Vutrisiran

AMVUTTRA is a transthyretin-directed small interfering RNA indicated for the treatment of: the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults ( 1.1 ) the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits ( 1.2 )

1.1 Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis AMVUTTRA is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults.

1.2 Cardiomyopathy of Wild-type or Hereditary Transthyretin-mediated Amyloidosis AMVUTTRA is indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.

The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months. ( 2.1 ) AMVUTTRA is for subcutaneous use only and should be administered by a healthcare professional. ( 2.2 )

2.1 Recommended Dosage The recommended dosage of AMVUTTRA is 25 mg administered by subcutaneous injection once every 3 months [see Dosage and Administration (2.2) ] . Missed Dose If a dose is missed, administer AMVUTTRA as soon as possible. Resume dosing every 3 months from the most recently administered dose.

2.2 Administration Instructions AMVUTTRA is for subcutaneous use only and should be administered by a healthcare professional. Syringe Appearance Before and After Use Before Use After Use Image Image Preparation and Administration 1. Prepare the syringe If stored cold, allow the syringe to warm to room temperature for 30 minutes prior to use. Remove the syringe from the packaging by gripping the syringe body. Do not touch the plunger rod until ready to inject. Visually inspect the drug solution for discoloration and particulate matter prior to administration. AMVUTTRA is a sterile, preservative-free, clear, colorless-to-yellow solution. Do not use if it contains particulate matter or if it is cloudy or discolored. Check the following: Syringe is not damaged, such as cracked or leaking Needle cap is attached to the syringe Expiration date on syringe label Do not use the syringe if any issues are found while checking the syringe. 2. Choose and prepare the injection site Choose an injection site from the following areas: the abdomen, thighs, or upper arms. Avoid the following: 5-cm area around the navel Scar tissue or areas that are reddened, inflamed, or swollen Clean the chosen injection site. 3. Prepare the syringe for injection Hold the syringe body with one hand. Pull the needle cap straight off with other hand and dispose of needle cap immediately. It is normal to see a drop of liquid at the tip of the needle. Do not touch the needle or let it touch any surface. Do not recap the syringe. Do not use the syringe if it is dropped. 4. Perform the injection Pinch the cleaned skin. Fully insert the needle into the pinched skin at a 45°-90° angle. Inject all of the medication. Push the plunger rod as far as it will go to administer the dose and activate the needle shield. Release the plunger rod to allow the needle shield to cover the needle. Do not block plunger rod movement. 5. Dispose of the syringe Immediately dispose of the used syringe into a sharps container. Image Image Image Image Image

Injection: 25 mg/0.5 mL of vutrisiran as a clear, colorless-to-yellow solution in a single-dose prefilled syringe. Injection: 25 mg/0.5 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 AMVUTTRA treatment leads to a decrease in serum vitamin A levels [see Adverse Reactions (6.1) and Clinical Pharmacology (12.2) ] . Supplementation at the recommended daily allowance of vitamin A is advised for patients taking AMVUTTRA. 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 AMVUTTRA, 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).

