Leaflet AMVUTTRA 25mg 50mg / ml solution for injection in pre-filled syringe

Amvuttra 25 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains vutrisiran sodium equivalent to 25 mg vutrisiran in 0.5 mL solution.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless-to-yellow solution (pH of approximately 7; osmolality 210 to 390 mOsm/kg).

Amvuttra is indicated for the treatment of hereditary transthyretin amyloidosis in adult patients withstage 1 or stage 2 polyneuropathy (hATTR-PN).

Amvuttra is indicated for the treatment of wild-type or hereditary transthyretin amyloidosis in adultpatients with cardiomyopathy (ATTR-CM).

Therapy should be initiated under the supervision of a physician knowledgeable in the management ofamyloidosis. Treatment should be started as early as possible in the disease course to prevent theaccumulation of disability.

The recommended dose of Amvuttra is 25 mg administered via subcutaneous injection once every3 months.

Vitamin A supplementation at approximately, but not exceeding, 2 500 IU to 3 000 IU vitamin A perday is advised for patients treated with Amvuttra (see section 4.4).

The decision to continue treatment in those patients whose disease progresses to stage 3polyneuropathy should be taken at the discretion of the physician based on the overall benefit and riskassessment.

There is limited data with vutrisiran in patients with New York Heart Association (NYHA) Class IVand in patients who have both NYHA Class III and National Amyloidosis Centre (NAC) stage III.

However, if patients on vutrisiran progress to these stages, these data suggest that patients can remainon treatment.

If a dose is missed, Amvuttra should be administered as soon as possible. Dosing should be resumedevery 3 months, from the most recently administered dose.

No dose adjustment is required in patients ≥ 65 years of age (see section 5.2).

No dose adjustment is necessary in patients with mild (total bilirubin ≤ 1 x upper limit of normal(ULN) and aspartate aminotransferase (AST) > 1 x ULN, or total bilirubin > 1.0 to 1.5 x ULN and any

AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any AST) hepatic impairment. Vutrisiran hasnot been studied in patients with severe hepatic impairment and should only be used in these patientsif the anticipated clinical benefit outweighs the potential risk (see section 5.2).

No dose adjustment is necessary in patients with mild or moderate renal impairment (estimatedglomerular filtration rate [eGFR] ≥ 30 to < 90 mL/min/1.73 m2). Vutrisiran has not been studied inpatients with severe renal impairment or end-stage renal disease and should only be used in thesepatients if the anticipated clinical benefit outweighs the potential risk (see section 5.2).

The safety and efficacy of Amvuttra in children or adolescents < 18 years of age have not beenestablished. No data are available.

Amvuttra is for subcutaneous use only.

Amvuttra may be administered by a healthcare professional, the patient, or a caregiver.

Patients or caregivers may inject Amvuttra after guidance has been provided by a healthcareprofessional on proper subcutaneous injection technique.

This medicinal product is ready-to-use and for single-use only.

Visually inspect the solution for particulate matter and discolouration. Do not use if discoloured or ifparticles are present.

Prior to administration, if stored cold, the pre-filled syringe should be allowed to warm by leavingcarton at room temperature for about 30 minutes.

* The subcutaneous injection should be administered into one of the following sites: the abdomen,thighs, or upper arms. If injected in the upper arm, the injection should be administered by ahealthcare professional or a caregiver. Amvuttra should not be injected into scar tissue or areasthat are reddened, inflamed, or swollen.

* If injecting into the abdomen, the area around the navel should be avoided.

Severe hypersensitivity (e.g., anaphylaxis) to the active substance or to any of the excipients listed insection 6.1.

Vitamin A deficiency

By reducing serum transthyretin (TTR) protein, Amvuttra treatment leads to a decrease in serumvitamin A (retinol) levels (see section 5.1). Serum vitamin A levels below the lower limit of normalshould be corrected and any ocular symptoms or signs due to vitamin A deficiency should beevaluated prior to initiation of treatment with Amvuttra.

Patients receiving Amvuttra should take oral supplementation of approximately, but not exceeding,2 500 IU to 3 000 IU vitamin A per day to reduce the potential risk of ocular symptoms due tovitamin A deficiency. Ophthalmological assessment is recommended if patients develop ocularsymptoms suggestive of vitamin A deficiency, including reduced night vision or night blindness,persistent dry eyes, eye inflammation, corneal inflammation or ulceration, corneal thickening orcorneal perforation.

