Olezarsen

Introduction Overview

Generic Name

olezarsen

Brand Name

Tryngolza

Dosage Form

single-dose autoinjector (80 mg/0.8 mL)

Drug Class

Miscellaneous antihyperlipidemic agents (ASO-GalNAc3 conjugates)

Pharmacokinetics

Absorption:
Olezarsen, administered subcutaneously via the Tryngolza autoinjector, demonstrates efficient absorption through the subcutaneous tissue. The ASO (antisense oligonucleotide)-GalNAc3 conjugate design specifically facilitates targeted delivery to hepatocytes via the asialoglycoprotein receptor, enhancing hepatic uptake. Absorption into systemic circulation occurs gradually with a slow release profile enabling sustained target engagement, consistent with its once-monthly dosing regimen. Peak plasma concentrations are typically reached within several hours to days post-injection, underpinning its prolonged pharmacodynamic effects.

Distribution:
Following systemic absorption, olezarsen preferentially distributes to the liver due to the GalNAc3 moiety which binds hepatocyte receptors, minimizing off-target tissue deposition. This hepatoselective distribution reduces systemic exposure while maximizing efficacy in modulating hepatic apoC-III production. Plasma protein binding is moderate and the drug exhibits a distinct tissue distribution profile characteristic of antisense oligonucleotides, with limited penetration beyond hepatic tissues.

Metabolism:
Olezarsen undergoes metabolism primarily by endogenous endonucleases and exonucleases which degrade the antisense oligonucleotide backbone into shorter oligonucleotides and nucleotides. This enzymatic catabolism occurs within liver cells following receptor-mediated endocytosis. No involvement of classical cytochrome P450 enzymes is reported, thereby reducing potential drug-drug interaction risks related to hepatic metabolism pathways.

Elimination:
The metabolites of olezarsen are predominantly excreted via the renal route. Clearance is relatively slow, supporting a sustained pharmacologic effect that permits monthly dosing. Renal function may affect clearance to some extent, although formal studies in patients with renal impairment are limited. The elimination half-life values from published trials support monthly dosing, with drug levels declining slowly yet retaining therapeutic activity throughout the dosing interval.

Dosage Forms

Available Dosage Forms:
- Single-dose autoinjector: 80 mg/0.8 mL solution for subcutaneous injection

Dosages for Adults and Adolescents:
- Recommended dose for adults with familial chylomicronemia syndrome (FCS): 80 mg subcutaneously once a month
- No established dosing for pediatric populations; safety and efficacy in children are not known

Specific Patient Populations:
- Adults with familial chylomicronemia syndrome, used alongside a very low-fat diet (less than 20 grams of fat daily)
- No current dosage adjustments established for renal or hepatic impairment due to limited data
- Not studied or approved for pediatric or geriatric patients specifically; caution advised

Clinical Guidelines:
- Administered by subcutaneous injection into the abdomen or front of the thighs; injections in the back of the upper arm should only be given by healthcare providers or caregivers
- Must be taken with strict dietary fat restriction to optimize therapeutic effect and reduce complications associated with FCS

Storage:
- Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton
- Can be stored at room temperature (15°C to 30°C) for up to 6 weeks
- Protect from freezing, heat, and light
- Do not use if autoinjector is left at room temperature more than 6 weeks

Mechanism Of Action

Olezarsen (Tryngolza) exerts its pharmacologic action through an innovative antisense oligonucleotide (ASO) mechanism. As a GalNAc3-conjugated ASO, olezarsen selectively targets the messenger RNA (mRNA) encoding apolipoprotein C-III (apoC-III) in hepatocytes. ApoC-III is a crucial regulator of plasma triglyceride metabolism that inhibits the breakdown of triglyceride-rich lipoproteins.

Upon subcutaneous administration, olezarsen is taken up by hepatocytes via receptor-mediated endocytosis facilitated by its GalNAc3 ligand targeting the asialoglycoprotein receptor highly expressed on liver cells. Inside hepatocytes, olezarsen hybridizes with the apoC-III mRNA, triggering RNase H-mediated degradation of this transcript. This selective degradation reduces apoC-III protein synthesis, which in turn decreases the inhibitory effect apoC-III has on lipoprotein lipase and hepatic clearance mechanisms.

By lowering apoC-III protein levels, the drug enhances the hydrolysis and clearance of very-low-density lipoprotein (VLDL) and chylomicrons, effectively reducing plasma triglyceride concentrations. This biochemical modulation addresses the underlying pathophysiology of familial chylomicronemia syndrome (FCS), characterized by impaired triglyceride metabolism and chylomicron accumulation.