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) ] The most common adverse reactions (≥5%) were pain in extremity, arthralgia, dyspnea, and vitamin A decreased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Alnylam Pharmaceuticals at 1-877-256-9526 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 AMVUTTRA cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two Phase 3 randomized, multi-center studies evaluated the safety of AMVUTTRA in 448 transthyretin-mediated amyloidosis (ATTR) patients, including 122 patients with hATTR-PN (HELIOS-A) and 326 patients with ATTR-CM (HELIOS-B) [see Clinical Studies (14) ] . In both studies, patients were instructed to take the recommended daily allowance of vitamin A [see Warnings and Precautions (5.1) ] . Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis In HELIOS-A, 118 patients received at least 18 months of treatment. The mean duration of treatment was 18.8 months (range: 1.7 to 19.4 months). The median patient age at baseline was 60 years and 65% of the patients were male. Seventy percent of AMVUTTRA-treated patients were Caucasian, 17% were Asian, 3% were Black, and 9% were reported as Other. Forty-four percent of patients had the Val30Met mutation in the transthyretin gene; the remaining patients had one of 21 other mutations. At baseline, 70% of patients were in Stage 1 of the disease and 30% were in Stage 2. The most common adverse reactions (at least 5%) were pain in extremity, arthralgia, dyspnea, and vitamin A decreased (see Table 1 ) . Seventy-four percent of patients treated with AMVUTTRA had normal vitamin A levels at baseline, and 98% of those with a normal baseline developed low vitamin A levels. In some cases, the decreased vitamin A level was reported as an adverse reaction (see Table 1 ) . Table 1: Adverse Reactions Reported in at least 5% of Patients Treated with AMVUTTRA in HELIOS-A Adverse Reaction AMVUTTRA N=122 % Pain in extremity 15 Arthralgia Comprised of several similar terms 11 Dyspnea 7 Vitamin A decreased Percentage only reflects those reported as an adverse reaction 7 In HELIOS-A, two serious adverse reactions of atrioventricular (AV) heart block (1.6%) occurred in patients treated with AMVUTTRA, including one case of complete AV block. Injection site reactions were reported in 5 (4%) patients treated with AMVUTTRA. Reported symptoms included bruising, erythema, pain, pruritus, and warmth. Injection site reactions were mild and transient. Cardiomyopathy of Wild-type or Hereditary Transthyretin-mediated Amyloidosis In HELIOS-B, safety was evaluated in 654 patients with ATTR-CM, which included 257 patients treated with AMVUTTRA for ≥30 months, and 77 patients treated with AMVUTTRA for ≥36 months [see Clinical Studies (14) ] . No new safety issues were identified. Eighty-two percent of patients treated with AMVUTTRA had normal vitamin A levels at baseline, and 80% of those with a normal baseline developed low vitamin A levels.

8.1 Pregnancy Risk Summary There are no available data on AMVUTTRA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. AMVUTTRA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking AMVUTTRA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by AMVUTTRA and of vitamin A supplementation are unknown [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . In animal studies, subcutaneous administration of vutrisiran to pregnant rats resulted in developmental toxicity (reduced fetal body weight and embryofetal mortality) at doses associated with maternal toxicity (see Data ) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal mortality at the high dose and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity. Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits resulted in no adverse effects on embryofetal development. Subcutaneous administration of vutrisiran (0, 5, 10, or 20 mg/kg) to pregnant rats every 6 days throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring.

8.2 Lactation Risk Summary There is no information regarding the presence of vutrisiran in human milk, the effects on the breastfed 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 AMVUTTRA and any potential adverse effects on the breastfed infant from AMVUTTRA 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 HELIOS-A, a total of 46 (38%) patients ≥65 years of age, including 7 (6%) patients ≥75 years of age, received AMVUTTRA In HELIOS-B, a total of 299 (92%) patients ≥65 years old, including 203 (62%) ≥75 years old, received AMVUTTRA. No overall differences in safety or effectiveness were observed between these patients and younger patients.

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

8.7 Hepatic Impairment No dose adjustment is recommended in patients with mild (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST) or moderate (total bilirubin >1.5 to 3 × ULN and any AST) hepatic impairment [see Clinical Pharmacology (12.3) ] . AMVUTTRA has not been studied in patients with severe hepatic impairment.

Risk Summary There are no available data on AMVUTTRA use in pregnant women to inform a drug-associated risk of adverse developmental outcomes. AMVUTTRA treatment leads to a decrease in serum vitamin A levels, and vitamin A supplementation is advised for patients taking AMVUTTRA. Vitamin A is essential for normal embryofetal development; however, excessive levels of vitamin A are associated with adverse developmental effects. The effects on the fetus of a reduction in maternal serum TTR caused by AMVUTTRA and of vitamin A supplementation are unknown [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] . In animal studies, subcutaneous administration of vutrisiran to pregnant rats resulted in developmental toxicity (reduced fetal body weight and embryofetal mortality) at doses associated with maternal toxicity (see Data ) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rats during the period of organogenesis resulted in embryofetal mortality at the high dose and reduced fetal body weight at the mid and high doses, which were associated with maternal toxicity. Subcutaneous administration of vutrisiran (0, 3, 10, or 30 mg/kg/day) to pregnant rabbits resulted in no adverse effects on embryofetal development. Subcutaneous administration of vutrisiran (0, 5, 10, or 20 mg/kg) to pregnant rats every 6 days throughout pregnancy and lactation resulted in no adverse developmental effects on the offspring.

