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.

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)].

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

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.

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).

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)].

8.1 Pregnancy

8.2 Lactation

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 m2) [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.

12.1 Mechanism 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.

12.2 Pharmacodynamics

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.

12.3 Pharmacokinetics

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.

12.6 Immunogenicity

The observed incidence of anti-drug antibody (ADA, including neutralizing antibody) is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of ADA in the studies described below with the incidence of ADA in the other studies, including those of AMVUTTRA or of other siRNA products.

In HELIOS-A and HELIOS-B studies, 3 (2.5%) and 1 (0.3%) patient treated with AMVUTTRA, respectively, developed transient, low titer anti-drug antibodies. The available data are limited to make definitive conclusions regarding the effect of anti-drug antibodies on pharmacokinetics or pharmacodynamics of AMVUTTRA.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Polyneuropathy 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].

A decrease in mNIS+7 indicates improvement Δ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for AMVUTTRA – placebo

* External placebo group from another randomized controlled trial (NCT01960348)

Figure 1: Change from Baseline in mNIS+7 (Comparison of AMVUTTRA Treatment in HELIOS-A to an External Placebo Control*)

Categories are mutually exclusive; patients who died before 9 months are summarized in the "Death" category only

* External placebo group from another randomized controlled trial (NCT01960348)

Figure 2: Histogram of mNIS+7 Change from Baseline at Month 9 (Comparison of AMVUTTRA Treatment in HELIOS-A to an External Placebo Control*)

A decrease in Norfolk QoL-DN score indicates improvement Δ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for AMVUTTRA – placebo

* External placebo group from another randomized controlled trial (NCT01960348)

Figure 3: Change from Baseline in Norfolk QoL-DN Total Score (Comparison of AMVUTTRA Treatment in HELIOS-A to an External Placebo Control*)

Categories are mutually exclusive; patients who died before 9 months are summarized in the "Death" category only

* External placebo group from another randomized controlled trial (NCT01960348)

Figure 4: Histogram of Norfolk QoL-DN Total Score Change from Baseline at Month 9 (Comparison of AMVUTTRA Treatment in HELIOS-A to an External Placebo Control*)

Patients receiving AMVUTTRA in HELIOS-A experienced similar improvements relative to those in the external placebo group in mNIS+7 and Norfolk QoL-DN total score across all subgroups including age, sex, race, region, NIS score, Val30Met genotype status, and disease stage.

14.2 Cardiomyopathy of Wild-type or Hereditary Transthyretin-mediated Amyloidosis

The efficacy of AMVUTTRA was evaluated in a multicenter, international, randomized, double-blind, placebo-controlled trial (HELIOS-B, NCT04153149) in 654 adult patients with wild-type or hereditary ATTR-CM. Patients were randomized 1:1 to receive 25 mg of AMVUTTRA (n=326) subcutaneously once every 3 months, or matching placebo (n=328).

Treatment assignment was stratified by baseline tafamidis use (yes versus no), ATTR disease type (wtATTR or hATTR amyloidosis), and by baseline New York Heart Association (NYHA) Class I or II and age <75 years versus all other. At baseline, 40% of patients were on tafamidis. The mean age of study participants was 75 years, 93% were male, 84% were White, 7% were Black or African American, 6% were Asian, 2% did not report race and 1% were race other, 88% had wild-type ATTR, 13% were NYHA Class I, 78% were NYHA Class II, and 9% NYHA Class III. No significant imbalance in baseline characteristics was observed between the two treatment groups.

Participants were permitted to initiate open-label tafamidis during the study. A total of 85 participants initiated tafamidis: 44 (22%) in the AMVUTTRA arm and 41 (21%) in the placebo arm. The median time to initiation of tafamidis for these 85 participants was 18 months.

The primary efficacy endpoint was the composite outcome of all-cause mortality and recurrent CV events (CV hospitalizations and urgent heart failure [UHF] visits) during the double-blind treatment period of up to 36 months, evaluated in the overall population and in the monotherapy population (defined as patients not receiving tafamidis at study baseline).

AMVUTTRA led to significant reduction in the risk of all-cause mortality and recurrent CV events compared to placebo in the overall and monotherapy population of 28% and 33%, respectively (Table 4). The majority of the deaths (77%) were CV-related. A Kaplan-Meier curve illustrating time to first CV event or all-cause mortality is presented in Figure 5.

Both components of the primary composite endpoint individually contributed to the treatment effect in the overall and monotherapy population (Table 4).

Figure 5: Time to All-Cause Mortality or First CV Event (Overall population)

Abbreviations: CI=confidence interval; CV=cardiovascular; HR = hazard ratio. Heart transplantation and left ventricular assist device placement are treated as death. HR and 95% CI are based on a Cox proportional hazard model. First CV event = First CV hospitalization or urgent heart failure visit after randomization.

Results from the subgroup analysis for the primary composite endpoint were consistent across prespecified subgroups in the overall population (Figure 6) and monotherapy population.

Figure 6: Subgroup Analyses of the Primary Composite Endpoint (Overall Population)

Abbreviations: ATTR = transthyretin amyloidosis; CI = confidence interval; hATTR = hereditary transthyretin amyloidosis; HR = hazard ratio; NT-pro-BNP = N-terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart Association; wtATTR = wild-type transthyretin amyloidosis. HR and 95% CI are based on modified Andersen-Gill model analyses.

The treatment effect of AMVUTTRA on functional capacity and health status were assessed by the change from baseline to Month 30 in distance walked on 6-Minute Walk Test (6-MWT), and the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, respectively.

At Month 30, the LS mean difference in change from baseline in distance walked on 6-MWT was 22 (95% CI: 8, 35; p=0.002) meters and 25 (95% CI: 7, 44; p=0.006) meters favoring AMVUTTRA over placebo in the overall population and monotherapy population, respectively.

At Month 30, the LS mean difference in the change from baseline in KCCQ-OS was 6 (95% CI: 2, 9; p=0.001) and 8 (95% CI: 4, 13; p=0.0003) favoring AMVUTTRA over placebo in the overall population and monotherapy population respectively.

16.1 How Supplied

AMVUTTRA is a sterile, preservative-free, clear, colorless-to-yellow solution for subcutaneous injection. AMVUTTRA is supplied as 25 mg/0.5 mL solution in a single-dose 1-mL prefilled syringe made from Type I glass with stainless steel 29-gauge needle with a needle shield. The prefilled syringe components are not made with natural rubber latex.

AMVUTTRA is available in cartons containing one single-dose prefilled syringe each.

The NDC is: 71336-1003-1.

16.2 Storage and Handling

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

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)].