TRYNGOLZA

Indications and Usage ( 1 ) 06/2026 Dosage and Administration, Recommended Dosage ( 2.1 ) 06/2026 Warnings and Precautions Liver Enzyme Abnormalities ( 5.2 ) 06/2026

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.

3 DOSAGE FORMS AND STRENGTHS Injection: 50 mg/0.8 mL of olezarsen as a clear, colorless to yellow solution in a single-dose autoinjector 80 mg/0.8 mL of olezarsen as a clear, colorless to yellow solution in a single-dose autoinjector Injection: 50 mg/0.8 mL in a single-dose autoinjector. ( 3 ) 80 mg/0.8 mL in a single-dose autoinjector. ( 3 )

4 CONTRAINDICATIONS 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 [see Warnings and Precautions (5.1) ] . History of serious hypersensitivity reactions to olezarsen or any of the excipients in TRYNGOLZA. ( 4 )

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 rea …

8 USE IN SPECIFIC POPULATIONS 8.1 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 [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 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 [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). 8.2 Lactation 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 breastfed infant from TRYNGOLZA or from the underl …

12.1 Mechanism of Action Olezarsen is an ASO-GalNAc 3 conjugate that binds to apoC-III mRNA leading to mRNA degradation and resulting in a reduction of serum apoC-III protein. Reduction of apoC-III protein leads to increased clearance of plasma TG and very low-density lipoprotein (VLDL).

11 DESCRIPTION Olezarsen is an ASO directed inhibitor of apolipoprotein C-III (apoC-III) mRNA, conjugated to a ligand containing three GalNAc residues to enable delivery of the ASO to hepatocytes. TRYNGOLZA contains olezarsen sodium as the active ingredient. Olezarsen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of olezarsen sodium is C 296 H 419 N 71 O 154 P 20 S 19 Na 20 and the molecular weight is 9124.48 daltons. The chemical name of olezarsen sodium is DNA, d(P-thio) ([2'- O -(2-methoxyethyl)] rA-[2'- O -(2-methoxyethyl)] rG-[2'- O -(2-methoxyethyl)] m5rC-[2'- O -(2-methoxyethyl)] m5rU-[2'- O -(2-methoxyethyl)] m5rU-m5C-T-T-G-T-m5C-m5C-A-G-m5C-[2'- O -(2-methoxyethyl)] m5rU-[2'- O -(2-methoxyethyl)] m5rU-[2'- O -(2-methoxyethyl)] m5rU-[2'- O -(2-methoxyethyl)] rA-[2'- O -(2-methoxyethyl)]m5rU), 5'-[26-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]-14,14-bis[[3-[[6-[[2-(acetylamino)-2-deoxy-β-D-galactopyranosyl]oxy]hexyl]amino]-3-oxopropoxy]methyl]-8,12,19-trioxo-16-oxa-7,13,20-triazahexacos-1-yl hydrogen phosphate], sodium salt (1:20). The structure of olezarsen sodium is presented below: TRYNGOLZA is a sterile, preservative-free solution for subcutaneous injection. Each single-dose autoinjector contains 50 mg olezarsen (equivalent to 53 mg of olezarsen sodium) in 0.8 mL of solution or 80 mg olezarsen (equivalent to 84 mg of olezarsen sodium) in 0.8 mL of solution. The solution also contains the following inactive ingredients: disodium hydrogen phosphate, sodium chloride, sodium dihydrogen phosphate to maintain pH and provide tonicity, and water for injection. The solution may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 to 7.9. Each 50 mg dose of TRYNGOLZA injection contains 4 mg of phosphorous and 4 mg of sodium. Each 80 mg dose of TRYNGOLZA injection contains 6 mg of phosphorous and 5 mg of sodium. Chemical Structure

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied TRYNGOLZA injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of TRYNGOLZA is filled to deliver 0.8 mL of solution containing 50 mg or 80 mg of olezarsen. TRYNGOLZA is supplied as: Carton containing one 50 mg single-dose autoinjector: (NDC 71860-102-01). Carton containing one 80 mg single-dose autoinjector: (NDC 71860-101-01). 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.

16.1 How Supplied TRYNGOLZA injection is a sterile, preservative-free, clear, colorless to yellow solution supplied in a single-dose autoinjector. Each autoinjector of TRYNGOLZA is filled to deliver 0.8 mL of solution containing 50 mg or 80 mg of olezarsen. TRYNGOLZA is supplied as: Carton containing one 50 mg single-dose autoinjector: (NDC 71860-102-01). Carton containing one 80 mg single-dose autoinjector: (NDC 71860-101-01).