During the first 60 days of pregnancy, both too high or too low vitamin A levels may be associatedwith an increased risk of foetal malformation. Therefore, pregnancy should be excluded beforeinitiating Amvuttra and women of childbearing potential should practise effective contraception (seesection 4.6). If a woman intends to become pregnant, Amvuttra and vitamin A supplementation shouldbe discontinued and serum vitamin A levels should be monitored and have returned to normal beforeconception is attempted. Serum vitamin A levels may remain reduced for more than 12 months afterthe last dose of Amvuttra.

In the event of an unplanned pregnancy, Amvuttra should be discontinued (see section 4.6). Norecommendation can be given whether to continue or discontinue vitamin A supplementation duringthe first trimester of an unplanned pregnancy. If vitamin A supplementation is continued, the dailydose should not exceed 3 000 IU per day, due to the lack of data supporting higher doses. Thereafter,vitamin A supplementation of 2 500 IU to 3 000 IU per day should be resumed in the second and thirdtrimesters if serum vitamin A levels have not yet returned to normal, because of the increased risk ofvitamin A deficiency in the third trimester.

It is not known whether vitamin A supplementation in pregnancy will be sufficient to preventvitamin A deficiency if the pregnant female continues to receive Amvuttra. However, increasingvitamin A supplementation to above 3 000 IU per day during pregnancy is unlikely to correct plasmaretinol levels due to the mechanism of action of Amvuttra and may be harmful to the mother andfoetus.

This medicinal product contains less than 1 mmol sodium (23 mg) per mL, that is to say essentially‘sodium-free’.

No clinical interaction studies have been performed. Vutrisiran is not expected to cause interactions orto be affected by inhibitors or inducers of cytochrome P450 enzymes, or to modulate the activity oftransporters. Therefore, vutrisiran is not expected to have clinically significant interactions with othermedicinal products.

Treatment with Amvuttra reduces serum levels of vitamin A. Both too high or too low vitamin Alevels may be associated with an increased risk of foetal malformation. Therefore, pregnancy shouldbe excluded before initiation of treatment and women of childbearing potential should use effectivecontraception. If a woman intends to become pregnant, Amvuttra and vitamin A supplementationshould be discontinued and serum vitamin A levels should be monitored and have returned to normalbefore conception is attempted (see section 4.4.). Serum vitamin A levels may remain reduced formore than 12 months after the last dose of treatment.

There are no data on the use of Amvuttra in pregnant women. Animal studies are insufficient withrespect to reproductive toxicity (see section 5.3). Due to the potential teratogenic risk arising fromunbalanced vitamin A levels, Amvuttra should not be used during pregnancy. As a precautionarymeasure, vitamin A (see section 4.4) and thyroid stimulating hormone levels should be obtained earlyin pregnancy. Close monitoring of the foetus should be carried out, especially during the firsttrimester.

It is unknown whether vutrisiran is excreted in human milk. There is insufficient information on theexcretion of vutrisiran in animal milk (see section 5.3).

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from

Amvuttra, taking into account the benefit of breast-feeding for the child and the benefit of therapy forthe woman.

There are no data on the effects of Amvuttra on human fertility. No impact on male or female fertilitywas detected in animal studies (see section 5.3).

Amvuttra has no or negligible influence on the ability to drive and use machines.

The safety profile of Amvuttra was characterised based on the data from randomised-controlledphase 3 clinical studies. Adverse reactions reported in the pooled dataset of HELIOS-A and

HELIOS-B studies are presented in Table 1. The adverse reactions are presented as MedDRApreferred terms and under the MedDRA System Organ Class (SOC). The frequency of the adversereactions is expressed according to the following category: Common (≥1/100 to <1/10).

Table 1: Adverse reactions reported for Amvuttra

System Organ Class Adverse Reaction Frequency

General disorders and administration Injection site reactiona Commonsite conditions

Investigations Alanine transaminase increased Common

Blood alkaline phosphatase Commonincreaseda Reported symptoms included bruising, erythema, pain, pruritus, and warmth. Injection sitereactions were mild, transient, and did not lead to treatment discontinuation

In the HELIOS-B study, 97 (30%) of patients treated with Amvuttra and 78 (24%) patients treatedwith placebo had a mild increased alanine aminotransferase (ALT) greater than the ULN and less thanor equal to 3×ULN. All patients treated with Amvuttra with mild ALT elevations were asymptomaticand the majority had normalization of ALT levels with continued dosing.

In the HELIOS-A and HELIOS-B studies, 4 (3.3%) and 1 (0.3%) Amvuttra-treated patients,respectively, developed anti-drug antibodies (ADA). In both studies, ADA titres were low andtransient with no evidence of an effect on clinical efficacy, safety, or pharmacokinetic orpharmacodynamic profiles of vutrisiran.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In case of overdose, it is recommended that the patient be monitored as medically indicated for anysigns or symptoms of adverse reactions and appropriate symptomatic treatment be instituted.

