A phase 3 study to evaluate the efficacy and safety of ARO-APOC3 in adults with familial chylomicronemia syndrome (FCS)
Familial Chylomicronemia Syndrome
Experimental Arm: ARO-APOC3 25mg 4 doses of ARO-APOC3 by subcutaneous (sc) injection (every 3 months for 1 year) Placebo Comparator Arm: Placebo (sterile normal saline 0.9% NaCl) calculated volume to match active treatment (25mg ARO-APOC3) by sc injection (4 doses in total - every 3 months for 1 year) Experimental Arm: ARO-APOC3 50mg 4 doses of ARO-APOC3 by subcutaneous (sc) injection (every 3 months for 1 year) Placebo Comparator Arm: Placebo (sterile normal saline 0.9% NaCl) calculated volume to match active treatment (50mg ARO-APOC3) by sc injection (4 doses in total - every 3 months for 1 year) Randomisation: Each participant will be randomly assigned 2:1:2:1 to the dose cohorts (ARO-APOC3 25 mg, volume-matched placebo, ARO-APOC3 50 mg, and volume-matched placebo, respectively). Treatments will be administered per the randomised sequence generated by an Interactive Web Response System (IWRS). The allocation of active treatment or placebo will be performed using a block randomisation algorithm. Follow-Up: After Month 12, participants will be eligible and invited to consent and continue in an open-label extension study. All participants in the placebo group who opt to continue will switch to active drug during the extension study. Subjects who do not enter the open-label extension study will be monitored monthly for safety and pharmacodynamic endpoints for 9 months post last dose.
Current inclusion criteria as of 22/07/2025: 1. Males or nonpregnant (who do not plan to become pregnant), nonlactating females ≥18 years of age (or ≥19 years of age, where applicable according to the local regulation) 2. Able and willing to provide written informed consent prior to the performance of any study specific procedures 3. Fasting TG ≥10 mmol/L (≥880 mg/dL) at screening, that is refractory to standard lipid lowering therapy (sample drawn after at least the minimum time on stable lipid lowering regimen described in the protocol). Two repeat tests are allowed to qualify. 4. A diagnosis of FCS based on a documented history of fasting TG levels in excess of 1000 mg/dL on repeated testing (for at least 3 prior occasions), and at least one of the following: 4.1. A supportive genetic test (from a source-verifiable medical record or based on screening genotype). Supportive genetic testing includes but is not limited to homozygous, compound heterozygous, or double heterozygote for loss of function or otherwise inactivating mutations in genes affecting lipoprotein lipase activity including LPL, APOC2, APOA5, GPIHBP1, GPD1, or LMF1; or evidence of low LPL activity (<20% of normal) based on source verifiable documentation; or 4.2. Documented history of recurrent episodes of acute pancreatitis, not caused by alcohol or cholelithiasis; or 4.3. Documented history of recurrent hospitalizations for severe abdominal pain without other explainable cause; or 4.4. Documented history of childhood pancreatitis; or 4.5. Family history of hypertriglyceridemia-induced pancreatitis 5. Willing to follow dietary counseling as per PI judgment based on local standard of care, consistent with an intake of ≤20 g of fat per day during the study 6. If on medications for management of type 2 diabetes, or other medications specified in the protocol, the dosing regimen must be stable before collection of qualifying lipid parameter at screening. 7. Participants with a medical history of clin
Current exclusion criteria as of 22/07/2025: 1. Current use or use within the last 365 days from Day 1 of any hepatocyte-targeted siRNA or antisense oligonucleotide molecule 2. Diabetes mellitus with any of the following: a. Newly diagnosed within 12 weeks of screening b. HbA1c ≥9.0% (or >75 mmol/mol International Federation of Clinical Chemistry [IFCC] units) at screening 3. Active pancreatitis within 12 weeks before Day 1 4. History of acute coronary syndrome events (myocardial infarction or unstable angina) or procedures (coronary revascularization, angioplasty, or stenting) within 24 weeks of Day 1 5. History of major surgery within 12 weeks of Day 1 (including cardiac and vascular surgeries, eg, coronary artery bypass graft) 6. Any of the following laboratory values at screening: 6.1. ALT or AST ≥3×ULN at screening 6.2. Total bilirubin ≥1.5 ULN (if the participant has a prior diagnosis and documentation of Gilbert’s syndrome, then total bilirubin must be ≤3 mg/dL at screening) 6.3. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening, using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) creatinine equation (Levey 2009) 6.4. Spot urine protein/spot urine creatinine ratio greater than 3 grams per day 6.5. Clinically significant abnormality in prothrombin time, partial thromboplastin time, or INR 7. Uncontrolled hypertension (blood pressure >160/100 mmHg at screening); if untreated, participant may be rescreened once hypertension is treated and controlled 8. Use of any of the following: 8.1. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or planned use during the study 8.2. GLP-1 receptor agonists 8.3. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study 8.4. Blood donation of 50 to 499 mL within 4 weeks of collection of qualifying lipid parameter collection or of >499 mL within 8 weeks of qualifying lipid parameter collection 9. On treatment with HIV antiretroviral therap