparticles for targeted editing of the APOC3 gene in hepatocytes. In this study, participants receive a single intravenous infusion of CS-121 at escalating dose levels. The investigational product is designed to reduce ApoC3 protein expression and serum triglyceride levels in adults with familial chylomicronemia syndrome (FCS).
The First Affiliated Hospital of Anhui Medical University
Hefei, Anhui, China
RECRUITINGTreatment-Emergent Adverse Events (TEAEs)
Incidence, nature, and severity of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), adverse events of special interest (AESIs), and abnormalities in clinical symptoms, vital signs, physical examinations, laboratory tests, and electrocardiograms (ECGs). Severity will be graded according to NCI CTCAE version 5.0.
Time frame: From the start of dosing through approximately 10 months of follow-up
Dose-Limiting Toxicities (DLTs)
Within 14 days after CS-121 infusion
Time frame: Number and type of dose-limiting toxicities (DLTs), defined as CTCAE grade ≥3 adverse events considered possibly, probably, or definitely related to CS-121 and persisting ≥7 days, or other adverse events/laboratory abnormalities that lead to suspension o
Change from Baseline in Fasting Serum Triglycerides (TG)
Absolute and relative change in fasting serum triglyceride levels compared with baseline values.
Time frame: Baseline through approximately 10 months after dosing
Change from Baseline in Serum ApoC3 Protein Levels
Absolute and relative change in serum ApoC3 protein concentrations compared with baseline values.
Time frame: Baseline through approximately 10 months after dosing
Peak Concentration (Cmax) of CS-121 Components
Maximum observed concentration of CS-121 components following intravenous infusion.
Time frame: From dosing through approximately 1 month after infusion.
Time to Maximum Concentration (Tmax) of CS-121 Components
Time to reach maximum observed concentration of CS-121 components following intravenous infusion
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Time frame: From dosing through approximately 1 month after infusion
Area Under the Curve (AUC) of CS-121 Components
Area under the Curve of CS-121 components to characterize systemic exposure
Time frame: From dosing through approximately 1 month after infusion.