Pharmacotherapeutic group: Other Nervous System Drugs; ATC code: N07XX18

Amvuttra contains vutrisiran, a chemically stabilized double-stranded small interfering ribonucleicacid (siRNA) that specifically targets variant and/or 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.

Through a natural process called RNA interference (RNAi), vutrisiran causes the catalytic degradationof TTR mRNA in the liver, resulting in the reduction of serum levels of variant and wild-typeamyloidogenic TTR protein thus reducing the deposition of TTR amyloid in tissues.

In HELIOS-A, mean serum TTR was rapidly reduced as early as Day 22, with mean near to steadystate TTR reduction of 73% by Week 6. With repeat dosing of 25 mg once every 3 months, meanreductions of serum TTR after 9 and 18 months of treatment were 83% and 88%, respectively. Similar

TTR reductions were observed regardless of genotype (V30M or non-V30M), prior TTR stabiliseruse, weight, sex, age, or race.

In HELIOS-B, the mean serum TTR reduction profile was consistent with that observed in

HELIOS-A, and similar across all subgroups studied (age, sex, race, body weight, anti-drug antibody[ADA] status, ATTR disease type [wild-type or hereditary], NYHA class, and baseline tafamidis use).

Serum TTR is a carrier of retinol binding protein 4, which is the principal carrier of vitamin A in theblood. In HELIOS-A, Amvuttra decreased serum vitamin A levels with mean steady state peak andtrough reductions of 70% and 63%, respectively (see sections 4.4 and 4.5). In HELIOS-B, serumvitamin A reductions were consistent with those observed in HELIOS-A.

In HELIOS-B, NT-proBNP and Troponin I, cardiac biomarkers associated with heart failure,demonstrated relative stability in Amvuttra-treated patients for median change from baseline through

Month 30 in the overall population (NT-proBNP: 9% increase; Troponin I: 10% decrease) while levelsin placebo patients demonstrated worsening (NT-proBNP: 52% increase; Troponin I: 22% increase).

Consistent trends were observed in the monotherapy population.

In HELIOS-B, centrally-assessed echocardiograms showed reduction relative to placebo favouring

Amvuttra in LV wall thickness (LS mean difference: -0.4 mm [95% CI -0.8, -0.0]) and longitudinalstrain (LS mean difference: -1.23% [95% CI -1.73, -0.73]) in the overall population. Results in themonotherapy population were consistent.

Clinical efficacy and safetyhATTR amyloidosis with polyneuropathy

The efficacy of Amvuttra was studied in a global, randomised, open-label clinical study (HELIOS-A)in adult patients with hATTR-PN. Patients were randomised 3:1 to receive 25 mg of Amvuttra(N=122) subcutaneously once every 3 months, or 0.3 mg/kg patisiran (N=42) intravenously onceevery 3 weeks. The treatment period of the study was conducted over 18 months with two analyses at

Month 9 and at Month 18. Ninety-seven percent (97%) of Amvuttra-treated patients completed at least18 months of the assigned treatments (vutrisiran or patisiran). Efficacy assessments were based on acomparison of the vutrisiran arm of the study with an external placebo group (placebo arm of the

APOLLO Phase 3 study) comprised of a similar population of patients with hATTR-PN. Assessmentof non-inferiority of serum TTR reduction was based on comparison of the vutrisiran arm to thewithin-study patisiran arm.

Of the patients who received Amvuttra, the median patient age at baseline was 60 years (range 34 to80 years), 38% were ≥ 65 years old, and 65% of patients were male. Twenty-two (22) different TTRvariants were represented: V30M (44%), T60A (13%), E89Q (8%), A97S (6%), S50R (4%), V122I(3%), L58H (3%), and Other (18%). Twenty percent (20%) of patients had the V30M genotype andearly onset of symptoms (< 50 years old). At baseline, 69% of patients had stage 1 disease(unimpaired ambulation; mild sensory, motor, and autonomic neuropathy in the lower limbs), and 31%had stage 2 disease (assistance with ambulation required; moderate impairment of the lower limbs,upper limbs, and trunk). There were no patients with stage 3 disease. Sixty-one percent (61%) ofpatients had prior treatment with TTR tetramer stabilisers. According to the New York Heart

Association (NYHA) classification of heart failure, 9% of patients had class I and 35% had class II.

