TRYNGOLZA Solution for injection Ref.[115519] Active ingredients: Olezarsen

5.1 Hypersensitivity Reactions

Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias) have been reported in patients treated with TRYNGOLZA [see Adverse Reactions (6.1)]. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur.

The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of TRYNGOLZA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434) [see Clinical Studies (14)]. In this trial, 43 patients received at least one dose of TRYNGOLZA, 50 mg (N=21) or 80 mg (N=22) and 23 patients received placebo. TRYNGOLZA 50 mg is not an approved dosing regimen for FCS [see Dosage and Administration (2.1)]. Across treatment groups, the mean age was 45 years and 42% of patients were male. Eighty-five percent (85%) of patients were White, 9% were Asian and 6% were reported as other races; 11% identified as Hispanic or Latino ethnicity. Forty-three (43) patients were exposed to TRYNGOLZA for a median of 52 weeks; 22 patients were treated with TRYNGOLZA 80 mg every 4 weeks for a median of 52 weeks.

Adverse reactions led to discontinuation of treatment in 7% of TRYNGOLZA-treated patients and 0% of placebo-treated patients. The most common reasons for TRYNGOLZA treatment discontinuation were hypersensitivity reactions. Adverse reactions (>5% of patients treated with TRYNGOLZA and at >3% higher frequency than placebo) are presented in Table 1.

Table 1. Adverse Reactions That Occurred in >5% of Patients Treated with TRYNGOLZA and at >3% Higher Frequency than Placebo (Trial 1):

^* Grouped terms composed of several similar terms

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).

The observed incidence of anti-drug antibodies (ADAs) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADAs in the study described below with the incidence of anti-drug antibodies in other studies, including those of olezarsen.

In Trial 1, with duration of treatment up to 53 weeks, 18 out of 43 (42%) patients treated with TRYNGOLZA developed treatment-emergent ADAs. The presence of ADAs did not affect olezarsen plasma C_max, but increased C_trough. Although ADA development was not found to affect the pharmacodynamics, safety, or efficacy of TRYNGOLZA in these patients, the available data are limited to make definitive conclusions.

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

Disease-Associated Maternal and/or Embryo-Fetal Risk

During pregnancy, triglyceride levels increase during the third trimester of pregnancy. In patients with underlying defects in lipid metabolism, such as FCS, severe gestational hypertriglyceridemia may occur, increasing the risk of acute pancreatitis during pregnancy.

Data

Animal Data

Olezarsen was not evaluated for potential effects on embryofetal development (EFD). However, effects of the administration of the unconjugated antisense oligonucleotide (ASO), which shares the same nucleotide sequence but lacks the N-acetyl galactosamine [GalNAc] moiety [see Description (11)], were evaluated.

In a combined fertility and embryo-fetal development study in mice, the unconjugated ASO was administered to male and female mice by subcutaneous injection at doses of 10.5, 35, and 87.5 mg/kg/week prior to mating and through to the completion of organogenesis (gestation day 15). No adverse developmental outcomes occurred at doses up to 87.5 mg/kg/week (approximately 21-times the monthly maximum recommended human dose (MRHD) based on a body surface area (BSA) comparison of the unconjugated ASO).

In an embryo-fetal development study in pregnant rabbits, the unconjugated ASO was administered by subcutaneous injection at doses of 10.5, 21, and 52.5 mg/kg/week during the period of organogenesis (gestation days 6 to 18). No adverse developmental effects were observed at doses up to 21 mg/kg/week (approximately 20-times the monthly MRHD based on a BSA comparison of the unconjugated ASO).

In a pre-/postnatal toxicity study in mice, the unconjugated ASO was administered at 10.5, 35, or 87.5 mg/kg/week during the period of organogenesis and continuing until weaning (gestation day 6 through lactation day 21). Offspring body weights at 87.5 mg/kg/week (21-times the monthly MRHD based on BSA) were lower throughout their lives and were associated with slight delays in the attainment of morphological and developmental landmarks. No adverse effects on offspring were observed at 35 mg/kg/week (approximately 9-times the monthly MRHD based on a BSA comparison of the unconjugated ASO).

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.

Safety and effectiveness of TRYNGOLZA in pediatric patients have not been established.

No dose adjustment is recommended in patients aged 65 years and older [see Clinical Pharmacology (12.3)]. In clinical studies, 111 (38%) patients treated with TRYNGOLZA were ≥65 years of age. No overall differences in safety or effectiveness of TRYNGOLZA have been observed between patients 65 years of age and older and younger adult patients.

No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min) [see Clinical Pharmacology (12.3)]. TRYNGOLZA has not been studied in patients with severe renal impairment or end-stage renal disease.

No dose adjustment is recommended in patients with mild hepatic impairment [see Clinical Pharmacology (12.3)]. TRYNGOLZA has not been studied in patients with moderate or severe hepatic impairment.