Introduction Transthyretin amyloidosis (ATTR) is a progressive and fatal condition caused by deposition of misfolded transthyretin (TTR) as amyloid fibrils in multiple tissues. ATTR is classified as either hereditary (hATTR) or wild-type (wtATTR), depending on the presence or absence of amyloidogenic TTR gene variants, and manifests as either primarily cardiomyopathy (ATTR-CM), polyneuropathy, or a mixed phenotype. RNA interference (RNAi) therapeutics suppress the hepatic production of TTR by targeting wild-type and variant TTR mRNA for degradation. Previous studies showed that rapid TTR knockdown with RNAi therapeutics improves outcomes for ATTR patients regardless of etiology or manifestation. Most recently, vutrisiran was shown to improve outcomes for patients with ATTR-CM across multiple domains in the HELIOS-B study, including reducing cardiovascular events and all-cause mortality, and improving functional capacity and quality of life. Larger reductions in TTR levels correlated with greater clinical benefit in patients with hATTR and polyneuropathy, suggesting that greater TTR knockdown may offer similar benefits in ATTR-CM. Nucresiran (ALN-TTRsc04) is a next-generation RNAi therapeutic designed for the treatment of ATTR. In a Phase 1, ascending-single-dose study in healthy adults (NCT05661916), nucresiran led to rapid and sustained knockdown of TTR. Up to 95% knockdown by Day 15 and >90% mean reductions through Month 6 were achieved with subcutaneously administered doses ≥300 mg that were well tolerated. Hypothesis The efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of nucresiran in patients with ATTR-CM will be evaluated in a global, Phase 3, randomized, placebo-controlled study, the rationale and design of which will be described. Methods The study design, including inclusion and exclusion criteria, will be finalized in Q1 2025. Enrollment of adult patients with ATTR-CM is expected to begin in 2025. Key endpoints will assess mortality and cardiovascular events. Results The nucresiran Phase 3 ATTR-CM study design and rationale will be presented. Conclusions The Phase 3 study will investigate the efficacy, safety, and PK/PD of nucresiran in patients with ATTR-CM. Nucresiran has the potential to provide greater and more sustained TTR knockdown with lower inter-patient variability and less frequent dosing than current TTR-lowering therapies. This abstract will be presented at HFA 2025, May 17-20, 2025, Belgrade, Serbia.

Importance Right ventricular (RV) dysfunction is common among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and portends worse prognosis. The effects of vutrisiran on RV function remain incompletely characterized. Objective To determine the prevalence and prognostic importance of RV dysfunction in ATTR-CM, and to evaluate the effect of vutrisiran on RV function. Design, Setting, and Participants This post hoc analysis of the HELIOS-B randomized clinical trial (December 2019 and August 2021) included participants with ATTR-CM who had adequate echocardiographic images. Median (IQR) follow-up was 36 (33-36) months. Data analysis was performed from September to December 2025. Interventions Vutrisiran, 25 mg, subcutaneously every 12 weeks vs placebo. Main Outcomes and Measures The primary outcome was a composite of all-cause mortality and recurrent cardiovascular events. RV function was assessed using tricuspid annular systolic myocardial velocity (RV S′), RV fractional area change (RV FAC), RV free wall strain (RVFWS), and RVFWS indexed to pulmonary artery systolic pressure (RVFWS/PASP). Associations with outcomes and treatment effects were evaluated. Results Among 655 participants with ATTR-CM who were randomized, 548 had adequate echocardiographic images. The mean (SD) age was 75 (7) years; 506 patients (92%) were men and 42 (8%) were women. RV dysfunction was more prevalent if defined by abnormal RVFWS (absolute RVFWS ≤20%, 85%) vs RV S′ (≤9.5cm/s, 56%) or RV FAC (≤35%, 31%). Patients in the worst RVFWS quartile (<10.8%, n = 137) had lower estimated glomerular filtration rate, lower left ventricular ejection fraction, and more advanced National Amyloidosis Centre (NAC) stage. Worse RVFWS and RVFWS/PASP were significantly associated with greater risk of all-cause mortality and recurrent cardiovascular events, independent of clinical characteristics, NAC stage, and LV global longitudinal strain. In contrast, associations of RV S′ and RV FAC with outcomes were attenuated after multivariable adjustment. At 30 months, vutrisiran stabilized RVFWS (between-group difference: 1.6%, 95% CI, 0.7 to 2.6%) and improved RVFWS/PASP compared with placebo (between-group difference: +0.08%/mm Hg; 95% CI, 0.03%/mm Hg to 0.13%/mm Hg), with no significant effect on RV FAC (−1.6%; 95% CI, −3.7% to 0.6%). Conclusions and Relevance RV dysfunction assessed by RVFWS is highly prevalent in ATTR-CM and independently predicts mortality and recurrent CV events, whereas conventional RV measures may underestimate RV dysfunction and lack independent prognostic value. This study found that, consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran stabilized RVFWS and improved RVFWS/PASP at 30 months. Trial Registration ClinicalTrials.gov Identifier: NCT04153149

