Olezarsen for Lipid Metabolism Disorders

INDICATIONS AND USAGE TRYNGOLZA is indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). TRYNGOLZA is an APOC-III -directed antisense oligonucleotide (ASO) indicated as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). ( 1 )

DOSAGE AND ADMINISTRATION The recommended dosage of TRYNGOLZA is 80 mg administered subcutaneously once monthly. ( 2.1 ) Administer TRYNGOLZA 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. ( 2.2 ) 2.1 Recommended Dosage The recommended dosage of TRYNGOLZA is 80 mg administered subcutaneously once monthly [see Dosage and Administration (2.2) ] . 2.2 Administration Instructions Prior to initiation, train patients and/or caregivers on proper preparation and administration of TRYNGOLZA [see Instructions for Use ] . Remove the single-dose autoinjector from the refrigerator 30 minutes prior to the injection and allow to warm to room temperature. Do not use other warming methods. Inspect TRYNGOLZA visually for particulate matter prior to administration. The solution should be clear and colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed prior to administration. Maintain a low-fat diet (≤20g fat per day) in conjunction with TRYNGOLZA. 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.

WARNINGS AND PRECAUTIONS Hypersensitivity reactions have been reported in patients treated with olezarsen. 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. ( 5.1 ) 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.

ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions [ see Warnings and Precautions (5.1) ] Most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count, and arthralgia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ionis Pharmaceuticals Inc. at toll free number 1-833-644-6647 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 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. 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) Adverse Reaction Grouped terms composed of several similar terms Total TRYNGOLZA (N = 43) Placebo (N = 23) Injection site reactions 8 (19%) 2 (9%) Decreased platelet count 5 (12%) 1 (4%) Arthralgia 4 (9%) 0 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 mm 3 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/mm 3 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/mm 3 . 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).