Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterised by severely elevated triglycerides due to accumulation of chylomicrons. Symptoms typically present in infancy and include failure to thrive, abdominal pain, nausea, vomiting, pancreatitis, fatigue, irritability, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly.
Most cases result from bi-allelic loss-of-function mutations in LPL (lipoprotein lipase). Less commonly, mutations in genes affecting LPL function such as APOA5, APOC2, GPIHBP1, or LMF1, can cause FCS. The disorder is inherited in an autosomal recessive manner, with a 25% recurrence risk for children of carrier parents.
Symptoms include pancreatitis, lipemia retinalis, xanthomas, hepatosplenomegaly, and lifelong dietary fat intolerance. Management relies on strict fat restriction, weight maintenance, exercise, and avoidance of alcohol and processed foods. Standard lipid-lowering drugs and plasmapheresis are largely ineffective. Emerging therapies like volanesorsen (apo C-III antisense oligonucleotide) show promise. Prognosis is favourable with strict adherence to diet, and patients rarely develop atherosclerosis despite severe hypertriglyceridemia.
FCS has an estimated prevalence of 1/300,000 (ranging from 1/100,000 to 1/1,000,000 in Europe and North America).
Official title:
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
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.