Thirty-three percent (33%) of patients met pre-defined criteria for cardiac involvement (baseline LVwall thickness ≥ 13 mm with no history of hypertension or aortic valve disease).

The primary efficacy endpoint was the change from baseline to Month 18 in modified Neuropathy

Impairment Score +7 (mNIS+7). This endpoint is a composite measure of motor, sensory, andautonomic neuropathy including assessments of motor strength, reflexes, quantitative sensory testing,nerve conduction studies, and postural blood pressure, with the score ranging from 0 to 304 points,where an increasing score indicates worsening impairment.

The change from baseline to Month 18 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN)total score was assessed as a secondary endpoint. The Norfolk QoL-DN questionnaire (patient-reported) includes domains relating to small fibre, large fibre, and autonomic nerve function,symptoms of polyneuropathy, and activities of daily living, with the total score ranging from -4 to 136,where increasing score indicates worsening quality of life.

Other secondary endpoints included gait speed (10-meter walk test), nutritional status (mBMI), andpatient-reported ability to perform activities of daily living and social participation (Rasch-Built

Overall Disability Scale [R-ODS]).

Treatment with Amvuttra in the HELIOS-A study demonstrated statistically significant improvementsin all endpoints (Table 2 and Figure 1) measured from baseline to Month 9 and 18, compared to theexternal placebo group of the APOLLO study (all p < 0.0001).

The time-averaged trough TTR percent reduction through Month 18 was 84.7% for vutrisiran and80.6% for patisiran. The percent reduction in serum TTR levels in the vutrisiran arm was non-inferior(according to predefined criteria) to the within-study patisiran arm through Month 18 with a mediandifference of 5.3% (95% CI 1.2%, 9.3%).

Table 2: Summary of clinical efficacy results from the HELIOS-A study

Baseline, Mean (SD) Change from Baseline, Amvuttra -Placebob

Endpointa LS Mean (SEM) Treatment

Amvuttra Placebob b Difference, p-value

N=122 N=77 Amvuttra Placebo LS Mean (95% CI)

Month 9mNIS+7c 60.6 (36.0) 74.6 (37.0) -2.2 (1.4) 14.8 (2.0) -17.0(-21.8, -12.2) p<0.0001

Norfolk

QoL-DNc 47.1 (26.3) 55.5 (24.3) -3.3 (1.7) 12.9 (2.2) -16.2(-21.7, -10.8) p<0.000110-meterwalk test 1.01 (0.39) 0.79 (0.32) 0 (0.02) -0.13 (0.03) 0.13(m/sec)d (0.07, 0.19) p<0.0001

Month 18mNIS+7c 60.6 (36.0) 74.6 (37.0) -0.5 (1.6) 28.1 (2.3) -28.5(-34.0, -23.1) p<0.0001

Norfolk -21.0

QoL-DNc 47.1 (26.3) 55.5 (24.3) -1.2 (1.8) 19.8 (2.6) (-27.1, -14.9) p<0.000110-meterwalk test 1.01 (0.39) 0.79 (0.32) -0.02 0.24(m/sec)d (0.03) -0.26 (0.04) (0.15, 0.33) p<0.0001mBMIe 1057.5 989.9 25.0 (9.5) -115.7 (13.4) 140.7(233.8) (214.2) (108.4, 172.9) p<0.0001

R-ODSf 34.1 (11.0) 29.8 (10.8) -1.5 (0.6) -9.9 (0.8) 8.4(6.5, 10.4) p<0.0001

Abbreviations: 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=standarderror of the meana All Month 9 endpoints analysed using the analysis of covariance (ANCOVA) with multiple imputation (MI) method and all

Month 18 analysed using the mixed-effects model for repeated measures (MMRM)b External placebo group from APOLLO randomised controlled studyc A lower number indicates less impairment/fewer symptomsd A higher number indicates less disability/less impairmente mBMI: body mass index (BMI; kg/m2) multiplied by serum albumin (g/L); a higher number indicates better nutritionalstatus.f A higher number indicates less disability/less impairment.

Figure 1: Change from Baseline in mNIS+7 (Month 9 and Month 18)28.1 (2.3)

Placeboa14.8 (2.0) -28.5(95% Cl: -34.0, -23.1)p = 6.5x10-20

- 17.0(95% Cl: -21.8, -12.2)p = 3.5x10-12

Amvuttra

- 0.5 (1.6)

- 2.2 (1.4)

Baseline Month 9 Month 18

N evaluable

Placeboa

Amvuttr

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

All Month 9 endpoints analysed using the analysis of covariance (ANCOVA) with multiple imputation (MI) method and all

Month 18 analysed using the mixed-effects model for repeated measures (MMRM)a External placebo group from APOLLO randomised controlled study

Patients receiving Amvuttra experienced similar benefit relative to placebo in mNIS+7 and Norfolk

QoL-DN total score at Month 9 and Month 18 across all subgroups including age, sex, race, region,

NIS score, V30M genotype status, prior TTR stabiliser use, disease stage, and patients with or withoutpre-defined criteria for cardiac involvement.