Background Vutrisiran, an RNA interference therapeutic, reduced all-cause mortality and recurrent cardiovascular events in patients with transthyretin amyloid cardiomyopathy (ATTR-CM) in the HELIOS-B trial. Whether concomitant disease-modifying or heart failure therapy modifies the efficacy of vutrisiran has not been described. Objectives We aimed to characterize patterns of concomitant therapy use in HELIOS-B, describe medication initiation rates by treatment arm, and evaluate whether concomitant therapy modified vutrisiran’s treatment effect. Methods In HELIOS-B, 654 randomized patients with ATTR-CM received vutrisiran or placebo. We assessed baseline use and postrandomization initiation of tafamidis, sodium-glucose cotransporter-2 (SGLT2) inhibitors, mineralocorticoid receptor antagonists (MRA), beta-blockers, and renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors), and used time-updated Lin-Wei-Yang-Ying models to evaluate treatment effect modification on the primary composite endpoint of all-cause mortality and recurrent cardiovascular events. Results At baseline, 40% of participants were receiving tafamidis and 77% at least 1 heart failure medication. MRAs and SGLT2 inhibitors were the most frequently initiated therapies during follow-up, with initiation rates numerically higher across all heart failure medication classes in the placebo group. There was no statistically significant evidence that the treatment effect of vutrisiran was modified by baseline or time-updated use of any medication class (P-interaction: tafamidis 0.95, SGLT2 inhibitors 0.59, MRA 0.92, beta-blockers 0.75, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors 0.82). Conclusions In HELIOS-B, there was no statistically significant evidence that the treatment benefit of vutrisiran on all-cause mortality and recurrent cardiovascular events was modified by concomitant use of tafamidis or heart failure therapies. These findings support the consistency of vutrisiran’s efficacy across the spectrum of contemporary ATTR-CM pharmacotherapy. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149)

AIMS:Sex differences in transthyretin cardiac amyloidosis (ATTR-CM) are increasingly recognised; however, women are underrepresented in trials and sex-specific treatment effects remain incompletely understood. We evaluated sex differences in baseline phenotype, outcomes and vutrisiran response in ATTR-CM. METHODS:HELIOS-B was a phase 3, randomised, double-blind, placebo-controlled trial enrolling patients with wild-type or variant ATTR-CM, randomised 1:1 to receive subcutaneous vutrisiran (25 mg every 12 weeks) or placebo. This prespecified analysis assessed baseline characteristics, efficacy, and safety according to sex. RESULTS:Among 654 participants, 49 (7.5%) were women. Variant ATTR-CM was more prevalent in women (42.9% vs 9.1%, p < 0.001). At baseline, women had smaller absolute left ventricular dimensions and wall thicknesses (p < 0.05), but when indexed to body surface area, wall thicknesses were higher. Women demonstrated better systolic function, but worse 6-minute walk distances and quality-of-life scores. Vutrisiran reduced the primary composite endpoint of all-cause mortality and recurrent cardiovascular events in both sexes (women, HR 0.59, 95% CI 0.26-1.30; men, HR 0.71, 95% CI 0.54-0.94; p-interaction = 0.66). Confidence intervals were wide in women, reflecting limited precision from small subgroup size. Mortality reduction was observed in both sexes (HR 0.56, 95% CI 0.14-2.34 in women, HR 0.65, 95% CI 0.46-0.90 in men, p-interaction = 0.91 for all-cause mortality at 42 months). Decline in 6-minute walk distance and quality-of-life scores was attenuated in both sexes, with no statistically detectable sex-specific interaction, and safety outcomes were comparable. CONCLUSION:Women with ATTR-CM demonstrated a distinct baseline phenotype in HELIOS-B. Despite this, vutrisiran showed no statistically detectable heterogeneity of treatment effect by sex within the limits of statistical power, supporting therapeutic benefit across the phenotypic spectrum of ATTR-CM.