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 HELIOS-A, a total of 46 (38%) patients ≥65 years of age, including 7 (6%) patients ≥75 years of age, received AMVUTTRA In HELIOS-B, a total of 299 (92%) patients ≥65 years old, including 203 (62%) ≥75 years old, received AMVUTTRA. No overall differences in safety or effectiveness were observed between these patients and younger patients.

AMVUTTRA contains vutrisiran, a chemically modified double-stranded small interfering ribonucleic acid (siRNA) that targets mutant and wild-type transthyretin (TTR) messenger RNA (mRNA) and is covalently linked to a ligand containing three N -acetylgalactosamine (GalNAc) residues to enable delivery of the siRNA to hepatocytes. The structural formula of vutrisiran sodium is presented below. Dashed lines denote Watson-Crick base pairing The molecular formula of vutrisiran sodium is C 530 H 672 F 9 N 171 Na 43 O 323 P 43 S 6 with a molecular weight of 17,290 Da. The molecular formula of the free acid is C 530 H 715 F 9 N 171 O 323 P 43 S 6 with a molecular weight of 16,345 Da. AMVUTTRA is supplied as a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous injection. Each 0.5 mL of solution contains 25 mg of vutrisiran (equivalent to 26.5 mg vutrisiran sodium), 0.2 mg sodium phosphate monobasic dihydrate, 0.7 mg sodium phosphate dibasic dihydrate, 3.2 mg sodium chloride, water for injection, and sodium hydroxide and/or phosphoric acid to adjust the pH to ~7. Chemical Structure Chemical Structure

Vutrisiran is a double-stranded siRNA-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

The pharmacodynamic effects of AMVUTTRA were evaluated in patients with hATTR-PN and ATTR-CM, treated with 25 mg AMVUTTRA administered by subcutaneous injection once every 3 months. Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis In HELIOS-A [see Clinical Studies (14) ] , vutrisiran reduced mean serum TTR at steady state by 83%. Similar TTR reductions were observed regardless of Val30Met genotype status, weight, sex, age, or race. Vutrisiran also reduced the mean steady state serum vitamin A by 62% over 9 months [see Warnings and Precautions (5.1) ] . Cardiomyopathy of Wild-type (wt) or Hereditary Transthyretin-mediated Amyloidosis (hATTR) In HELIOS-B, the mean serum TTR reduction profile was similar with that observed in HELIOS-A, and consistent across the subgroups studied (age, sex, race, body weight, anti-drug antibody [ADA] status, ATTR disease type (wtATTR versus hATTR), NYHA class, and baseline tafamidis use). Vutrisiran reduced the mean steady state serum vitamin A by 65% over 36 months. [see Warnings and Precautions (5.1) ] . Cardiac Biomarkers Biomarkers associated with heart failure (NT-proBNP and Troponin I) favored AMVUTTRA over placebo. Cardiac Electrophysiology At a dose 12 times the recommended dosage of 25 mg once every three months, AMVUTTRA does not prolong the QT interval to any clinically relevant extent.