The N-terminal prohormone-B-type natriuretic peptide (NT-proBNP) is a prognostic biomarker ofcardiac dysfunction. NT-proBNP- baseline values (geometric mean) were 273 ng/L and 531 ng/L in

Amvuttra-treated and placebo-treated patients, respectively. At Month 18, the geometric mean

NT-proBNP levels decreased by 6% in Amvuttra patients, while there was a 96% increase in placebopatients.

Centrally-assessed echocardiograms showed changes in LV wall thickness (LS mean difference: -0.18mm [95% CI -0.74, 0.38]) and longitudinal strain (LS mean difference: -0.4% [95% CI -1.2, 0.4]) with

Amvuttra treatment relative to placebo.

wtATTR or hATTR amyloidosis with cardiomyopathy

The efficacy of Amvuttra was demonstrated in a global, randomised, double-blind, placebo-controlledclinical study (HELIOS-B) in adult patients with ATTR-CM. Patients were randomized 1:1 to receive25 mg of Amvuttra subcutaneously once every 3 months, or matching placebo. At baseline, 40% ofpatients were receiving treatment with tafamidis. Treatment assignment was stratified by baselinetafamidis use, ATTR disease type (wtATTR or hATTR amyloidosis), and by baseline severity ofdisease and age (NYHA Class I or II and age < 75 years versus all other).

Of the patients who received Amvuttra, at baseline, the median patient age was 77 years (range 45 to85 years) and 92% were male. Eighty five percent (85%) of patients were Caucasian, 7% were Blackor African American, 6% were Asian. Eighty nine percent (89%) of patients had wtATTRamyloidosis and 11% had hATTR amyloidosis. According to the NYHA classification of heart failure(HF), 15% of patients had Class I, 77% had Class II, and 8% had Class III and were NAC ATTR

LS Mean (SE) Change in mNIS+7disease stage 1 or 2. Patient demographics and baseline disease characteristics were similar betweenthe treatment groups.

The primary efficacy endpoint was the composite outcome of all-cause mortality and recurrent CVevents (CV hospitalisations and urgent heart failure [UHF] visits) during the double-blind treatmentperiod 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 reductions in the risk of all-cause mortality and recurrent CV eventscompared to placebo in the overall and monotherapy populations of 28.2% and 32.8%, respectively(Table 3). Approximately 77% of all deaths in HELIOS-B were CV-related. The rate of both CVdeaths and non-CV deaths was lower in Amvuttra-treated patients compared to placebo. Of the totalnumber of CV events, 87.9% were CV hospitalisations, and 12.1% were UHF visits. A Kaplan-Meiercurve illustrating time to first CV event or all-cause mortality is presented in Figure 2.

Both components of the primary composite endpoint individually contributed to the treatment effect inthe overall population and monotherapy population (Table 3).

In the secondary endpoint analysis of all-cause mortality including data up to Month 42, incorporatingthe double-blind period and up to an additional 6 months of survival data for all patients, Amvuttra ledto a 35.5% reduction in the risk of death relative to placebo in the overall population (hazard ratio:0.645; 95% CI: 0.463, 0.898; p=0.0098), and to a 34.5% reduction in the monotherapy population(hazard ratio: 0.655; 95% CI: 0.440, 0.973; p=0.0454).

Table 3: Primary composite endpoint and its individual components in HELIOS-B

Endpoint Overall population  Monotherapy population

Amvuttra  Placebo Amvuttra Placebo(N=326)  (N=328)  (N=196)  (N=199)

Primary composite Hazard Ratio (95% CI)b 0.718 (0.555, 0.929)   0.672 (0.487, 0.929)endpointa p-valueb 0.0118 0.0162

Components of the Primary Composite Endpoint

All-causemortality  Hazard Ratio (95% CI)c 0.694 (0.490, 0.982)  0.705 (0.467, 1.064)

CV hospitalisationsand UHF visits Relative Rate Ratio (95% CI)d  0.733 (0.610, 0.882)  0.676 (0.533, 0.857)

Abbreviations: CI=confidence interval; CV=cardiovascular; UHF=urgent heart failure

Heart transplantation and left ventricular assist device placement are treated as death. Deaths after study discontinuation areincluded in the all-cause mortality component analysis.

a Primary composite endpoint defined as: composite outcome of all-cause mortality and recurrent CV events. Primary analysisincluded at least 33 months (and up to 36 months) follow-up on all patients.b Hazard Ratio (95% CI) and p-value are based on a modified Andersen-Gill model.c Hazard Ratio (95% CI) is based on a Cox proportional hazard model.d Relative rate ratio (95% CI) is based on a Poisson regression model.