Importance Left atrial (LA) dysfunction may play an important role in the pathophysiology of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and is driven by LA remodeling and amyloid infiltration. Objectives To evaluate the prognostic significance of LA structure and function among patients with ATTR-CM and to assess the effects of vutrisiran on these parameters. Design, Setting, and Participants Post hoc analyses were conducted of the HELIOS-B phase 3 randomized clinical trial, which enrolled patients with ATTR-CM between December 2019 and August 2021 at 87 sites in 26 countries. Median (IQR) follow-up was 36 (33-36) months. Data were analyzed from July through November 2025. Interventions Vutrisiran (25 mg subcutaneously every 3 months) vs placebo. Main Outcomes and Measures The primary outcome was all-cause mortality (ACM) and recurrent cardiovascular events. LA structure (LA volume index [LAVi]) and function (LA reservoir [LASr], conduit [LAScd], and contractile strain [LASct]) were assessed, including the effect of vutrisiran on these measures at 30 months. Results A total of 655 patients were enrolled. Among 644 patients with measurable LA strain (median [IQR] age, 77 [72-80] years; 48 female patients [7.5%]; 569 (88.4%) with wild-type ATTR), mean (SD) LA strain measures were substantially below normal (LASr: 9.5% [6.0%]; LAScd: 6.9% [3.9%]; LASct: 4.2% [4.0%]). Patients with worse LASr had more advanced disease, more atrial fibrillation, and more left ventricular systolic and diastolic dysfunction. LASr and LASct were independently associated with ACM and recurrent cardiovascular events (LASr: hazard ratio [HR] per 5% worsening, 1.37; 95% CI, 1.13-1.68; P = .002; LASct: HR per 5% worsening, 1.53; 95% CI, 1.08-2.17; P = .02), recurrent heart failure hospitalizations (LASr: HR, 1.66; 95% CI, 1.22-2.25; P = .001; LASct: HR, 2.23; 95% CI. 1.46-3.71; P < .001), and incident atrial fibrillation (LASr: HR, 1.30; 95% CI, 1.03-1.63; P = .03; LASct: HR, 2.02; 95% CI, 1.38-2.96; P < .001). In contrast, LAVi was not associated with these outcomes. LA strain measures at baseline did not modify the treatment effect of vutrisiran on ACM and recurrent cardiovascular events (LASr: P value for interaction = .60; LAScd: P value for interaction = .58; LASct: P value for interaction = .47). Vutrisiran attenuated worsening in LA strain vs placebo at month 30 (LASr: +1.2%; 95% CI, +0.4% to +1.9%; LAScd: +0.8%; 95% CI, +0.3% to +1.4%; LASct: +0.8%; 95% CI, 0% to +1.6%). Conclusions and Relevance Per the results of this secondary analysis of the HELIOS-B randomized clinical trial, LA dysfunction is common among patients with ATTR-CM and portends a worse prognosis. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran attenuated worsening in LA strain at 30 months, supporting the importance of LA function in the pathophysiology of ATTR-CM and the ability of silencer therapy with vutrisiran to attenuate worsening atrial myopathy in amyloid heart disease. Trial Registration ClinicalTrials.gov Identifier: NCT04153149

