Tryngolza: Package Insert / Prescribing Info

Laboratory Tests
Decrease in Platelet Count: TRYNGOLZA can cause reductions in platelet count. In Trial 1, the mean platelet count in the TRYNGOLZA 80 mg group was 188,000 mm3 at baseline, and the mean percent change in platelet count was -10% at Week 53. In comparison, the mean platelet count in the placebo group was 215,000/mm3 at baseline, and the mean percent change in platelet count was 22% at Week 53. No TRYNGOLZA-treated patient with FCS had a platelet count <50,000/mm3. There were no major bleeding events associated with a low platelet count. Overall, the proportion of patients experiencing a bleeding adverse event was similar across the TRYNGOLZA and placebo treatment groups.

Increase in Glucose: Small increases in average values in fasting glucose (≤17 mg/dL) and HbA1c (<0.2 percentage points) were observed over time with TRYNGOLZA treatment in the FCS population in Trial 1. The incidence of hyperglycemia (defined as adverse events, new antidiabetic medication, or laboratory values) was higher in olezarsen-treated patients without a medical history of diabetes at baseline (52%) compared to placebo-treated patients (35%).

Increase in Liver Enzymes: Increases from baseline in liver enzymes within the normal range were observed with olezarsen treatment in the FCS population. These increases occurred within the first 3 months of treatment and stabilized. Liver enzymes returned towards baseline with discontinuation of olezarsen.

Increase in LDL-cholesterol: Increases in low-density lipoprotein cholesterol (LDL-C) and total apolipoprotein B (apoB) were observed in the FCS population treated with TRYNGOLZA compared to those treated with placebo [see Clinical Studies (14)]. Despite increases in LDL-C, the maximum LDL-C value remained low for most patients (i.e., <70 mg/dL for 74% of patients treated with TRYNGOLZA).

Risk Summary

There are no available data on TRYNGOLZA use in pregnant women to inform drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Patients with FCS are at risk for pancreatitis during pregnancy because of defects in lipid metabolism and increased triglyceride levels (see Clinical Considerations).

In animal reproduction studies conducted with the unconjugated antisense oligonucleotide (lacking GalNAc) in rabbits and mice, no adverse effects on development or pregnancy were observed at doses 21 times or 20 times, respectively, the maximum recommended clinical dose.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20% respectively.

Clinical Considerations

Data

Risk Summary

There are no data on the presence of olezarsen in either human or animal milk, the effects on the breastfed infant, or the effects on milk production. However, the unconjugated antisense ASO, which shares the same nucleotide sequence but lacks GalNAc, was present in the milk of lactating mice at low levels. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Oligonucleotide-based products typically have poor oral bioavailability; therefore, it is considered unlikely that low levels present in milk will lead to clinically relevant levels in breastfed infants. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TRYNGOLZA and any potential adverse effects on the breast-fed infant from TRYNGOLZA or from the underlying maternal condition.

Cardiac Electrophysiology

At a dose 1.5-times the maximum approved recommended dosage, TRYNGOLZA does not prolong the QT interval to any clinically relevant extent.

Absorption

Olezarsen time to Cmax (Tmax) is approximately 2 hours following subcutaneous administration.

Distribution

The population estimates for the apparent central volume of distribution is 91.9 L and the apparent peripheral volume of distribution is 2960 L for olezarsen. Olezarsen is greater than 99% bound to plasma proteins, in vitro.

Olezarsen distributes primarily to the liver and kidney after subcutaneous dosing.

Elimination

Olezarsen terminal elimination half-life is approximately 4 weeks.

Specific Populations

No clinically significant differences in the pharmacokinetics of olezarsen were observed based on age (< 65 to ≥ 75 years), body weight, sex, race (White, Black or African American, Asian, Japanese, American Indian or Alaska Native, Native Hawaiian or Pacific Islander), mild-to-moderate renal impairment (eGFR ≥30 to <90 mL/min) [CKD-EPI], or mild hepatic impairment (total bilirubin ≤ ULN and AST > ULN; , or total bilirubin >1 to 1.5 x ULN and any AST, National Cancer Institute Organ Dysfunction Working Group criteria). The effect of severe renal impairment (eGFR < 30 mL/min), end-stage renal disease, moderate or severe hepatic impairment (total bilirubin > 1.5 x ULN with any AST) on olezarsen pharmacokinetics is unknown.

Drug Interaction Studies

In Vitro Studies
CYP450 Enzymes: Olezarsen is not an inhibitor or inducer of CYP450 enzymes.

Transporter Systems: Olezarsen is not a substrate or inhibitor of OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP.

Protein Binding: Olezarsen does not displace warfarin and ibuprofen from plasma protein binding sites.

Carcinogenesis

No long-term carcinogenicity studies were conducted with olezarsen in animals. However, the unconjugated antisense oligonucleotide (ASO) lacking GalNAc was administered weekly in mice and rats at subcutaneous doses of 0, 6, 25, 40 mg/kg/week (along with a mouse-specific surrogate ASO at 25 mg/kg/week) and 0, 0.2, 1, 5 mg/kg/week, respectively, for 2 years. In male mice, there were statistically significant increases in the incidences of hepatocellular adenomas and carcinomas at ≥25 mg/kg/week and hemangiomas and hemangiosarcomas at all doses. In female mice, there were statistically significant increases in the incidences of histiocytic sarcomas at all doses (including the mouse-specific surrogate) and pituitary gland adenomas at 25 mg/kg/week. In rats, the incidence of malignant fibrous histiocytoma at the injection site was increased in both sexes at doses ≥1 mg/kg/week. These tumors are considered a response to chronic tissue irritation and inflammation caused by repeated subcutaneous injection. The clinical significance of these findings is uncertain.

Mutagenesis

Olezarsen was negative for genotoxicity in vitro (bacterial reverse mutation assay and chromosome aberration assay in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus assay).

Impairment of Fertility

Olezarsen was administered at doses of 0, 5, 10, or 20 mg/kg given every other week to male and female mice prior to mating, followed by every other day dosing after mating and until gestation day 6 in females. There was no effect on fertility in mice administered olezarsen at doses up to 20 mg/kg (approximately 2-times the monthly maximum recommended human dose based on body surface area).