The pharmacokinetic (PK) properties of AMVUTTRA were evaluated following a single dose in healthy subjects and multiple doses in patients with hATTR amyloidosis, as summarized in Table 2. Table 2: Pharmacokinetic Parameters of Vutrisiran Vutrisiran AUC inf = area under the concentration-time curve from the time of dosing extrapolated to infinity; AUC last = area under the concentration-time curve from the time of dosing to the last measurable concentration; C max = maximum plasma concentration; CV = coefficient of variation; RSE = relative standard error; T max = time to maximum concentration; Vd/F = apparent volume of distribution General Information Dose Proportionality Vutrisiran C max showed dose proportional increase while AUC last and AUC inf were slightly more than dose proportional following single subcutaneous doses ranging from 5 to 300 mg (i.e., 0.2 to 12 times the recommended dose) Accumulation No accumulation of vutrisiran was observed in plasma after repeated every 3 months dosage After 25 mg every 3 months dosage in hATTR amyloidosis patients Absorption T max [Median (Range)] 4 (0.17, 12.0) hours After 25 mg single dose in healthy subjects Distribution Estimated Vd/F (%RSE) 10.1 (5.8) L Based on population PK model estimation Protein Binding 80% Vutrisiran plasma protein binding was concentration-dependent and decreased with increasing vutrisiran concentrations (from 78% at 0.5 mcg/mL to 19% at 50 mcg/mL) Organ Distribution Vutrisiran distributes primarily to the liver after subcutaneous dosing Elimination Half-Life [Median (Range)] 5.2 (2.2, 6.4) hours Apparent Clearance [Median (Range)] 21.4 (19.8, 30) L/hour Metabolism Primary Pathway Vutrisiran is metabolized by endo- and exonucleases to short nucleotide fragments of varying sizes within the liver Excretion Primary Pathway The mean fraction of unchanged vutrisiran eliminated in urine was approximately 19.4% at the recommended dose of 25 mg. The mean renal clearance of vutrisiran ranged from 4.5 to 5.7 L/hour After single subcutaneous vutrisiran dose from 5 to 300 mg (i.e., 0.2 to 12 times the recommended dose) in healthy subjects Specific Populations No clinically significant differences in the pharmacokinetics of vutrisiran were observed based on age, sex, race, mild and moderate renal impairment (eGFR≥30 to <90 mL/min/1.73 m 2 ), or mild (total bilirubin ≤1 × ULN and AST >1 × ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST) and moderate (total bilirubin >1.5 to 3 × ULN and any AST) hepatic impairment. Vutrisiran has not been studied in patients with severe renal impairment, end-stage renal disease, severe hepatic impairment, or in patients with prior liver transplant. Drug Interaction Studies No clinical drug-drug interaction studies have been performed with vutrisiran. In vitro studies suggest that vutrisiran is not a substrate or inhibitor of cytochrome P450 enzymes. Vutrisiran is not expected to cause drug-drug interactions by inducing CYP enzymes or modulating the activities of drug transporters.

, Mutagenesis, Impairment of Fertility Carcinogenesis Subcutaneous administration of vutrisiran to male mice (0, 2, 6, or 13 mg/kg once every 4 weeks) for 100 weeks and to female mice (0, 3, 9, or 18 mg/kg once every 4 weeks) for 98 weeks resulted in no increase in tumors. Subcutaneous administration of vutrisiran to male rats (0, 4, 7.5, or 15 mg/kg once every 4 weeks or 15 mg/kg once every 12 weeks) for 99 weeks and to female rats (0, 6, 12.5, or 25 mg/kg once every 4 weeks or 25 mg/kg once every 12 weeks) for 86-87 weeks resulted in no increase in tumors. Mutagenesis Vutrisiran was negative for mutagenicity in in vitro (bacterial mutagenicity, chromosomal aberration in human blood peripheral lymphocytes) and in vivo (rat bone marrow micronucleus) assays. Impairment of Fertility Subcutaneous administration of vutrisiran (0, 15, 30, or 70 mg/kg/week) to male and female rats prior to and during mating and continuing in females to gestation day 6 resulted in no adverse effects on fertility or reproductive performance.

17 PATIENT COUNSELING INFORMATION Recommended Vitamin A Supplementation Inform patients that AMVUTTRA treatment leads to a decrease in serum vitamin A levels. 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) 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 AMVUTTRA they should inform their healthcare provider. Inform patients of the potential risk to the fetus, including that AMVUTTRA treatment leads to a decrease in serum vitamin A levels [see Use in Specific Populations (8.1) and Clinical Pharmacology (12.2) ] .

Store at 2°C to 30°C (36°F to 86°F) in the original carton, until ready for use. Do not freeze.