Importance:Right ventricular (RV) dysfunction is common among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and portends worse prognosis. The effects of vutrisiran on RV function remain incompletely characterized. Objective:To determine the prevalence and prognostic importance of RV dysfunction in ATTR-CM, and to evaluate the effect of vutrisiran on RV function. Design, Setting, and Participants:This post hoc analysis of the HELIOS-B randomized clinical trial (December 2019 and August 2021) included participants with ATTR-CM who had adequate echocardiographic images. Median (IQR) follow-up was 36 (33-36) months. Data analysis was performed from September to December 2025. Interventions:Vutrisiran, 25 mg, subcutaneously every 12 weeks vs placebo. Main Outcomes and Measures:The primary outcome was a composite of all-cause mortality and recurrent cardiovascular events. RV function was assessed using tricuspid annular systolic myocardial velocity (RV S'), RV fractional area change (RV FAC), RV free wall strain (RVFWS), and RVFWS indexed to pulmonary artery systolic pressure (RVFWS/PASP). Associations with outcomes and treatment effects were evaluated. Results:Among 655 participants with ATTR-CM who were randomized, 548 had adequate echocardiographic images. The mean (SD) age was 75 (7) years; 506 patients (92%) were men and 42 (8%) were women. RV dysfunction was more prevalent if defined by abnormal RVFWS (absolute RVFWS ≤20%, 85%) vs RV S' (≤9.5cm/s, 56%) or RV FAC (≤35%, 31%). Patients in the worst RVFWS quartile (<10.8%, n = 137) had lower estimated glomerular filtration rate, lower left ventricular ejection fraction, and more advanced National Amyloidosis Centre (NAC) stage. Worse RVFWS and RVFWS/PASP were significantly associated with greater risk of all-cause mortality and recurrent cardiovascular events, independent of clinical characteristics, NAC stage, and LV global longitudinal strain. In contrast, associations of RV S' and RV FAC with outcomes were attenuated after multivariable adjustment. At 30 months, vutrisiran stabilized RVFWS (between-group difference: 1.6%, 95% CI, 0.7 to 2.6%) and improved RVFWS/PASP compared with placebo (between-group difference: +0.08%/mm Hg; 95% CI, 0.03%/mm Hg to 0.13%/mm Hg), with no significant effect on RV FAC (-1.6%; 95% CI, -3.7% to 0.6%). Conclusions and Relevance:RV dysfunction assessed by RVFWS is highly prevalent in ATTR-CM and independently predicts mortality and recurrent CV events, whereas conventional RV measures may underestimate RV dysfunction and lack independent prognostic value. This study found that, consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran stabilized RVFWS and improved RVFWS/PASP at 30 months. Trial Registration:ClinicalTrials.gov Identifier: NCT04153149.

Importance:Left atrial (LA) dysfunction may play an important role in the pathophysiology of transthyretin amyloidosis with cardiomyopathy (ATTR-CM) and is driven by LA remodeling and amyloid infiltration. Objectives:To evaluate the prognostic significance of LA structure and function among patients with ATTR-CM and to assess the effects of vutrisiran on these parameters. Design, Setting, and Participants:Post hoc analyses were conducted of the HELIOS-B phase 3 randomized clinical trial, which enrolled patients with ATTR-CM between December 2019 and August 2021 at 87 sites in 26 countries. Median (IQR) follow-up was 36 (33-36) months. Data were analyzed from July through November 2025. Interventions:Vutrisiran (25 mg subcutaneously every 3 months) vs placebo. Main Outcomes and Measures:The primary outcome was all-cause mortality (ACM) and recurrent cardiovascular events. LA structure (LA volume index [LAVi]) and function (LA reservoir [LASr], conduit [LAScd], and contractile strain [LASct]) were assessed, including the effect of vutrisiran on these measures at 30 months. Results:A total of 655 patients were enrolled. Among 644 patients with measurable LA strain (median [IQR] age, 77 [72-80] years; 48 female patients [7.5%]; 569 (88.4%) with wild-type ATTR), mean (SD) LA strain measures were substantially below normal (LASr: 9.5% [6.0%]; LAScd: 6.9% [3.9%]; LASct: 4.2% [4.0%]). Patients with worse LASr had more advanced disease, more atrial fibrillation, and more left ventricular systolic and diastolic dysfunction. LASr and LASct were independently associated with ACM and recurrent cardiovascular events (LASr: hazard ratio [HR] per 5% worsening, 1.37; 95% CI, 1.13-1.68; P = .002; LASct: HR per 5% worsening, 1.53; 95% CI, 1.08-2.17; P = .02), recurrent heart failure hospitalizations (LASr: HR, 1.66; 95% CI, 1.22-2.25; P = .001; LASct: HR, 2.23; 95% CI. 1.46-3.71; P < .001), and incident atrial fibrillation (LASr: HR, 1.30; 95% CI, 1.03-1.63; P = .03; LASct: HR, 2.02; 95% CI, 1.38-2.96; P < .001). In contrast, LAVi was not associated with these outcomes. LA strain measures at baseline did not modify the treatment effect of vutrisiran on ACM and recurrent cardiovascular events (LASr: P value for interaction = .60; LAScd: P value for interaction = .58; LASct: P value for interaction = .47). Vutrisiran attenuated worsening in LA strain vs placebo at month 30 (LASr: +1.2%; 95% CI, +0.4% to +1.9%; LAScd: +0.8%; 95% CI, +0.3% to +1.4%; LASct: +0.8%; 95% CI, 0% to +1.6%). Conclusions and Relevance:Per the results of this secondary analysis of the HELIOS-B randomized clinical trial, LA dysfunction is common among patients with ATTR-CM and portends a worse prognosis. Consistent with its beneficial effects on other measures of cardiac structure and function, vutrisiran attenuated worsening in LA strain at 30 months, supporting the importance of LA function in the pathophysiology of ATTR-CM and the ability of silencer therapy with vutrisiran to attenuate worsening atrial myopathy in amyloid heart disease. Trial Registration:ClinicalTrials.gov Identifier: NCT04153149.

