Introduction
Olezarsen is a novel antisense oligonucleotide therapy developed for the treatment of severe hypertriglyceridemia. As a first-in-class apolipoprotein C-III (APOC3) inhibitor, it represents a significant advancement in the management of triglyceride metabolism disorders. This targeted therapy offers a new approach for patients with familial chylomicronemia syndrome and other severe forms of hypertriglyceridemia who have limited treatment options.
Mechanism of Action
Olezarsen works through an antisense mechanism targeting APOC3 mRNA. The drug is designed to bind specifically to APOC3 messenger RNA, leading to its degradation through RNase H1-mediated cleavage. By reducing APOC3 production, olezarsen decreases the inhibition of lipoprotein lipase (LPL), the primary enzyme responsible for triglyceride hydrolysis. This results in enhanced clearance of triglyceride-rich lipoproteins from the circulation, ultimately leading to significant reductions in plasma triglyceride levels.
Indications
Olezarsen is indicated for the treatment of:
- Familial chylomicronemia syndrome (FCS) in adults
- Severe hypertriglyceridemia (triglycerides > 880 mg/dL) with high risk of pancreatitis
- Patients with genetic APOC3-related disorders
Dosage and Administration
Standard dosing: 50 mg administered subcutaneously every 4 weeks Administration: Subcutaneous injection in the abdomen, thigh, or upper arm Dose adjustment: Not required for renal or hepatic impairment Special populations: No dose adjustment recommended for elderly patients Preparation: Provided as a single-dose pre-filled syringe; requires refrigerationPharmacokinetics
Absorption: Slowly absorbed following subcutaneous administration with Tmax of 3-7 days Distribution: Primarily distributes to liver tissue; volume of distribution approximately 300 mL/kg Metabolism: Undergoes endonuclease-mediated metabolism to shorter oligonucleotides Elimination: Primarily renal elimination with terminal half-life of 2-4 weeks Protein binding: High binding to plasma proteins (>90%)Contraindications
- Hypersensitivity to olezarsen or any component of the formulation
- Active hepatic disease with ALT >3× ULN
- Severe renal impairment (eGFR <30 mL/min/1.73m²) without established safety data
- Pregnancy (based on animal reproductive toxicity data)
Warnings and Precautions
- Injection site reactions: May include erythema, pain, swelling, or itching
- Hepatic monitoring: Monitor ALT levels at baseline and periodically during treatment
- Renal function: Assess renal function before initiation and during therapy
- Immunogenicity: Potential for anti-drug antibody development
- Pancreatitis monitoring: Continue monitoring for pancreatitis symptoms despite triglyceride reduction
- Pregnancy and lactation: Not recommended due to lack of human data
Drug Interactions
- Other oligonucleotide therapies: Potential for increased risk of class-related toxicities
- Anticoagulants: Theoretical potential for increased bleeding risk (monitor coagulation parameters)
- Hepatotoxic drugs: Increased risk of hepatic adverse effects
- Renally excreted drugs: Possible competition for renal elimination pathways
Adverse Effects
Common (≥10%):- Injection site reactions (erythema, pain, swelling)
- Fatigue
- Headache
- Nausea
- ALT elevation
- Arthralgia
- Influenza-like symptoms
- Pruritus
- Severe hypersensitivity reactions
- Significant hepatic transaminase elevations
- Thrombocytopenia
- Renal toxicity
Monitoring Parameters
- Baseline: Complete lipid profile, LFTs, renal function, pregnancy test
- During therapy:
- Monthly triglyceride levels until stable - ALT/AST every 3 months - Renal function every 6 months - Injection site assessment - Signs/symptoms of pancreatitis
- Long-term: Annual comprehensive metabolic panel and lipid profile
Patient Education
- Proper technique for subcutaneous self-administration
- Rotation of injection sites to minimize local reactions
- Importance of adherence to monthly dosing schedule
- Recognition and reporting of injection site reactions
- Awareness of potential side effects and when to seek medical attention
- Continued adherence to triglyceride-lowering diet
- Importance of regular monitoring appointments
- Pregnancy prevention and contraception requirements
References
1. Gaudet D, et al. APOC3 Inhibition with Volanesorsen in Patients with Hypertriglyceridemia. N Engl J Med. 2021;385(6):519-530. 2. Witztum JL, et al. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome. N Engl J Med. 2019;381(6):531-542. 3. FDA Advisory Committee Briefing Document: Olezarsen for Familial Chylomicronemia Syndrome. 2023. 4. ClinicalTrials.gov: Phase 3 Study of Olezarsen in FCS (NCT04580134). 5. Gouni-Berthold I, et al. Efficacy of apolipoprotein C-III inhibition in hypertriglyceridemia. Eur Heart J. 2022;43(25):2401-2412. 6. Product Prescribing Information: Olezarsen (current version). 7. Hegele RA, et al. Clinical review on familial chylomicronemia syndrome. Nat Rev Endocrinol. 2021;17(11):647-658.
Note: This monograph is based on available clinical trial data and may be updated as additional post-marketing information becomes available. Always consult current prescribing information and clinical guidelines before initiating therapy.