Eplontersen

WAINUA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. WAINUA is a transthyretin-directed antisense oligonucleotide indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. ( 1 )

• The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly. ( 2.1 )
• Administer WAINUA into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection. ( 2.2 )
• The prefilled syringe must be administered by a healthcare provider. ( 2.4 )

2.1 Recommended Dosage The recommended dosage of WAINUA is 45 mg administered by subcutaneous injection once monthly [see Dosage and Administration (2.2) ] . Missed Dose Administer WAINUA as soon as possible after a missed dose. Resume dosing at monthly intervals from the date of the most recently administered dose.

2.2 General Administration Instructions Each autoinjector and prefilled syringe contains a single dose of WAINUA. Prior to administration of the autoinjector or prefilled syringe:

• Do not use if WAINUA has been dropped or damaged, appears to be tampered with, or if the expiration date has passed.
• Remove WAINUA from the refrigerator 30 minutes prior to the injection to reach room temperature. Do not use other warming methods.
• Visually inspect WAINUA before use. The solution should appear colorless to yellow. Do not use if cloudiness, particulate matter, or discoloration is observed. To deliver a 45 mg dose of WAINUA, administer the entire contents of one autoinjector or prefilled syringe [see Dosage and Administration (2.3) , (2.4) ] , as a subcutaneous injection in the upper thigh or the abdomen. The back of the upper arm can also be used as an injection site if a healthcare provider or caregiver administers the injection. Do not inject WAINUA into the area 2 inches (5 cm) around the navel or into areas where the skin is red, warm, tender, bruised, scaly or hard. Rotate the injection site with each injection .

2.3 Administration Instructions for WAINUA Autoinjector The autoinjector is intended for self-administration by patients or administration by caregivers. Prior to initiation, train patients and/or caregivers on proper preparation and administration of WAINUA autoinjector [see Instructions for Use ] .

2.4 Administration Instructions for WAINUA Prefilled Syringe (Healthcare Providers Only) The prefilled syringe must be administered by a healthcare provider. Refer to Figure 1 to identify the prefilled syringe components for use in the administration steps. Do not remove the needle cover until you are ready to inject WAINUA. Do not touch the needle guard activation clips to prevent premature activation of the needle safety guard. Figure 1: WAINUA Prefilled Syringe Components Administration Steps Step 1 Remove the prefilled syringe from its tray. Hold the syringe body and remove the needle cover by pulling straight off. Do not recap. If small air bubbles are present, do not expel them prior to administration. Step 2 Choose an injection site (i.e., back of upper arm, upper thigh, or abdomen). Gently pinch the skin and insert the needle subcutaneously at approximately a 45° angle into the chosen injection site. Step 3 Once the entire dose has been injected, the needle safety device will be triggered. As you let go of the plunger, the needle is automatically pulled from the skin, and into the device; the entire needle will be covered by the needle guard. Figure_1

Injection: 45 mg/0.8 mL of eplontersen as a clear, colorless-to-yellow solution available in a single dose autoinjector or a single-dose prefilled syringe. Injection:

• 45 mg/0.8 mL in a single-dose autoinjector. ( 3 )
• 45 mg/0.8 mL in a single-dose prefilled syringe. ( 3 )

None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation : Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ( 5.1 )

5.1 Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA treatment leads to a decrease in serum vitamin A levels [see Adverse Reactions (6.1) , Use in Specific Populations (8.1) , and Clinical Pharmacology (12.2) ] . Supplementation at the recommended daily allowance of vitamin A is advised for patients taking WAINUA. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with WAINUA, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes).