BACKGROUND:Patisiran rapidly knocked down transthyretin and preserved functional capacity in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in the global Phase 3 APOLLO-B study (NCT03997383). OBJECTIVES:To evaluate patisiran efficacy and safety in post hoc analysis of the Brazilian subpopulation of APOLLO-B. METHODS:Patients were randomized 1:1 to patisiran 0.3 mg/kg or placebo every 3 weeks for 12 months. The primary endpoint was the change from baseline (CFB) in functional capacity (6-minute walk test [6MWT]) at Month 12. Secondary endpoints included CFB to Month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. Exploratory endpoints included CFB in cardiac biomarkers and Perugini grade of cardiac uptake during technetium-99m scintigraphy. RESULTS:Forty-two patients enrolled in Brazil (patisiran, n=20; placebo, n=22). Patisiran showed benefit in 6MWT and KCCQ-OS scores vs. placebo; CFB (95% confidence interval [CI]) in 6MWT (median) and KCCQ-OS scores (least squares mean) was -2.0 m (-58.5, 42.9) and 9.37 (1.93, 16.81) points with patisiran vs. -30.1 m (-72.2, 3.5) and 2.62 (-4.68, 9.92) points for placebo. For cardiac biomarkers, the mean fold-change from baseline (95% CI) for N-terminal prohormone B-type natriuretic peptide and troponin I was 1.31 (1.06, 1.61) and 1.12 (0.94, 1.34) for patisiran, and 1.71 (1.39, 2.10) and 1.28 (1.08, 1.53) for placebo, respectively. Perugini grade improved in 11/18 (61.1%) and 0/10 evaluable patients with patisiran and placebo, respectively. There were no deaths in the patisiran group vs. 3 in the placebo group.

In the HELIOS-B randomized clinical trial, the RNA interference therapeutic agent vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events among patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). In this secondary analysis of HELIOS-B, we evaluated vutrisiran’s effects on echocardiographic measures of cardiac structure and function in patients with ATTR-CM receiving vutrisiran or placebo ( n = 654, 93% men). At 30 months after treatment, as compared to the placebo group, vutrisiran treatment attenuated increases in mean left ventricular (LV) wall thickness (least squares mean difference: −0.4 mm; 95% confidence interval (CI): −0.8, 0.0; P = 0.03) and LV mass index (−10.6 g m − 2 ; 95% CI: −18.0, −3.3; P < 0.01). Vutrisiran treatment also attenuated declines in LV ejection fraction (2.0%; 95% CI: 0.3, 3.7; P = 0.02), absolute global longitudinal strain (1.2%; 95% CI: 0.7, 1.7; P < 0.01) and LV stroke volume (4.1 ml; 95% CI: 1.7, 6.4; P < 0.01), and decreased both the average ratio of early diastolic transmitral flow velocity to early diastolic mitral annular tissue velocity (−2.0; 95% CI: −2.9, −1.2; P < 0.01) and the early to late diastolic transmitral flow velocities ratio (−0.3; 95% CI: −0.6, −0.0; P = 0.04), as compared to placebo. Consistent with its clinical benefits, these echocardiographic findings indicate favorable effects of vutrisiran on cardiac structure and function in patients with ATTR-CM. ClinicalTrials.gov registration: NCT04153149 .

