olezarsan

Action and Spectrum

Actions and Spectrum:

Olezarsen is a GalNAc3-conjugated antisense oligonucleotide that is intended to reduce the expression of APOC3. This can be realized by the fact that SIAPP binds to apolipoprotein C-III (APOC3) mRNA resulting to its degradation. APOC3, at high concentration, inhibits lipoprotein lipase (LPL) leading to chylomicronemia and severe hypertriglyceridemia.

Drug Interaction

Adverse Reaction

Frequency not defined

>10%

Decreased platelet count

Injection site reactions

1-10%

Arthralgia (9%)

<1%

Enhanced liver enzymes from the baseline

Increased LDL-C and total apo B

Increased fasting glucose levels

Black Box Warning

Black box warning:

None

Contraindication / Caution

Contraindications/caution:

Hypersensitivity

Pregnancy / Lactation

Pregnancy / Lactation

Pregnancy consideration: Insufficient data available

Lactation: Excretion of the drug in human breast milk is unknown

Pregnancy category:

Category A: well-controlled and Satisfactory studies show no risk to the fetus in the first or later trimester.

Category B: there was no evidence of risk to the fetus in animal studies, and there were not enough studies on pregnant women.

Category C: there was evidence of risk of adverse effects in animal reproduction studies, and no adequate evidence in human studies must take care of potential risks in pregnant women.

Category D: adequate data with sufficient evidence of human fetal risk from various platforms, but despite the potential risk, and used only in emergency cases for potential benefits.

Category X: Drugs listed in this category outweigh the risks over benefits. Hence these categories of drugs need to be avoided by pregnant women.

Category N: There is no data available for the drug under this category

Pharmacology

Pharmacology

Olezarsen is an experimental antisense oligonucleotide that has been developed to target APOC3 mRNA exclusively. It works through an RNA-based pathway where it binds to APOC3 mRNA and inhibits the translation of APOC3 protein through degradation by RNase H1.

Pharmacodynamics

It belongs to the class of antisense oligonucleotide that binds and cleaves apolipoprotein C-III (APOC3) mRNA decreasing APOC3 protein concentration. These effects inhibit enhance lipoprotein lipase (LPL) activity and increase the efficiency of triglyceride clearance resulting to low plasma triglyceride. It is particularly beneficial where the patient has familial chylomicronemia syndrome or severe hypertriglyceridemia. Substantial and long-lasting therapeutic effects are observed because of its slow onset, dose proportional, and long duration of action mediated by its long half-life.

Pharmacokinetics:

Absorption

Time to peak plasma concentration: ~2 hours

Peak plasma concentration (Cmax): 883 ng/mL

Area under the curve (AUC): 7,440 ng⋅hr/mL

Distribution

Protein binding: >99% (in vitro)

Volume of distribution (Vd):

Peripheral compartment: 2,960 L

Central compartment: 91.9 L

Predominantly distributes to the liver and kidneys

Metabolism

Metabolized in the liver by endo- and exonucleases, resulting in short oligonucleotide fragments of various sizes.

Elimination/Excretion

Half-life: Approximately 4 weeks

Excretion: Less than 1% excreted unchanged in urine within 24 hours

Adminstartion

Administration:

The patients and their caregivers should be educated on how to prepare for administration of the treatment before beginning therapy. The autoinjector must be brought out of the refrigerator at least half an hour prior to its use to allow it to come to room temperature. Study the solution’s clarity and color, and do not use it if the solution appears to be cloudy or colored. Give the injection subcutaneously in the abdomen or in the front of the thigh after a low fat diet containing not more than 20 grams of fat per day. If in the upper arm, a healthcare provider or any qualified caregiver should give it.

Patient Information Leaflet

Patient information leaflet

Generic Name: olezarsen

Why do we use Olezarsen?

Olezarsen is employed mainly for the treatment of severe hypertriglyceridemia (SHTG) and familial chylomicronemia syndrome (FCS) where high levels of triglycerides are present. These conditions are marked with high levels of triglycerides, which may cause severe health problems, including pancreatitis.