AMVUTTRA VUTRISIRAN 25 mg/.5mL Injection, 1 syringe — NDC 71336-1003-1 (Billing 71336-1003-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action 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.

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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

5.7L/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 t… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action 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.

12.3Pharmacokinetics 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

5.7L/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.

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES

14.1Polyneuropathy of Hereditary Transthyretin-mediated Amyloidosis The efficacy of AMVUTTRA was evaluated in a randomized, open-label clinical trial in adult patients with hATTR-PN (HELIOS-A; NCT03759379). Patients were randomized 3:1 to receive 25 mg of AMVUTTRA subcutaneously once every 3 months (N=122), or 0.3 mg/kg patisiran intravenously every 3 weeks (N=42) as a reference group. Ninety-seven percent of AMVUTTRA-treated patients and 93% of patisiran-treated patients completed at least 9 months of the assigned treatment.

Efficacy assessments were based on a comparison of the AMVUTTRA arm of HELIOS-A with an external placebo group in another study (NCT01960348) composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis. The primary efficacy endpoint was the change from baseline to Month 9 in modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 composite scores.

In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The mNIS+7 has a total score range from 0 to 304 points, with higher scores representing a greater severity of disease. The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 9 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score.

The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The Norfolk QoL-DN has a total score range from -4 to 136, with higher scores representing greater impairment. Additional endpoints were gait speed, as measured by the 10-meter walk test (10MWT), and modified body mass index (mBMI).

Treatment with AMVUTTRA in HELIOS-A resulted in statistically significant improvements in the mNIS+7, Norfolk QoL-DN total score, and 10-meter walk test at Month 9 compared to placebo in the external study ( p <0.001) [Table 3, Figure 1, and Figure 3]. The distributions of changes in mNIS+7 and Norfolk QoL-DN total scores from baseline to Month 9 by percent of patients are shown in Figure 2 and Figure 4, respectively. The change from baseline to Month 9 in modified body mass index nominally favored AMVUTTRA [Table 3].

Table 3: Clinical Efficacy Results (Comparison of AMVUTTRA Treatment in HELIOS-A to an External Placebo Control External placebo group from another randomized controlled trial (NCT01960348) ) Endpoint All endpoints analyzed using the analysis of covariance (ANCOVA) with multiple imputation (MI) method) Baseline, Mean (SD) Change from Baseline to Month 9, LS Mean (SEM) AMVUTTRA-Placebo Treatment Difference, LS Mean (95% CI) p -value AMVUTTRA N=122 (HELIOS-A) Placebo N=77 (NCT01960348) AMVUTTRA (HELIOS-A) Placebo (NCT01960348) CI = confidence interval; LS mean = least squares mean; mBMI = modified body mass index; mNIS = modified Neuropathy Impairment Score; QoL-DN = Quality of Life-Diabetic Neuropathy; SD = standard deviation; SEM = standard error of the mean mNIS+7 A lower number indicates less impairment/fewer symptoms 60.6 (36.0) 74.6 (37.0) -2.2 (1.4) 14.8 (2.0) -17.0 (-21.8, -12.2) p <0.001 Norfolk QoL-DN 47.1 (26.3) 55.5 (24.3) -3.3 (1.7) 12.9 (2.2) -16.2 (-21.7, -10.8) p <0.001 10-meter walk test (m/sec) A higher number indicates less disability/less impairment 1.01 (0.39) 0.79 (0.32) 0 (0.02) -0.13 (0.03) 0.13 (0.07, 0.19) p <0.001 mBMI mBMI: nominal p -value; body mass index (BMI; kg/m 2 ) multiplied by serum albumin (g/L).

1058 (234) 990 (214) 7.6 (7.9) -60.2 (10.1) 67.8 (43.0, 92.6) p <0.001 A decrease in mNIS+7 indicates improvement Δ indicates between-gro… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.