Background Transthyretin amyloid cardiomyopathy (ATTR-CM), caused by deposition of transthyretin amyloid fibrils in the heart, is associated with high morbidity and mortality. In HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), the RNA interference therapeutic agent vutrisiran reduced rates of the primary composite outcome of all-cause death and recurrent cardiovascular events among patients with ATTR-CM and had beneficial effects on cardiac structure and function over 30 months. Objectives The purpose of this study was to investigate associations of echocardiographic measures of cardiac structure and function with the primary outcome and to assess whether favorable changes in cardiac structure and function with vutrisiran were associated with improvements in outcomes. Methods HELIOS-B randomized 655 patients with ATTR-CM to vutrisiran (25 mg subcutaneously every 12 weeks) or placebo. Echocardiograms were performed at baseline and months 12, 18, 24, and 30. Associations of baseline echocardiographic parameters with the primary outcome were analyzed using modified Andersen-Gill models adjusted for age, sex, ATTR disease type, and National Amyloidosis Centre stage, and stratified by baseline tafamidis use and treatment assignment. Changes in cardiac function from baseline to month 18 were compared between treatment arms and related to outcomes in landmark analyses. Results Among the 654 participants with available echocardiographic data (median age 77 years, 93% male, 88% wild-type transthyretin), baseline left and right ventricular systolic and diastolic function were independently associated with the primary outcome (HR per unit increase, left ventricular ejection fraction, 0.90 per 5% increase, 95% CI: 0.86-0.95; absolute global longitudinal strain, 0.92 per 1% increase, 95% CI: 0.89-0.96; tricuspid annular systolic myocardial velocity, 0.94 per 1-cm/s increase, 95% CI: 0.90-0.98; average E/e’, 1.03 per 1-U increase, 95% CI: 1.01-1.04). At 18 months, vutrisiran attenuated declines in left ventricular and right ventricular systolic function (least squares mean difference: left ventricular ejection fraction, 1.6%, 95% CI: 0.1-3.2; absolute global longitudinal strain, 0.7%, 95% CI: 0.3-1.2; tricuspid annular systolic myocardial velocity, 0.5 cm/s, 95% CI: 0.1-0.9). Worsening in these parameters at 18 months was associated with a heightened risk of the primary outcome. Conclusions Echocardiographic measures of biventricular systolic and diastolic function provide important prognostic information beyond National Amyloidosis Centre stage in patients with ATTR-CM. Vutrisiran improved diastolic function and attenuated declines in left ventricular and right ventricular systolic function over 18 months. The benefits on cardiac function with vutrisiran may partly underlie its beneficial effects on clinical outcomes.

ImportanceThere is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN.ObjectiveTo present the long-term efficacy and safety of patisiran in adults with hATTR-PN.Design, Setting, and ParticipantsThis global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE.InterventionPatisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years.Main Outcomes and MeasuresOutcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed.ResultsAt the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival.Conclusions and RelevanceIn the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine.Trial RegistrationClinicalTrials.gov Identifier: NCT02510261

BACKGROUND:Patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) suffer substantial morbidity and mortality. The meaningful preservation of functional capacity and quality of life are important priorities. OBJECTIVES:The 6-minute walk test (6MWT), a measure of functional capacity, was the primary outcome in the APOLLO-B study of patisiran in patients with ATTR-CM; the treatment benefit vs placebo was +15 m over 12 months. We estimated the minimal clinically important difference for change in 6MWT performance. METHODS:Change from baseline in 6MWT performance was anchored to established categories of clinically important change in the Kansas City Cardiomyopathy Questionnaire-Overall Summary score. To relate changes in 6MWT performance to activities of daily living, we fit a proportional-odds cumulative logit model for items in the Kansas City Cardiomyopathy Questionnaire Physical Limitation domain. RESULTS:The APOLLO-B trial randomized 360 patients to receive placebo (n = 179) or patisiran (n = 181). The estimated minimal clinically important difference in 6MWT was 6.9 to 7.8 m. When comparing the change from baseline in 6MWT at month 12 between 2 patients, 15 m greater preservation was associated with approximately 10% to 16% lower odds of deterioration in walking 1 block (OR: 0.88 [95% CI: 0.83-0.93]), climbing stairs (OR: 0.84 [95% CI: 0.80-0.89]), hurrying/jogging (OR: 0.88 [95% CI: 0.83-0.93]), dressing oneself (OR: 0.85 [95% CI: 0.81-0.90]), and performing yard/housework or carrying groceries (OR: 0.89 [95% CI: 0.84-0.93]). CONCLUSIONS:In patients with ATTR-CM treated with patisiran, mean population-level differences of 7 to 8 m in 6MWT have practical relevance. The magnitude of the impact of patisiran on 6MWT performance over 12 months in APOLLO-B was associated with preserving the ability to perform activities of daily living.

