Amvuttra 25 mg solution for injection in pre-filled syringe

Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX18 Mechanism of action Amvuttra contains vutrisiran, a chemically stabilised 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) moieties, which enable delivery of the siRNA to hepatocytes. Through the natural process known as RNA interference (RNAi), vutrisiran causes catalytic degradation of TTR mRNA in the liver, resulting in a reduction in serum levels of variant and wild-type amyloidogenic TTR protein, thereby reducing the deposition of TTR amyloid in tissues.​‍​​​​​‍​‍‍‍‍​‍‍ Pharmacodynamic effects In the HELIOS-A study, mean serum TTR levels decreased rapidly by Day 22, with mean TTR reaching near steady-state reduction of 73% by Week 6. With repeat dosing of 25 mg once every 3 months, the mean reduction in serum TTR was 83% after 9 months and 88% after 18 months of treatment. Similar TTR reductions were observed regardless of genotype (V30M or non-V30M), prior TTR stabiliser use, body weight, sex, age, or race. In the HELIOS-B study, the mean serum TTR reduction profile was consistent with that observed in the HELIOS-A study and was similar across all subgroups examined (age, sex, race, body weight, anti-drug antibody [ADA] status, ATTR disease type [wild-type or hereditary], NYHA class, and tafamidis use at baseline). Serum TTR is a carrier of retinol binding protein 4, which is the major carrier of vitamin A in the blood. In the HELIOS-A study, Amvuttra reduced serum vitamin A levels with a mean maximum reduction of 70% and trough reduction of 63% at steady state (see sections 4.4 and 4.5 ). In the HELIOS-B study, serum vitamin A reductions were consistent with those observed in the HELIOS-A study. In the HELIOS-B study, cardiac biomarkers associated with heart failure, NT-proBNP and troponin I, demonstrated relative stability in patients treated with Amvuttra with a median change from baseline to Month 30 in the overall population (NT-proBNP: increase of 9%; troponin I: decrease of 10%), while patients receiving placebo experienced worsening (NT-proBNP: increase of 52%; troponin I: increase of 22%). Consistent trends were also observed in the monotherapy population. In the HELIOS-B study, centrally assessed echocardiographic evaluations demonstrated a reduction in left ventricular (LV) wall thickness in favour of Amvuttra compared with placebo (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 evaluated in a global, randomised, open-label clinical study (HELIOS-A) in adult patients with hATTR-PN. Patients were randomised in a 3:1 ratio to receive 25 mg Amvuttra (N = 122) subcutaneously once every 3 months or 0.3 mg/kg patisiran (N = 42) intravenously once every 3 weeks. The on-study treatment period lasted 18 months with two analyses at Month 9 and Month 18. Ninety-seven percent (97%) of patients treated with Amvuttra completed at least 18 months of assigned treatment (vutrisiran or patisiran). Efficacy assessments were based on comparison of the vutrisiran arm with an external placebo group (placebo arm from the Phase 3 APOLLO study), which comprised a similar population of patients with hATTR-PN. Non-inferiority assessment of serum TTR reduction was based on comparison of the vutrisiran arm with the patisiran arm within the study. In patients receiving Amvuttra, the median age at baseline was 60 years (range 34 to 80 years), 38% of patients were ≥ 65 years, and 65% 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 others (18%). Twenty percent (20%) of patients had V30M genotype with early onset (< 50 years). 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 required for walking; moderate progression of impairment to lower limbs, upper limbs, and trunk). No patients with Stage 3 disease were enrolled. Sixty-one percent (61%) of patients had previously been treated with TTR tetramer stabilisers. By NYHA heart failure classification, 9% of patients were Class I and 35% were Class II. Thirty-three percent (33%) of patients met pre-defined criteria for cardiac involvement (baseline LV wall thickness ≥ 13 mm without a history of hypertension or aortic valve disease). The primary efficacy endpoint was the change from baseline to 18 months in the 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 