Clinical studies, including the pivotal BALANCE trial, demonstrate that consistent monthly dosing with olezarsen significantly lowers triglyceride levels by up to 57-59% at one year. This translates into a measurable reduction in acute pancreatitis risk, a severe complication of FCS. Compared to other triglyceride-lowering agents such as fibrates or omega-3 fatty acids that act by activating lipoprotein lipase or reducing hepatic triglyceride synthesis, olezarsen operates via a targeted molecular genetic approach, offering specificity and potentially fewer systemic side effects. Research continues to evolve on the long-term impacts and potential broader applications of antisense oligonucleotide therapies in dyslipidemias.

Pharmacological Actions

Selective inhibition of apoC-III synthesis via antisense oligonucleotide mechanism.
Reduction of plasma triglyceride levels by enhancing lipolysis and clearance of triglyceride-rich lipoproteins.
Hepatoselective targeting due to GalNAc3 conjugation, leading to improved efficacy and reduced systemic exposure.
Monthly subcutaneous administration provides sustained pharmacodynamic effect.
Decreases the incidence of acute pancreatitis by lowering chylomicron accumulation.
Modulation of lipid metabolism pathways specific to familial chylomicronemia syndrome.
Does not involve cytochrome P450 metabolism, minimizing drug-drug interaction potential.
Improves clearance of very-low-density lipoprotein (VLDL) particles by reducing apoC-III mediated inhibition.
Acts downstream of genetic mutations causing FCS by targeting mRNA rather than protein function.
Promotes improved plasma lipid profiles in severely hypertriglyceridemic patients.
Exhibits minimal off-target effects due to precise nucleotide sequence complementarity.
Facilitates better dietary fat tolerance when combined with strict low-fat diet adherence.
Does not induce general immunosuppression, but may elicit local injection site reactions.
Represents a novel therapeutic class of antisense therapies in hyperlipidemia management.

Therapeutic Or Clinical Uses

Treatment of familial chylomicronemia syndrome (FCS) in adults to reduce triglyceride levels.
Adjunct therapy alongside a strict low-fat diet (less than 20 grams of fat daily) for FCS management.
Reduction in risk and frequency of acute pancreatitis associated with elevated chylomicrons.
Management of severe hypertriglyceridemia related to apoC-III dysregulation.
Targeted therapy for genetically mediated lipid metabolism disorders unresponsive to conventional lipid-lowering agents.
Potential option for patients unable to tolerate fibrates or omega-3 fatty acids or with inadequate response.
First FDA-approved treatment specifically for familial chylomicronemia syndrome.
Use in adults requiring monthly dosing convenience for chronic triglyceride management.
Reduction of VLDL and triglyceride-rich lipoproteins to improve lipid profiles.
Use in patients with a history of pancreatitis secondary to chylomicronemia.
Adjunct to dietary fat restriction to enable better triglyceride control.
Part of a comprehensive management strategy including genetic counseling and lifestyle modifications.
Investigational potential for other rare lipid disorders involving apoC-III overexpression.
May facilitate improved quality of life by reducing pancreatitis hospitalizations.

Side Or Adverse Effects

Injection site reactions including redness, pain, swelling, or discomfort.
Thrombocytopenia or decreased platelet counts leading to potential bleeding risks.
Joint pain or stiffness potentially related to immune-mediated inflammation.
Allergic reactions including rash, hives, swelling of face, chills, or respiratory difficulty.
Potential for hypersensitivity reactions; observe closely after dosing.
Mild flu-like symptoms or malaise reported in some patients.
Possible transient elevation of liver enzymes, although data are limited.
Risk of injection site infections if aseptic technique not maintained.
Uncommon systemic adverse effects given hepatoselective targeting.
No significant reports of renal toxicity to date, but monitoring advised.
Unknown long-term safety profile beyond clinical trial durations.
Potential for immunogenicity given antisense oligonucleotide class.
Reduced platelet counts may necessitate periodic blood count monitoring.
Local discomfort may impair adherence if persistent or severe.
No established safety data in pediatric populations or during pregnancy.

Precautions

Assess patient history for hypersensitivity to olezarsen or formulation components before initiation.
Monitor platelet counts regularly due to observed thrombocytopenia in trials.
Counsel patients on recognition and immediate reporting of signs of allergic reactions.
Instruct on proper injection technique and rotating injection sites to reduce local irritation.
Maintain strict dietary fat restriction (less than 20 grams daily) to optimize efficacy and safety.
Avoid use in pediatric patients until further safety and efficacy data become available.
Evaluate hepatic and renal function periodically due to limited data in organ impairment.
Use caution in patients with bleeding disorders or concomitant anticoagulant therapy due to platelet effects.
Educate patients on the importance of adherence to monthly dosing schedule for therapeutic benefit.
Inform patients about storage requirements to preserve drug stability and efficacy.
Pregnant or breastfeeding patients should weigh potential benefits against unknown risks.
Advise patients to avoid exposure to heat or freezing conditions that can degrade the drug.
Ensure comprehensive medication reconciliation to check for possible interactions.
Be alert to joint symptoms that could indicate inflammatory adverse events.
Encourage immediate medical attention if symptoms of hypersensitivity or severe adverse effects arise.