BACKGROUND:Before the development of disease-modifying therapies for transthyretin amyloidosis cardiomyopathy (ATTR-CM), N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and troponin I/T were recognized as independent prognostic biomarkers of mortality. This study evaluated the prognostic value of these biomarkers in a contemporary patient population and the impact of vutrisiran, an RNA interference therapeutic that rapidly knocks down circulating transthyretin, on biomarker levels. OBJECTIVES:This study sought to evaluate the association between risk of cardiovascular events and all-cause mortality with baseline NT-proBNP and troponin I levels and changes from baseline at month 6 in patients from HELIOS-B and explore how vutrisiran impacts biomarkers over time. METHODS:In HELIOS-B, a double-blind, placebo-controlled study, 655 patients with ATTR-CM were randomized 1:1 to receive vutrisiran or placebo for up to 36 months. The primary endpoint was a composite outcome of all-cause mortality and recurrent cardiovascular events. All-cause mortality through 42 months was a secondary endpoint. NT-proBNP and troponin I were assessed as prespecified exploratory endpoints. RESULTS:Baseline NT-proBNP and troponin I levels were independently associated with risks of the composite outcome and all-cause mortality (P < 0.0001 for both biomarkers and endpoints). At month 6, increases in NT-proBNP from baseline were associated with higher risk of the composite outcome and all-cause mortality, and decreases in troponin I were associated with a lower risk of the composite outcome. At month 30, the median changes from baseline of NT-proBNP and troponin I were 753 pg/mL (Q1-Q3: -8 to 2,573 pg/mL) and 9.7 pg/mL (Q1-Q3: -6.3 to 41.2 pg/mL) in the placebo arm and 118 pg/mL (Q1-Q3: -419 to 911 pg/mL) and -5.8 pg/mL (Q1-Q3: -25.0 to 10.0 pg/mL) in the vutrisiran arm. The geometric mean fold-change ratios (vutrisiran/placebo) were 0.68 (95% CI: 0.61-0.76) for NT-proBNP and 0.68 (95% CI: 0.62-0.75) for troponin I (P < 0.0001 for both). CONCLUSIONS:Patterns of associations between biomarkers and adverse outcomes support the importance of early treatment initiation and the potential for risk reduction in patients with ATTR-CM. Vutrisiran maintained stable or reduced levels of both biomarkers consistent with the benefit of treatment in reducing the risk of cardiovascular events and all-cause mortality. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).