Figure 2: Time to First CV Event or All-Cause Mortality (Overall population)60 AMVUTTRA50 Placebo0 HR:0.716 (0.566, 0.905), p-value:0.00620 3 6 9 12 15 18 21 24 27 30 33 36 39

Month

No. at Risk (Cumulative No. of Events)

Placebo 328 (0) 317 (11) 295 (31) 270 (53) 253 (70) 237 (84) 221 (96) 210 (105) 199 (115) 183 (131) 172 (142) 155 (154) 52 (159) 0 (159)

AMVUTTRA 326 (0) 306 (19) 294 (30) 284 (39) 271 (50) 254 (65) 247 (72) 237 (81) 227 (90) 216 (101) 206 (110) 185 (118) 62 (125) 0 (125)

Abbreviation: CI=confidence interval; CV=cardiovascular; HR = hazard ratio.

Heart transplantation and left ventricular assist device placement are treated as death. Kaplan-Meier curves are adjusted for baseline diseasecharacteristics using the inverse probability of treatment weighting method. HR and 95% CI are based on a Cox proportional hazard model,and p-value is based on log-rank test.

Results from the subgroup analysis for the primary composite endpoint favoured Amvuttra across allprespecified subgroups in the overall population and the monotherapy population. In the subgroup ofpatients on background tafamidis, Amvuttra led to a 21.5% numerical reduction in the risk of all-causemortality and recurrent CV events relative to placebo (hazard ratio: 0.785; 95% CI: 0.511, 1.207)(Figure 3).

Probability of CV Events or Mortality Free (%)

Figure 3: Subgroup Analyses of the Primary Composite Endpoint (Overall Population)

HR 95% CI

Overall (N=654) 0.718 (0.555, 0.929)

Tafamidis use at baseline

No (N=395) 0.672 (0.487, 0.929)

Yes (N=259) 0.785 (0.511, 1.207)

Age at baseline<75 (N=257) 0.545 (0.348, 0.854)≥75 (N=397) 0.806 (0.584, 1.114)

ATTR disease typehATTR (N=76) 0.922 (0.494, 1.724)wtATTR (N=578) 0.674 (0.506, 0.898)

NYHA class at baseline

I/II (N=592) 0.727 (0.552, 0.958)

III (N=62) 0.681 (0.330, 1.406)

NT-pro-BNP at baseline≤2000 (N=342) 0.525 (0.349, 0.788)>2000 (N=312) 0.798 (0.562, 1.133)0.5 1 2

Favours Amvuttra Favours Placebo

Abbreviations: ATTR = transthyretin amyloidosis; CI = confidence interval; hATTR = hereditary transthyretin amyloidosis; HR = hazardratio; NT-proBNP = N-terminal prohormone of B-type natriuretic peptide; NYHA = New York Heart Association; wtATTR = wild-typetransthyretin amyloidosis.

HR and 95% CI are based on modified Andersen-Gill model analyses.

The treatment effects of Amvuttra on functional capacity, patient-reported health status and quality oflife, and heart failure symptom severity were assessed by the change from baseline to Month 30 in6-Minute Walk Test (6-MWT), the Kansas City Cardiomyopathy Questionnaire-Overall Summary(KCCQ-OS) score and NYHA class, respectively. The KCCQ-OS is composed of four domainsincluding Total Symptoms (Symptom Frequency and Symptom Burden), Physical Limitation, Qualityof Life, and Social Limitation. The Overall Summary score and domain scores range from 0 to 100,with higher scores representing better health status.

A statistically significant treatment effect favouring Amvuttra was observed for 6-MWT distance,

KCCQ-OS score, and stable or improved NYHA class, in both the overall population andmonotherapy population (Table 4), with consistent results across all subgroups studied. The treatmenteffect on KCCQ-OS score was consistent across all four domain scores.