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

• Reduced Serum Vitamin A Levels and Recommended Supplementation [see Warnings and Precautions (5.1) ]. Most common adverse reactions (that occurred in at least 9% of patients treated with WAINUA) were vitamin A decreased and vomiting. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 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 WAINUA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In Study 1 [see Clinical Studies (14) ] , a total of 144 patients with polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) were randomized to WAINUA and received at least one dose of WAINUA. Of these, 141 patients received at least 6 months of treatment and 107 patients received at least 12 months of treatment. The mean duration of treatment was 15 months (range: 1.9 to 19.4 months). The median patient age at baseline was 52 years and 69% of the patients were male. Seventy-eight percent of patients treated with WAINUA were White, 15% were Asian, 4% were Black, 2% were reported as other races, and <1% were multiple races. Fifty-nine percent of patients had the Val30Met variant in the transthyretin gene; the remaining patients had one of 19 other variants. At baseline, 80% of patients were in Stage 1 of the disease and 20% were in Stage 2 with a mean duration from polyneuropathy diagnosis of 47 months. The mean duration from onset of polyneuropathy symptoms was 68 months. Table 1 lists the adverse reactions that occurred in at least 5% of patients treated with WAINUA in Study 1. Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with WAINUA (Study 1) Adverse Reaction WAINUA N=144 % Vitamin A decreased Vitamin A decreased includes vitamin A deficiency and vitamin A decrease. 15 Vomiting 9 Proteinuria 8 Injection site reactions Injection site reactions includes erythema, pain, and pruritus. 7 Blurred vision 6 Cataract 6 Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in WAINUA-treated patients, including 1 case of complete AV block. Laboratory Tests Vitamin A Decrease In Study 1, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1) ] . All patients treated with WAINUA had normal vitamin A levels at baseline, 95% of patients developed low vitamin A levels during the study. In some cases, the decreased vitamin A level was reported as an adverse reaction.

8.1 Pregnancy Risk Summary There are no available data on WAINUA use in pregnant women to inform drug-associated risk of adverse developmental outcomes. WAINUA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking WAINUA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by WAINUA administration is unknown [see Clinical Pharmacology (12.2) and Warnings and Precautions (5.1) ] . No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis [see Animal Data ] . 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and administration continued every other day in females throughout the period of organogenesis resulted in no adverse effects on embryofetal development.

8.2 Lactation Risk Summary There is no information regarding the presence of eplontersen in human milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WAINUA and any potential adverse effects on the breast-fed infant from WAINUA or from the underlying maternal condition.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use No dose adjustment is required in patients ≥65 years of age [see Clinical Pharmacology (12.3) ] . In Study 1 [see Clinical Studies (14) ] , 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Renal Impairment No dose adjustment is necessary in patients with mild to moderate renal impairment (estimated glomerular filtration rate [eGFR] ≥30 to <90 mL/min/1.73 m 2 ) [see Clinical Pharmacology (12.3) ] . WAINUA has not been studied in patients with severe renal impairment or end-stage renal disease.

8.7 Hepatic Impairment No dose adjustment is necessary in patients with mild hepatic impairment (total bilirubin ≤1 x ULN and AST >1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) [see Clinical Pharmacology (12.3) ] . WAINUA has not been studied in patients with moderate or severe hepatic impairment.

Risk Summary There are no available data on WAINUA use in pregnant women to inform drug-associated risk of adverse developmental outcomes. WAINUA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking WAINUA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effect of vitamin A supplementation on the fetus in the setting of a reduction in maternal serum TTR caused by WAINUA administration is unknown [see Clinical Pharmacology (12.2) and Warnings and Precautions (5.1) ] . No adverse developmental effects were observed when eplontersen or a mouse-specific surrogate was administered to mice prior to mating and continuing throughout organogenesis [see Animal Data ] . 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and administration continued every other day in females throughout the period of organogenesis resulted in no adverse effects on embryofetal development.

Safety and effectiveness in pediatric patients have not been established.

No dose adjustment is required in patients ≥65 years of age [see Clinical Pharmacology (12.3) ] . In Study 1 [see Clinical Studies (14) ] , 44 (31%) patients were 65 to 74 years of age, and 8 (5.6%) patients were ≥75 years of age. No overall differences in safety or effectiveness were observed between these patients and younger adult patients, but greater sensitivity of some older individuals cannot be ruled out.