Warnings

Risk of serious allergic or hypersensitivity reactions, including anaphylaxis.
Potential for significant thrombocytopenia requiring close monitoring.
Unknown safety and efficacy in pediatric populations.
Use during pregnancy only if clearly needed due to lack of human data.
Must be used alongside strict dietary fat restriction to prevent complications.
Injection site reactions may occur and could be severe in some cases.
Do not expose the drug to temperatures above 30°C (86°F) or freezing conditions.
Improper storage or handling may render product ineffective or unsafe.
Avoid use in patients with a history of severe allergic reactions to antisense oligonucleotides.
Monitor for signs of bleeding in patients with platelet count reductions.
Discontinue immediately and seek emergency care if symptoms of an allergic reaction appear.
Limited long-term safety data available; surveillance recommended.
May cause immune-mediated adverse events including joint symptoms.
Avoid use in patients with active infections at the injection site.
Risk mitigation through patient education on recognizing adverse events is essential.

Contraindication

History of severe hypersensitivity or allergic reactions to olezarsen or any component of Tryngolza.
Known allergy to any of the inactive ingredients such as disodium hydrogen phosphate or sodium chloride.
Patients with active bleeding disorders without appropriate medical supervision.
Not indicated or approved for use in pediatric patients under 18 years due to unknown safety profile.
Contraindicated in patients unable to comply with strict dietary fat restrictions required.
Avoid administration if the autoinjector shows signs of damage or compromised sterility.
Not recommended for use in pregnant or breastfeeding women unless clearly justified.
Contraindicated in patients with known hypersensitivity to other antisense oligonucleotide therapies targeting apoC-III.
Patients with marked thrombocytopenia at baseline should avoid use unless benefits outweigh risks.
Use is not suitable in patients with severe hepatic impairment awaiting further studies.
Contraindicated in individuals with uncontrolled or severe hypersensitivity skin disorders at injection sites.
Avoid use if patient has had prior severe injection-site reaction to subcutaneous treatments.
Use not recommended in individuals with active systemic infections.
Contraindicated when concomitant administration with drugs known to interact with antisense pathways occurs.
Patients with known hypersensitivity to GalNAc conjugates should not use Tryngolza.

Drug Interactions

No significant cytochrome P450 enzyme interactions due to antisense oligonucleotide metabolism.
Potential pharmacodynamic interactions with anticoagulants or antiplatelet agents due to thrombocytopenia risk.
Caution advised with concomitant use of drugs that may lower platelet counts or impair coagulation.
Limited data on interactions with lipid-lowering agents like fibrates or omega-3 fatty acids; combination may be considered under supervision.
No known interactions with commonly prescribed antihypertensives or antidiabetics.
Herbal supplements affecting coagulation (e.g., ginkgo, garlic) may increase bleeding risk when combined.
No established interactions with oral contraceptives or hormone replacement therapy.
No significant impact on absorption of concomitant oral medications reported.
Avoid concomitant use with other investigational antisense oligonucleotides unless monitored.
Potential additive effect with immunomodulatory drugs; monitoring for immune side effects is warranted.
Avoid combining with nephrotoxic drugs without renal function monitoring due to renal elimination of metabolites.
No established interactions with over-the-counter analgesics or NSAIDs but caution due to platelet changes.
No evidence of effect on warfarin pharmacokinetics, but coagulation status should be carefully monitored.
Drug interaction profiles may evolve as clinical use expands; clinicians should remain vigilant.
Recommend detailed medication reconciliation before starting therapy.

Preparations Of The Drug

Tryngolza is available as a single-dose autoinjector containing 80 mg of olezarsen sodium in 0.8 mL solution.
Formulated for subcutaneous administration once monthly.
The injectable solution contains inactive ingredients including disodium hydrogen phosphate, sodium chloride, sodium dihydrogen phosphate, and water for injection, with pH adjusted by hydrochloric acid and/or sodium hydroxide.
Provided in a prefilled autoinjector device designed for ease of use and accurate dosing.
Stored refrigerated in original carton to protect from light and temperature extremes.
Can be stored at controlled room temperature (15°C to 30°C) for up to 6 weeks without loss of potency.
Applies aseptic technique for administration; single-use, discard after injection.
Clear cap protects needle and must remain on until injection.
Device designed to deliver a fixed 80 mg dose to ensure consistent therapeutic exposure.
No oral or alternative formulations currently available.
Injection site selection limited to abdomen, front of thighs for self-administration;
Back of upper arm injection only by healthcare providers or caregivers.
Packaging includes patient instructions and guidance on handling, storage, and disposal.
Sensitive to heat and freezing; exposure can compromise drug integrity.
Manufactured by Ionis Pharmaceuticals Inc., Carlsbad, California with rigorous quality controls.