Table 4. Change from Baseline in 6-MWT distance, KCCQ-OS score and NYHA class at

Month 30

Overall population Monotherapy population

Amvuttra Placebo Amvuttra Placebo(N=326)  (N=328)  (N=196)  (N=199)6-MWT (metres)

Baseline Mean (SD) 372 (104) 377 (96) 363 (103) 373 (98)

Change from baseline to

Month 30, LS Mean (SE)a -45 (5) -72 (5) -60 (7) -92 (6)

Treatment Difference from 26 (13, 40) 32 (14, 50)

Placebo, LS Mean (95% CI)p-valuea,b <0.0001 0.0005

KCCQ-OS (points)

Baseline Mean (SD) 73 (19) 72 (20) 70 (20) 70 (21)

Change from baseline to

Month 30, LS Mean (SE)a -10 (1) -15 (1) -11 (2) -19 (2)

Treatment Difference from 6 (2, 9) 9 (4, 13)

Placebo, LS Mean (95% CI)p-valuea,b 0.0008 0.0003

NYHA Class% of patients with stable orimproved NYHA class at 68 61 66 56

Month 30

Difference from Placebo, (%) 9 (1, 16) 13 (3, 22)(95% CI)cp-valuec 0.0217 0.0121

Abbreviations: 6-MWT = 6-minute walk test; KCCQ-OS = Kansas City Cardiomyopathy Questionnaire, LS = least squares;

CI = confidence interval; SD = Standard deviation; SE = Standard Error; NYHA = New York Heart Associationa For assessment missing because of death (including heart transplantation and left ventricular assist device placement), andinability to walk as the result of ATTR disease progression (applicable to 6-MWT only), data were imputed from resampling ofthe worst 10% of observed changes.

b Estimated from the MMRM (mixed-effect model repeated measures) model.c Based on Cochran-Mantel-Haenszel method.

The European Medicines Agency has waived the obligation to submit the results of studies withvutrisiran in all subsets of the paediatric population in hATTR amyloidosis (see section 4.2 forinformation on paediatric use).

The pharmacokinetic properties of Amvuttra were characterised by measuring the plasma and urineconcentrations of vutrisiran.

Following subcutaneous administration, vutrisiran is rapidly absorbed with a time to maximum plasmaconcentration (tmax) of 3.0 (range: 2.0 to 6.5) hours. At the recommended dosing regimen of 25 mgonce every 3 months subcutaneously, the mean (% coefficient of variation [%CV]) steady state peakconcentrations (Cmax), and area under the concentration time curve from 0 to 24 hours (AUC0-24) were0.12 μg/mL (64.3%), and 0.80 μg·h/mL (35.0%), respectively. There was no accumulation ofvutrisiran in plasma after repeated quarterly dosing.

Vutrisiran is greater than 80% bound to plasma proteins over the concentration range observed inhumans at the dose of 25 mg once every 3 months subcutaneously. Vutrisiran plasma protein bindingwas concentration-dependent and decreased with increasing vutrisiran concentrations (from 78% at0.5 µg/mL to 19% at 50 µg/mL). The population estimate for the apparent central compartmentvolume of distribution (Vd/F) of vutrisiran in humans was 10.2 L (% Relative standard error[RSE]=5.71%). Vutrisiran distributes primarily to the liver after subcutaneous dosing.

Vutrisiran is metabolised by endo- and exo-nucleases to short nucleotide fragments of varying sizeswithin the liver. There were no major circulating metabolites in humans. In vitro studies indicate thatvutrisiran does not undergo metabolism by CYP450 enzymes.

Following a 25 mg single subcutaneous dose, the median apparent plasma clearance was 21.4 (range:19.8, 30.0) L/h. The median terminal elimination half-life (t1/2) of vutrisiran was 5.23 (range: 2.24,6.36) hours. After a single subcutaneous dose of 5 to 300 mg, the mean fraction of unchanged activesubstance eliminated in urine ranged from 15.4 to 25.4% and the mean renal clearance ranged from4.45 to 5.74 L/h for vutrisiran.

Following single subcutaneous doses over the 5 to 300 mg dose range, vutrisiran Cmax was shown to bedose proportional while area under the concentration-time curve from the time of dosing extrapolatedto infinity (AUCinf) and area under the concentration-time curve from the time of dosing to the lastmeasurable concentration (AUClast) were slightly more than dose proportional.

Population pharmacokinetic/pharmacodynamic analyses in healthy subjects and patients with hATTRamyloidosis (n=202) showed a dose-dependent relationship between predicted vutrisiran liverconcentrations and reductions in serum TTR. The model-predicted median steady state peak, trough,and average TTR reductions were 88%, 86%, and 87%, respectively, confirming minimal peak-to-trough variability across the 3-month dosing interval. Covariate analysis indicated similar TTRreduction in patients with mild-to-moderate renal impairment or mild hepatic impairment, as well asby sex, race, prior use of TTR stabilisers, genotype (V30M or non-V30M), age and weight.