Eplontersen is a transthyretin-directed antisense oligonucleotide (ASO), covalently linked to a ligand containing three N-acetyl galactosamine (GalNAc) residues to enable delivery of the ASO to hepatocytes. WAINUA contains eplontersen sodium as the active ingredient. Eplontersen sodium is a white to yellow solid and it is freely soluble in water and in phosphate buffer. The molecular formula of eplontersen sodium is C 296 H 417 N 77 O 156 P 20 S 13 Na 20 and the molecular weight is 9046.1 daltons. The chemical name of eplontersen sodium is DNA, d([2′-O-(2-methoxyethyl)]m5rU-sp-[2′-O-(2-methoxyethyl)]m5rC-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]rG-G-sp-T-sp-T-sp-A-sp-m5C-sp-A-sp-T-sp-G-sp-A-sp-A-sp-[2′-O-(2-methoxyethyl)]rA-[2′-O-(2-methoxyethyl)]m5rU-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC-sp-[2′-O-(2-methoxyethyl)]m5rC), 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 eplontersen sodium is presented below: WAINUA is a sterile, preservative-free, aqueous solution for subcutaneous injection supplied in a single dose autoinjector or single-dose prefilled syringe. Each dose contains 45 mg eplontersen (equivalent to 47 mg eplontersen sodium) in 0.8 mL of solution. The solution also contains 0.868 mg dibasic sodium phosphate, anhydrous (buffering agent); 0.238 mg monobasic sodium phosphate, dihydrate (buffering agent); 4.2 mg sodium chloride (tonicity modifier); water for injection; and may include hydrochloric acid and/or sodium hydroxide for pH adjustment between 6.9 - 7.9. Each dose of WAINUA injection contains less than 5 mg of sodium and less than 5 mg of phosphorus. Chemical_Structure

12.1 Mechanism of Action Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

12.2 Pharmacodynamics In Study 1 [see Clinical Studies (14) ] , following administration of the recommended WAINUA dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum TTR levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race. Eplontersen also reduced the mean steady state serum vitamin A by 71% by Week 37 [see Warnings and Precautions (5.1)]. Cardiac Electrophysiology At a dose 2.7-times the maximum recommended dose for WAINUA, clinically significant QTc interval prolongation was not observed.

12.3 Pharmacokinetics The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis. Eplontersen C max and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1- to 2.7-times the recommended dose) in healthy volunteers. Population estimates (mean ± SD) of steady state maximum concentrations (C max ), and area under the curve (AUC τ ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen C max and AUC was observed in repeated dosing (once every 4 weeks). Absorption Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates. Distribution Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. Eplontersen is bound to human plasma proteins (>98%) in vitro . The population estimate for the apparent central volume of distribution is 12 L and the apparent peripheral volume of distribution is 11,100 L. Elimination The terminal elimination half-life is approximately 3 weeks. Metabolism Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. Excretion The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose within 24 hours. Specific Populations Population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on age, body weight, sex, race, Val30Met variant status, mild and moderate renal impairment (eGFR≥30 to <90 mL/min/1.73m 2 ), or mild hepatic impairment (total bilirubin ≤1 x ULN and AST > 1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST). Eplontersen has not been studied in patients with severe renal impairment, end-stage renal disease, or in patients with moderate to severe hepatic impairment, or in patients with prior liver transplant. Drug Interaction Studies No clinical drug-drug interaction studies have been performed with eplontersen. In vitro studies show that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of cytochrome P450 (CYP) enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes.

12.6 Immunogenicity 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 eplontersen. In Study 1, with duration of treatment up to 85 weeks (mean treatment duration of 445 days (63.2 weeks), range: 57 to 582 days), 53 out of 144 (37%) patients developed treatment-emergent ADAs during treatment with WAINUA. The presence of ADAs did not affect eplontersen plasma C max or AUC, but increased C trough . Although anti-drug antibody development was not found to affect the pharmacokinetics, pharmacodynamics, safety, or efficacy of WAINUA in these patients, the available data are too limited to make definitive conclusions.

Eplontersen is an antisense oligonucleotide-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

In Study 1 [see Clinical Studies (14) ] , following administration of the recommended WAINUA dosage every 4 weeks to patients with hATTR amyloidosis, a decrease in serum TTR levels was observed at the first assessment and the (least square) mean serum TTR at Week 35 was reduced by 81% from baseline. Similar TTR reductions were observed across subgroups including Val30Met variant status, body weight, sex, age, or race. Eplontersen also reduced the mean steady state serum vitamin A by 71% by Week 37 [see Warnings and Precautions (5.1)]. Cardiac Electrophysiology At a dose 2.7-times the maximum recommended dose for WAINUA, clinically significant QTc interval prolongation was not observed.