scores ranging from 0 to 304 points, where higher scores indicate worsening impairment. The change from baseline to 18 months in the Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score was assessed as a secondary endpoint. The Norfolk QoL-DN questionnaire (patient-reported) encompasses functions related to small fibre, large fibre, and autonomic nerve fibres, polyneuropathy symptoms, and activities of daily living, with total scores ranging from –4 to 136, where higher scores indicate worsening quality of life. Additional secondary endpoints included walking speed (10-metre 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 improvement in all endpoints (Table 2 and Figure 1) measured from baseline to Month 9 and Month 18 compared with the external placebo group from the APOLLO study (all p < 0.0001). The time-averaged percentage reduction in TTR trough levels to Month 18 was 84.7% for vutrisiran and 80.6% for patisiran. The percentage reduction in serum TTR levels in the vutrisiran arm was non-inferior (by pre-specified criteria) to the patisiran arm within the study up to Month 18 with a median difference of 5.3% (95% CI 1.2%, 9.3%). Table 2: Summary of Clinical Efficacy Results in the HELIOS-A Study Endpoint a Mean baseline value (SD) Change from baseline,LS mean (SEM) Treatment differencebetween Amvuttra andplacebo b , LS mean (95% CI) p-value Amvuttra N = 122 Placebo b N = 77 Amvuttra Placebo b Month 9 mNIS+7 c 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-DN c 47.1 (26.3) 55.5 (24.3) –3.3 (1.7) 12.9 (2.2) –16.2(–21.7, –10.8) p < 0.0001 10-metre walk test (m/s) d 1.01 (0.39) 0.79 (0.32) 0 (0.02) –0.13 (0.03) 0.13(0.07, 0.19) p < 0.0001 Month 18 mNIS+7 c 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 QoL-DN c 47.1 (26.3) 55.5 (24.3) –1.2 (1.8) 19.8 (2.6) –21.0(–27.1, –14.9) p < 0.0001 10-metre walk test (m/s) d 1.01 (0.39) 0.79 (0.32) –0.02(0.03) –0.26 (0.04) 0.24(0.15, 0.33) p < 0.0001 mBMI e 1 057.5(233.8) 989.9(214.2) 25.0 (9.5) –115.7(13.4) 140.7(108.4, 172.9) p < 0.0001 R-ODS f 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 = standard error of the mean a All endpoints at Month 9 analysed using analysis of covariance (ANCOVA) with multiple imputation (MI) and all endpoints at Month 18 analysed using mixed-effect model repeated measures (MMRM). b External placebo group from the randomised controlled APOLLO clinical study. c Lower score indicates less impairment/fewer symptoms. d Higher score indicates less disability/less impairment. e mBMI: body mass index (BMI; kg/m 2 ) multiplied by serum albumin level (g/L); higher score indicates better nutritional status. f Higher score indicates less disability/less impairment. 28.1 2.3 Placebo a 14.8 2.0 -28.5 95% CI: -34.0, -23.1 p 6.5x10 -20 17.0 95% CI: -21.8, -12.2 p 3.5x10 -12 -2.2 1.4 Amvuttra -0.5 1.6 Baseline Month 9 Month 18 Evaluable N Placebo a Amvuttra LS mean (SE) change in mNIS+7 Figure 1: Change from Baseline in mNIS+7 (Month 9 and Month 18) Decrease in mNIS+7 indicates improvement. Δ denotes treatment difference between groups, shown as LS mean difference (95% CI) for the AMVUTTRA – external placebo comparison. All endpoints at Month 9 analysed using analysis of covariance (ANCOVA) with multiple imputation (MI) and all endpoints at Month 18 analysed using mixed-effect model repeated measures (MMRM). a External placebo group from the randomised controlled APOLLO clinical study. Patients receiving Amvuttra experienced similar improvements in mNIS+7 and Norfolk QoL-DN total scores at Month 9 and Month 18 compared with placebo across all subgroups including age, sex, race, region, NIS score, V30M genotype status (V30M or non-V30M), prior TTR stabiliser use, disease stage, and patients with or without pre-defined criteria for cardiac involvement. N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) is a prognostic biomarker of cardiac dysfunction. Baseline NT-proBNP levels (geometric mean) were 273 ng/L in Amvuttra-treated patients and 531 ng/L in placebo-treated patients. At Month 18, geometric mean NT-proBNP levels in Amvuttra-treated patients decreased by 6%, while in placebo-treated patients they increased by 96%. Centrally assessed echocardiograms demonstrated 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 compared with 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 randomised in a 1:1 ratio to receive 25 mg Amvuttra subcutaneously once every 3 months or matching placebo. At baseline, 40% of patients were being treated with tafamidis. Treatment assignment was stratified by tafamidis use at baseline, ATTR disease type (wtATTR or hATTR amyloidosis), and baseline disease severity and age (NYHA Class I or II and age < 75 years versus all others). In patients receiving Amvuttra, the median age at baseline was 77 years (range 45 to 85 years) and 92% of patients were male. Eighty-five percent (85%) of patients were White, 7% were Black or African American, and 6% were Asian. Eighty-nine percent (89%) of patients had wtATTR amyloidosis and 11% had hATTR amyloidosis. By NYHA heart failure (HF) classification, 15% of patients were Class I, 77% were Class II, and 8% were Class III, with Stage 1 or Stage 2 ATTR disease according to the National Amyloidosis Centre classification. Patient demographics and baseline disease characteristics were similar between treatment groups. The primary efficacy endpoint was a composite of all-cause mortality and recurrent cardiovascular (CV) events (hospitalisations for CV disease and urgent heart failure [UHF] visits) during the double-blind treatment period of up to 36 months. Assessment was performed in the overall population and in the monotherapy population (defined as patients not receiving tafamidis at baseline). Amvuttra resulted in a significant reduction in the risk of all-cause mortality and recurrent CV events compared with placebo of 28.2% in the overall population and 32.8% in the monotherapy population (Table 3). Approximately 77% of all deaths in the HELIOS-B study were CV-related. Both CV and non-CV mortality rates were lower in Amvuttra-treated patients compared with placebo. Of total CV events, CV hospitalisations accounted for 87.9% and UHF visits accounted for 12.1%. The Kaplan-Meier curve for time to first CV event or all-cause mortality is shown in Figure 2. Both components of the primary composite endpoint individually contributed to the treatment effect in both the overall population and the monotherapy population (Table 3). In the secondary endpoint analysis of all-cause mortality, which included data up to Month 42 including the double-blind period plus an additional 6-month survival follow-up of all patients, Amvuttra resulted in a 35.5% reduction in the risk of death compared with placebo in the overall population (hazard ratio: 0.645; 95% CI: 0.463; 0.898; p = 0.0098) and 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 the HELIOS-B Study Endpoint Overall Population Monotherapy Population Amvuttra (N = 326) Placebo (N = 328) Amvuttra (N = 196) Placebo (N = 199) Primary composite endpoint a Hazard ratio (95% CI) b p-value b 0.718 (0.555; 0.929)0.0118 0.672 (0.487; 0.929)0.0162 Components of the primary composite endpoint All-cause mortality Hazard ratio (95% CI) c 0.694 (0.490; 0.982) 0.705 (0.467; 1.064) CV hospitalisations and 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 failureHeart transplantation and left ventricular assist device implantation are considered as death. Post-study deaths are included in the all-cause mortality component analyses.a Primary composite endpoint defined as: composite of all-cause mortality and recurrent CV events. The primary analysis included follow-up of all patients for at least 33 months (and up to 36 months).b Hazard ratio (95% CI) and p-value are based on a modified Andersen and Gill model.c Hazard ratio (95% CI) is based on the Cox proportional hazards 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) AMVUTTRA Placebo HR: 0.716 (0.566; 0.905), p-value: 0.0062 Probability of CV Events or Mortality Free (%) 100 90 80 70 AMVUTTRA 60 Placebo 50 40 30 20 10 HR: 0.716 (0.566, 0.905), p-value: 0.0062 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 Month No. at Risk (Cumulative No. of Events) Month Placebo AMVUTTRA No. at Risk (Cumulative No. of Events) 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) 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) Abbreviations: CI = confidence interval; CV = cardiovascular; HR = hazard ratio. Heart transplantation and left ventricular assist