Clinical studies did not identify significant differences in steady state pharmacokinetic parameters or

TTR reduction according to gender or race.

In the HELIOS-A study, 46 (38%) patients treated with vutrisiran were ≥ 65 years old and of these7 (5.7%) patients were ≥ 75 years old. In the HELIOS-B study, 299 (91.7%) patients treated withvutrisiran were ≥ 65 years old, with a median age of 77.0 years, and of these 203 (62.3%) were≥75 years old. There were no significant differences in steady state pharmacokinetic parameters or

TTR reduction.

Clinical studies indicated no impact of mild (total bilirubin ≤ 1 x ULN and AST > 1 x ULN, or totalbilirubin > 1.0 to 1.5 x ULN and any AST) or moderate (total bilirubin > 1.5 to 3 × ULN and any

AST) hepatic impairment on vutrisiran exposure or TTR reduction compared to patients with normalhepatic function. Vutrisiran has not been studied in patients with severe hepatic impairment.

Clinical studies indicated no impact of mild or moderate renal impairment (eGFR ≥ 30 to< 90 mL/min/1.73 m2) on vutrisiran exposure or TTR reduction compared to subjects with normalrenal function. Vutrisiran has not been studied in patients with severe renal impairment or end-stagerenal disease.

General toxicology

Repeated once-monthly subcutaneous administration of vutrisiran at ≥ 30 mg/kg in monkeys producedthe expected sustained reductions of circulating TTR (up to 99%) and vitamin A (up to 89%) withoutany apparent toxicological findings.

Following once monthly repeated dosing for up to 6 months in rats and 9 months in monkeys, the mildand consistent non-adverse histological changes in liver (hepatocytes, Kupffer cells), kidneys (renaltubules), lymph nodes and injection sites (macrophages) reflected the principal distribution andaccumulation of vutrisiran. However, no toxicities were identified at up to more than 1 000- and3 000-fold higher plasma AUC, when normalised to quarterly dosing and compared to the anticipatedexposure at the maximum recommended human dose [MRHD].

Vutrisiran did not exert any genotoxic potential in vitro and in vivo. Vutrisiran was not carcinogenic inrats and in male mice. In female mice dosed once monthly with vutrisiran at 3, 9, or 18 mg/kg, astatistically significant dose-dependent trend for combined hepatocellular adenomas and carcinomaswas observed with unknown relevance for humans. The carcinogenic potential of vutrisiran isconsidered low if all toxicity data are taken into account.

Vutrisiran is not pharmacologically active in rats and rabbits, which limits the predictivity of theseinvestigations. Nevertheless, a single dose of a rat-specific orthologue of vutrisiran did not impact onfertility and early embryonic development in a combined study in rats.

Weekly subcutaneous administrations of vutrisiran did not affect fertility and early embryonicdevelopment at more than 300-times the normalised MRHD In an embryo-foetal study with dailysubcutaneous vutrisiran administration in pregnant rats, adverse effects on maternal body weight, foodconsumption, increased premature delivery and post-implantation loss were observed with a maternal

NOAEL of 10 mg/kg/day that was more than 300-times the normalised MRHD of 0.005 mg/kg/day.

Based on an adverse reduction in foetal body weights and increased skeletal variations at≥10 mg/kg/day, the foetal NOAEL of vutrisiran was 3 mg/kg/day which is 97-times the normalised

MRHD.

In an embryo-foetal development study in pregnant rabbits, no adverse effects on embryo-foetaldevelopment were observed at ≤ 30 mg/kg/day vutrisiran, which is more than 1 900-times thenormalised MRHD.

In a prenatal-postnatal development study, subcutaneous vutrisiran administration on every 6th day hadno effect on growth and development of the offspring with a NOAEL of 20 mg/kg, which was morethan 90-times the normalised MRHD.

Sodium dihydrogen phosphate dihydrate

Disodium phosphate dihydrate

Sodium chloride

Water for injections

Sodium hydroxide (for pH adjustment)

Phosphoric acid (for pH adjustment).

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

Do not store above 30 °C. Do not freeze.

Pre-filled syringe (Type I glass) with stainless steel 29-gauge needle with a needle shield.

Amvuttra is available in packs containing one single-use pre-filled syringe.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Alnylam Netherlands B.V.

Antonio Vivaldistraat 1501083 HP Amsterdam

Netherlands

EU/1/22/1681/001

Date of first authorisation: 15 September 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu