TRYNGOLZA

1 INDICATIONS AND USAGE 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). TRYNGOLZA is an apolipoprotein C-III (apoC-III)-directed antisense oligonucleotide (ASO) indicated as an adjunct to diet: To reduce triglycerides (TG) in adults with familial chylomicronemia syndrome (FCS). ( 1 ) To reduce TG and the risk of acute pancreatitis in adults with severe hypertriglyceridemia (sHTG: TG greater than or equal to 500 mg/dL). ( 1 )

2 DOSAGE AND ADMINISTRATION Adults with FCS: The recommended dosage of TRYNGOLZA is 80 mg injected subcutaneously once monthly. ( 2.1 ) Adults with sHTG: The recommended dosage of TRYNGOLZA is 50 mg injected subcutaneously once monthly. For patients with sHTG 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. ( 2.1 ) 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. ( 2.2 ) 2.1 Recommended Dosage In adults with FCS: The recommended dosage of TRYNGOLZA is 80 mg injected subcutaneously once monthly [see Dosage and Administration (2.2) ] . In adults with sHTG: The recommended dosage of TRYNGOLZA is 50 mg injected subcutaneously once monthly [see Dosage and Administration (2.2) ]. 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. 2.2 Administration Instructions Prior to initiation, train patients and/or caregivers on proper preparation and administration of TRYNGOLZA [see Instructions for Use ] . 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.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Hypersensitivity Reactions [ see Warnings and Precautions (5.1) ] Liver Enzyme Abnormalities [see Warnings and Precautions (5.2) ] Most common adverse reactions in patients with FCS (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count, and arthralgia. ( 6.1 ) Most common adverse reactions in patients with sHTG (incidence ≥2% higher than placebo) were injection site reactions and liver enzyme increases. ( 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. Clinical Trial in Patients with FCS The safety of TRYNGOLZA was evaluated in 66 patients with FCS enrolled in Trial 1 (NCT #04568434) [see Clinical Studies (14.1) ] . 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 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) 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 Clinical Trials in Patients with sHTG The safety of TRYNGOLZA was evaluated in two randomized, double-blind, placebo-controlled trials [Trial 2 (NCT #05079919) and Trial 3 (NCT #05552326)] that included a total of 1,061 adult patients with sHTG [see Clinical Studies (14.2) ] . In these trials, 705 patients received at least one dose of TRYNGOLZA, 50 mg (N=354) or 80 mg (N=351), and 356 patients received placebo. Across treatment groups, the mean age was 54 years and 76% of patients were male. Eighty-eight percent (88%) of patients were White, 5% Asian, 2% Black or African American, 2% American Indian or Alaskan Native, less than 1% Native Hawaiian or Pacific Islander, and 2% other or multiple races; 12% identified as Hispanic or Latino ethnicity. 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. Adverse reactions (in patients treated with TRYNGOLZA at ≥2% higher frequency than placebo) are presented in Table 2. Table 2. Adverse Reactions Occurring in ≥2% of Patients with sHTG Treated with TRYNGOLZA than with Placebo (Trial 2 and Trial 3) Adverse Reaction Grouped terms composed of several similar terms TRYNGOLZA 50 mg (N=354) TRYNGOLZA 80 mg (N=351) Placebo (N=356) Injection site reactions 43 (12%) 64 (18%) 8 (2%) Transaminases increased 11 (3%) 14 (4%) 2 (1%) Laboratory Tests Decrease in Platelet Count: TRYNGOLZA can cause reductions in platelet count. Across all trials (Trials 1, 2, and 3), mean decreases from baseline through Week 53 ranging from 6% (50 mg, Trial 2 and Trial 3) to 10% (80 mg across all trials), were observed in TRYNGOLZA-treated patients, whereas placebo-treated patients showed an increase of 22% in Trial 1 or no change in Trial 2 and Trial 3. 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%). In Trials 2 and 3, increases in average values in fasting glucose (≤9 mg/dL) and HbA1c (<0.3 percentage points) were observed over time in the sHTG population treated with TRYNGOLZA. 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. Mean HFFs were elevated at baseline (17% TRYNGOLZA 50 mg, 14% TRYNGOLZA 80 mg, 14% placebo). Dose-dependent changes in HFF at 12 months of treatment were a mean increase of 2 percentage points in the TRYNGOLZA 50 mg group and 4 percentage points in the TRYNGOLZA 80 mg group versus 0 percentage points in the placebo group. 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 [see Clinical Studies (14) ] .

16.2 Storage and Handling Store the TRYNGOLZA autoinjector in the refrigerator between 2°C and 8°C (36°F and 46°F) in the original carton. Once taken out of the refrigerator, the TRYNGOLZA autoinjector can be stored at room temperature between 15°C and 30°C (59°F and 86°F) in the original carton for up to 6 weeks. If not used within the 6 weeks stored at room temperature, discard TRYNGOLZA. Do not expose to heat. Protect from light.