Tryngolza Drug Information

TRYNGOLZA ® is indicated as an adjunct to diet: To reduce triglycerides (TG) in adults with familial chylomicronemia syndrome (FCS). To reduce TG and the risk of acute pancreatitis in adults with severe hypertriglyceridemia (sHTG: TG greater than or equal to 500 mg/dL).

Recommended Dosage

• In adults with FCS: The recommended dosage of TRYNGOLZA is 80 mg injected subcutaneously once monthly.
• In adults with sHTG: The recommended dosage of TRYNGOLZA is 50 mg injected subcutaneously once monthly. Assess TG when clinically appropriate. The TG-lowering effect of TRYNGOLZA may be measured within 3 months after initiation. For patients who tolerate the 50 mg dosage and additional TG reduction is clinically indicated, the dosage may be increased to 80 mg injected subcutaneously once monthly.

Administration Instructions Prior to initiation, train patients and/or caregivers on proper preparation and administration of TRYNGOLZA. Advise patients to maintain a low-fat diet in conjunction with TRYNGOLZA. Instruct patients with FCS to consume 20 g or less of fat per day.

Remove the single-dose autoinjector from the refrigerator and let the autoinjector come to room temperature 30 minutes prior to the injection. Do not use other warming methods. Inspect TRYNGOLZA visually for particulate matter prior to administration.

The solution should be a clear and colorless to yellow liquid. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. Inject TRYNGOLZA subcutaneously into the abdomen or front of the thigh.

The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. Administer TRYNGOLZA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.

Clinical Trials Experience

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. Clinical Trial in Patients with FCS The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434). TRYNGOLZA 50 mg is not an approved dosing regimen for FCS.

Across treatment groups, the mean age was 45 years and 42% of patients were male. Adverse reactions led to discontinuation of treatment in 7% of TRYNGOLZA-treated patients and 0% of placebo-treated patients. The most common reason for TRYNGOLZA treatment discontinuation was 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 with FCS Treated with TRYNGOLZA and at >3% Higher Frequency than with Placebo (Trial 1) 0 Clinical Trials in Patients with sHTG The safety of TRYNGOLZA was evaluated in two randomized, double-blind, placebo-controlled trials that included a total of 1,061 adult patients with sHTG.

Across treatment groups, the mean age was 54 years and 76% of patients were male. The median exposure to TRYNGOLZA was 364 days (N=705). Adverse reactions led to discontinuation of treatment in 5% of TRYNGOLZA-treated patients and 2% of placebo-treated patients.

The most common adverse reaction for TRYNGOLZA treatment discontinuation was injection site reactions. Table 2. Adverse Reactions Occurring in ≥2% of Patients with sHTG Treated with TRYNGOLZA than with Placebo (Trial 2 and Trial 3) Laboratory Tests Decrease in Platelet Count: TRYNGOLZA can cause reductions in platelet count.

The proportion of patients experiencing a bleeding adverse event was similar between the TRYNGOLZA and placebo groups. There were no major bleeding events associated with low platelet counts. Increase in Glucose: 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 patients with FCS treated with TRYNGOLZA without a medical history of diabetes at baseline (52%) compared to placebo-treated patients (35%). These increases were more pronounced in patients with a history of diabetes at baseline; however, increases in fasting glucose and HbA1c were also observed more frequently with TRYNGOLZA compared to placebo in patients without a history of diabetes at baseline. Increase in Liver Enzymes: Mean liver enzyme values increased from baseline with TRYNGOLZA treatment but remained within the normal range.

These increases occurred within the first 6 months of treatment and stabilized. However, when evaluating any liver enzyme increase in patients with sHTG, increases in liver enzymes greater than or equal to three times the upper limit of normal were reported more frequently with TRYNGOLZA 80 mg (7%) compared to TRYNGOLZA 50 mg (3%) and placebo (3%). Liver enzymes returned toward baseline with discontinuation of TRYNGOLZA.

Increase in Hepatic Fat Fraction: Hepatic fat fraction (HFF) was assessed in patients with sHTG in a substudy within Trial 2 and Trial 3. The clinical meaningfulness of these findings remains uncertain. Increase in LDL-cholesterol: In all trials, increases were observed in LDL-C in TRYNGOLZA-treated patients compared with placebo.

These increases were accompanied by decreases in non–high-density lipoprotein cholesterol (non-HDL-C). Among patients with FCS, total apolipoprotein B (apoB) increased, whereas among patients with sHTG, apoB decreased.

Pregnancy 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 or sHTG are at risk for pancreatitis during pregnancy because of increased TG levels (see Clinical Considerations ). In animal reproduction studies conducted with the unconjugated antisense oligonucleotide (lacking N -acetylgalactosamine ) 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 populations are 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 Triglyceride levels increase during the third trimester of pregnancy. In patients with underlying defects in triglyceride metabolism, 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 (GalNAc) moiety, 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).

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). 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).

Pediatric Use The safety and effectiveness of TRYNGOLZA in pediatric patients have not been established.

TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to olezarsen or any of the excipients in TRYNGOLZA. Hypersensitivity reactions, including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills, and myalgias, requiring medical treatment have occurred.