AMVUTTRA Solution for injection Ref.[50230] Active ingredients: Vutrisiran

Pharmacotherapeutic group: Other Nervous System Drugs
ATC code: N07XX18

Mechanism of action

Amvuttra contains vutrisiran, a chemically stabilized double-stranded small interfering ribonucleic acid (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 degradation of TTR mRNA in the liver, resulting in the reduction of serum levels of variant and wild-type amyloidogenic TTR protein thus reducing the deposition of TTR amyloid in tissues.

Pharmacodynamic effects

In HELIOS-A, mean serum TTR was rapidly reduced as early as Day 22, with mean near to steady state TTR reduction of 73% by Week 6. With repeat dosing of 25 mg once every 3 months, mean reductions 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 stabiliser use, 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 the blood. In HELIOS-A, Amvuttra decreased serum vitamin A levels with mean steady state peak and trough reductions of 70% and 63%, respectively (see sections 4.4 and 4.5). In HELIOS-B, serum vitamin 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 levels in 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 longitudinal strain (LS mean difference: -1.23% [95% CI -1.73, -0.73]) in the overall population. Results in the monotherapy population were consistent.

Clinical efficacy and safety

hATTR 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 once every 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 least 18 months of the assigned treatments (vutrisiran or patisiran). Efficacy assessments were based on a comparison 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. Assessment of non-inferiority of serum TTR reduction was based on comparison of the vutrisiran arm to the within-study patisiran arm.

Of the patients who received Amvuttra, the median patient age at baseline was 60 years (range 34 to 80 years), 38% were ≥65 years old, and 65% of patients were male. Twenty-two (22) different TTR variants 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 and early 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%) of patients 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 LV wall 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, and autonomic 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), and patient-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 improvements in all endpoints (Table 2 and Figure 1) measured from baseline to Month 9 and 18, compared to the external 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 and 80.6% 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 median difference of 5.3% (95% CI 1.2%, 9.3%).

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

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 = standard error of the mean
^a 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 study
^c A lower number indicates less impairment/fewer symptoms
^d A higher number indicates less disability/less impairment
^e mBMI: body mass index (BMI; kg/m²) multiplied by serum albumin (g/L); a higher number indicates better nutritional status.
^f A higher number indicates less disability/less impairment.

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

A decrease in mNIS+7 indicates improvement
∆ indicates between-group treatment difference, shown as the LS mean difference (95% CI) for AMVUTTRA–external placebo
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 without pre-defined criteria for cardiac involvement.

The N-terminal prohormone-B-type natriuretic peptide (NT-proBNP) is a prognostic biomarker of cardiac 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 placebo patients.

Centrally-assessed echocardiograms showed changes in LV wall thickness (LS mean difference: -0.18 mm [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-controlled clinical study (HELIOS-B) in adult patients with ATTR-CM. Patients were randomized 1:1 to receive 25 mg of Amvuttra subcutaneously once every 3 months, or matching placebo. At baseline, 40% of patients were receiving treatment with tafamidis. Treatment assignment was stratified by baseline tafamidis use, ATTR disease type (wtATTR or hATTR amyloidosis), and by baseline severity of disease 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 to 85 years) and 92% were male. Eighty five percent (85%) of patients were Caucasian, 7% were Black or African American, 6% were Asian. Eighty nine percent (89%) of patients had wtATTR amyloidosis 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 disease stage 1 or 2. Patient demographics and baseline disease characteristics were similar between the treatment groups.

The primary efficacy endpoint was the composite outcome of all-cause mortality and recurrent CV events (CV hospitalisations 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 reductions in the risk of all-cause mortality and recurrent CV events compared 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 CV deaths and non-CV deaths was lower in Amvuttra-treated patients compared to placebo. Of the total number of CV events, 87.9% were CV hospitalisations, and 12.1% were UHF visits. A Kaplan-Meier curve 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 in the overall population and monotherapy population (Table 3).

In the secondary endpoint analysis of all-cause mortality including data up to Month 42, incorporating the double-blind period and up to an additional 6 months of survival data for all patients, Amvuttra led to 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:

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 are included in the all-cause mortality component analysis.
^a Primary composite endpoint defined as: composite outcome of all-cause mortality and recurrent CV events. Primary analysis included 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):

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 disease characteristics 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 all prespecified subgroups in the overall population and the monotherapy population. In the subgroup of patients on background tafamidis, Amvuttra led to a 21.5% numerical reduction in the risk of all-cause mortality and recurrent CV events relative to placebo (hazard ratio: 0.785; 95% CI: 0.511, 1.207) (Figure 3).

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

Abbreviations: ATTR = transthyretin amyloidosis; CI = confidence interval; hATTR = hereditary transthyretin amyloidosis; HR = hazard ratio; NT-proBNP = 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 effects of Amvuttra on functional capacity, patient-reported health status and quality of life, and heart failure symptom severity were assessed by the change from baseline to Month 30 in 6-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 domains including Total Symptoms (Symptom Frequency and Symptom Burden), Physical Limitation, Quality of 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 and monotherapy population (Table 4), with consistent results across all subgroups studied. The treatment effect 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:

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 Association
^a For assessment missing because of death (including heart transplantation and left ventricular assist device placement), and inability to walk as the result of ATTR disease progression (applicable to 6-MWT only), data were imputed from resampling of the worst 10% of observed changes.
^b Estimated from the MMRM (mixed-effect model repeated measures) model.
^c Based on Cochran-Mantel-Haenszel method.

Paediatric population

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