The pharmacokinetic (PK) properties of WAINUA were evaluated following subcutaneous administration of single and multiple doses (once every 4 weeks) in healthy subjects and multiple doses (once every 4 weeks) in patients with hATTR amyloidosis. Eplontersen C max and AUC showed a slightly greater than dose-proportional increase following single subcutaneous doses ranging from 45 to 120 mg (i.e., 1- to 2.7-times the recommended dose) in healthy volunteers. Population estimates (mean ± SD) of steady state maximum concentrations (C max ), and area under the curve (AUC τ ) were 283 ± 152 ng/mL, and 2190 ± 689 ng/mL, respectively, following 45 mg monthly dosing in patients with hATTR amyloidosis. No accumulation of eplontersen C max and AUC was observed in repeated dosing (once every 4 weeks). Absorption Following subcutaneous administration, eplontersen is absorbed with the time to maximum plasma concentrations of approximately 2 hours, based on population estimates. Distribution Eplontersen is expected to distribute primarily to the liver and kidney cortex after subcutaneous dosing. Eplontersen is bound to human plasma proteins (>98%) in vitro . The population estimate for the apparent central volume of distribution is 12 L and the apparent peripheral volume of distribution is 11,100 L. Elimination The terminal elimination half-life is approximately 3 weeks. Metabolism Eplontersen is metabolized by endo- and exonucleases to short oligonucleotide fragments of varying sizes within the liver. Excretion The mean fraction of unchanged ASO eliminated in urine was less than 1% of the administered dose within 24 hours. Specific Populations Population pharmacokinetic and pharmacodynamic analysis showed no clinically meaningful differences in the pharmacokinetics or pharmacodynamics of eplontersen based on age, body weight, sex, race, Val30Met variant status, mild and moderate renal impairment (eGFR≥30 to <90 mL/min/1.73m 2 ), or mild hepatic impairment (total bilirubin ≤1 x ULN and AST > 1 x ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST). Eplontersen has not been studied in patients with severe renal impairment, end-stage renal disease, or in patients with moderate to severe hepatic impairment, or in patients with prior liver transplant. Drug Interaction Studies No clinical drug-drug interaction studies have been performed with eplontersen. In vitro studies show that eplontersen is not a substrate or inhibitor of transporters, does not interact with highly plasma protein bound drugs, and is not an inhibitor or inducer of cytochrome P450 (CYP) enzymes. Oligonucleotide therapeutics, including eplontersen, are not typically substrates of CYP enzymes. Therefore, eplontersen is not expected to cause or be affected by drug-drug interactions mediated through drug transporters, plasma protein binding or CYP enzymes.

, Mutagenesis, Impairment of Fertility Carcinogenesis In a 26-week carcinogenicity study in male and female Tg.rasH2 mice, subcutaneous administration of eplontersen (0, 250, 500, or 1500 mg/kg) monthly for 26 weeks resulted in no increase in neoplasms. Mutagenesis Eplontersen was negative for genotoxicity in in vitro (bacterial reverse mutation, chromosomal aberration in Chinese hamster lung cells) and in vivo (mouse bone marrow micronucleus) assays. Impairment of Fertility Subcutaneous administration of eplontersen (0, 5, 25, or 75 mg/kg) or a mouse-specific surrogate (25 mg/kg) to male and female mice weekly prior to and during mating and continuing in females throughout the period of organogenesis resulted in no adverse effects on fertility.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Recommended Vitamin A Supplementation Inform patients that WAINUA treatment leads to a decrease in vitamin A levels measured in the serum. Instruct patients to take the recommended daily allowance of vitamin A. Advise patients to contact their healthcare provider if they experience ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes) and refer them to an ophthalmologist if they develop these symptoms [see Warnings and Precautions (5.1) ] . Pregnancy Instruct patients that if they are pregnant or plan to become pregnant while taking WAINUA they should inform their healthcare provider. Advise patients of the potential risk to the fetus, including that WAINUA treatment leads to a decrease in serum vitamin A levels [see Use in Special Populations (8.1) ] . Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 ©AstraZeneca 2026