device implantation are considered as death. Kaplan-Meier curves are adjusted for baseline disease characteristics using inverse probability of treatment weighting. HR and 95% CI are based on the Cox proportional hazards model and p-value is based on the log-rank test. Subgroup analysis results for the primary composite endpoint were in favour of Amvuttra across all pre-specified subgroups in both the overall population and the monotherapy population. In the subgroup of patients receiving tafamidis as background therapy, Amvuttra resulted in a numerical reduction in the risk of all-cause mortality and recurrent CV events of 21.5% compared with placebo (hazard ratio: 0.785; 95% CI: 0.511; 1.207) (Figure 3). Figure 3: Subgroup Analyses of Primary Composite Endpoint (Overall Population) HR 95% CI 0.718 (0.555; 0.929) 0.672 (0.487; 0.929) 0.785 (0.511; 1.207) 0.545 (0.348; 0.854) 0.806 (0.584; 1.114) 0.922 (0.494; 1.724) 0.674 (0.506; 0.898) 0.727 (0.552; 0.958) 0.681 (0.330; 1.406) 0.525 (0.349; 0.788) 0.798 (0.562; 1.133) Overall (N=654) Tafamidis use at baseline No (N=395) Yes (N=259) Age at baseline <75 (N=257) ≥75 (N=397) ATTR disease type hATTR (N=76) wtATTR (N=578) NYHA class at baseline I/II (N=592) III (N=62) NT-proBNP at baseline ≤2000 (N=342) >2000 (N=312) HR 0.718 0.672 0.785 0.545 0.806 0.922 0.674 0.727 0.681 0.525 0.798 95% CI (0.555, 0.929) (0.487, 0.929) (0.511, 1.207) (0.348, 0.854) (0.584, 1.114) (0.494, 1.724) (0.506, 0.898) (0.552, 0.958) (0.330, 1.406) (0.349, 0.788) (0.562, 1.133) Favours Amvuttra Favours Placebo 0.5 Favours Placebo Overall (N=654) Tafamidis use at baseline No (N = 395) Yes (N = 259) Age at baseline < 75 (N = 257) ≥ 75 (N = 397) ATTR disease type hATTR (N = 76) wtATTR (N = 578) NYHA class at baseline I/II (N = 592) III (N = 62) NT-proBNP at baseline ≤ 2000 (N = 342) > 2000 (N = 312) Favours Amvuttra 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 and Gill model analyses. The treatment effects of Amvuttra on functional capacity, patient-reported health status and quality of life, and severity of heart failure symptoms were assessed based on the change from baseline to Month 30 in the 6-Minute Walk Test (6-MWT), Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score, and NYHA class. The KCCQ-OS consists of four domains encompassing total symptoms (symptom frequency and symptom burden), physical limitation, quality of life, and social limitation. The overall summary score and individual domain scores range from 0 to 100, with higher scores representing better health status. A statistically significant treatment effect in favour of Amvuttra was observed for 6-MWT distance, KCCQ-OS score, and stable or improved NYHA class in both the overall population and the monotherapy population (Table 4), with results consistent across all subgroups examined. The treatment effect on KCCQ-OS score was consistent across all four assessment domains. Table 4. Change from Baseline in 6-MWT Distance, KCCQ-OS Score, and NYHA Class at Month 30 Overall Population Monotherapy Population Amvuttra (N = 326) Placebo (N = 328) Amvuttra (N = 196) Placebo (N = 199) 6-MWT (metres) Mean baseline value (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 versus placebo, 26 (13; 40) 32 (14; 50) LS mean (95% CI) p-value a,b < 0.0001 0.0005 KCCQ-OS (points) Mean baseline value (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 versus placebo, 6 (2; 9) 9 (4; 13) LS mean (95% CI) p-value a,b 0.0008 0.0003 NYHA Class % of patients with stable or improved NYHA class at Month 30 68 61 66 56 Difference versus placebo, (%) (95% 9 (1; 16) 13 (3; 22) CI) c p-value c 0.0217 0.0121 Abbreviations: 6-MWT = 6-minute walk test; KCCQ-OS = Kansas City Cardiomyopathy Questionnaire-Overall Summary; LS = least squares; CI = confidence interval; SD = standard deviation; SE = standard error; NYHA = New York Heart Associationa For assessments missing due to death (including heart transplantation and left ventricular assist device implantation) or inability to walk due to ATTR disease progression (applicable to 6-MWT only), data were imputed by resampling from the worst 10% of observed changes.b Estimated from a MMRM (mixed-effect model repeated measures) model.c Based on the 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).