A Prospective, Single-center, Open-label, Single-arm Clinical Study to Evaluate the Safety and Efficacy of CS-121, an In Vivo Base Editing Therapy Delivered by Lipid Nanoparticles Targeting APOC3, in Children and Adolescents With Hyperchylomicronemia
Overview
- Phase
- Early Phase 1
- Status
- Recruiting
- Sponsor
- Shanghai Jiao Tong University School of Medicine
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Dose-limiting toxicities (DLTs)
Overview
Brief Summary
This is a Prospective, Single-center, Open-label, Single-arm Clinical Study to Evaluate the Safety and Efficacy of CS-121, an In Vivo Base Editing Therapy Delivered by Lipid Nanoparticles Targeting APOC3, in Children and Adolescents (4-18 years) With Hyperchylomicronemia
Detailed Description
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 hyperchylomicronemia. 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).
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Sequential
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 4 Years to 18 Years (Child, Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male or female participants aged 4 years ≤ age \< 18 years.
- •Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) level ≥ 500 mg/dL.
- •Confirmed diagnosis of genetically inherited FCS via genetic testing, or clinically diagnosed FCS plus persistent chylomicronemia.
- •Failure to achieve adequate TG control, For participants under 8 years of age, the investigator determine at their discretion whether prior lipidlowering therapy has been administered.
- •Participants aged 6 years and above must sign the informed consent form themselves; for participants under 18 years of age, their parent/legal guardian must sign the informed consent form. (Participants under 6 years of age are exempt from signing the written informed consent form).
- •Female participants of childbearing potential must have a negative result on serum pregnancy testing.
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.
- •History of acute pancreatitis within 1 month before dosing.
- •Patients who underwent major surgery within 3 months prior to study drug administration and are judged by the investigator as unsuitable for receiving the study drug, due to potential intolerance to adverse events such as cytokine release storm.
- •ALT or AST ≥2 × ULN
- •Total bilirubin ≥1.5 × ULN
- •eGFR \<30 mL/min/1.73 m²
- •Random urine albumin-to-creatinine ratio (UACR) \>30 mg/g, or urine protein is ≥ 2+
- •HbA1c ≥9%
- •Coagulation function abnormalities judged by the investigator as unsuitable for CS-121 administration.
Arms & Interventions
Low Dose CS-121
Participants in this arm will receive low dose of CS-121
Intervention: CS-121 (Biological)
Middle Dose CS-121
Participants in this arm will receive middle dose of CS-121
Intervention: CS-121 (Biological)
High Dose CS-121
Participants in this arm will receive high dose of CS-121
Intervention: CS-121 (Biological)
Outcomes
Primary Outcomes
Dose-limiting toxicities (DLTs)
Time Frame: Within 14 days post CS-121 dosing
The incidence and severity of treatment-emergent adverse events (TEAEs)
Time Frame: from screening to 10 months post last dosing
Secondary Outcomes
- Changes in serum triglyceride (TG) levels(From baseline to 10 months post last dosing)
- Changes in serum ApoC3 levels from baseline(From baseline to 10 months post last dosing)
- Concentrations of the active components of CS-121 (sgRNA and mRNA)(From baseline to 1 month post last dosing)
Investigators
Xiumin Wang, PhD
chief physician
Shanghai Jiao Tong University School of Medicine