BACKGROUND Outpatient worsening heart failure (HF), defined by initiation or intensification of diuretics, is adversely prognostic for patients with either reduced or preserved ejection fraction. OBJECTIVES This study sought to investigate the prognostic value of outpatient worsening HF in transthyretin amyloidosis with cardiomyopathy and the effect of patisiran treatment. METHODS Post hoc analyses of the APOLLO-B trial (NCT03997383) evaluated the associations between outpatient worsening HF (defined by oral diuretic initiation or intensification), measures of disease progression, and a composite endpoint of all-cause mortality and cardiovascular (CV) events. We further examined the effect of patisiran on outpatient worsening HF over 24 months (ie, during the double-blind and open-label extension periods). RESULTS In APOLLO-B, 144 (40.1%) patients had no event, 157 (43.7%) had outpatient worsening HF, 13 (3.6%) required an urgent HF visit, 118 (32.9%) had a CV hospitalization, and 47 (13.1%) died. Outpatient worsening HF was associated with an increased risk of all-cause mortality and CV events (HR: 2.21; 95% CI: 1.58-3.08), as well as a greater deterioration in 6-minute walk test distance, Kansas City Cardiomyopathy Questionnaire-Overall Summary score, and NYHA functional class and a greater increase in N-terminal prohormone of B-type natriuretic peptide. Addition of outpatient diuretic initiation or intensification to the composite endpoint of all-cause mortality and CV events increased the overall number of patients having an event from 141 to 215 (a 52% increase). Patisiran reduced the risk of outpatient worsening HF (HR: 0.70; 95% CI: 0.51-0.96) over 24 months. CONCLUSIONS During APOLLO-B, outpatient worsening HF in patients with transthyretin amyloidosis with cardiomyopathy was frequent, prognostic, and reduced by patisiran. (JACC. 2025;85:744-752) (c) 2025 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Transthyretin cardiomyopathy (ATTR-CM) is associated with high morbidity and mortality. Vutrisiran, an RNA interference therapeutic, rapidly knocks down circulating levels of TTR, thus suppressing the amyloid deposition that drives disease progression. In HELIOS-B, vutrisiran decreased risks of cardiovascular (CV) events and all-cause mortality (ACM) for patients with ATTR-CM. Vutrisiran also positively impacted echocardiographic measures of left ventricular (LV) structure and function compared to placebo. Effects on systolic and diastolic function were observed as early as month 12 of treatment. Objective To evaluate the impact of vutrisiran on echocardiographic measures of cardiac structure and function, and their prognostic value, in patients with ATTR-CM. Method HELIOS-B is a phase 3, randomized, double-blind, placebo-controlled, multicenter study. HELIOS-B randomized 655 patients with wild-type ATTR (wtATTR) or hereditary ATTR-CM to vutrisiran (25mg) or placebo Q3M. The primary endpoint was a composite of ACM and recurrent CV events (CV hospitalizations and urgent heart failure visits) assessed separately in the overall population and in the monotherapy population (defined as patients not on tafamidis at baseline). Patients underwent echocardiograms at baseline, months 12, 18, 24, and 30. The association of select echocardiographic parameters on outcomes, and the impact of vutrisiran on echocardiographic parameters was assessed. Results At baseline (median age 77 years, 93% male, 88% wtATTR) mean LV ejection fraction was 56±13%, absolute peak longitudinal strain 14±3%, and mean LV wall thickness 1.8±0.3cm. Prespecified analyses evaluating the prognostic significance of echocardiographic parameters and the impact of vutrisiran will be presented. Conclusion Improvements in cardiac structure and function support the benefits of vutrisiran in reducing the risk of CV events and ACM compared to placebo for patients with ATTR-CM.These results will likely demonstrate the prognostic significance of echocardiographic parameters of cardiac structure and function on later clinical outcomes of CV events and ACM, as well as the impact of vutrisiran treatment to improve cardiac structure and function.

BACKGROUND:This study assessed the effectiveness and safety of patisiran in patients with V122I/T60A variant transthyretin (ATTRv) amyloidosis with polyneuropathy. These variants have been under-represented in previous trials of gene-silencing agents. METHODS:This was a multicenter, phase IV study conducted at 27 sites in the USA. Patients were ≥ 18 years, diagnosed with ATTRv amyloidosis with polyneuropathy and a documented V122I or T60A variant. Patisiran-treated patients were enrolled prospectively, ambispectively, and retrospectively. The primary endpoint was the proportion of patients with a stable or improved polyneuropathy disability (PND) score at 12 months vs. baseline. Safety was monitored throughout the trial. RESULTS:Sixty-seven patients were enrolled, of whom 58 received ≥ 1 dose of patisiran. In the efficacy population, 42/45 (93.3%) patients demonstrated stable or improved PND scores from baseline to Month 12. Patients also showed stable or improved quality of life, health status, autonomic symptoms, and cardiac function vs. baseline. Adverse events occurred in 13/42 (31.0%) patients in the prospective and ambispective cohorts; most were mild or moderate. No deaths or cardiac hospitalizations were considered related to patisiran. CONCLUSIONS:Patisiran demonstrated a consistent positive effect across multiple endpoints in patients with V122I/T60A ATTRv amyloidosis, including polyneuropathy manifestations.

Resumo Fundamento A patisirana reduziu rapidamente a transtirretina e preservou a capacidade funcional em pacientes com amiloidose por transtirretina com cardiomiopatia (ATTR-CM) no estudo Fase 3 APOLLO-B (NCT03997383). Objetivos Avaliar a eficácia e segurança da patisirana (análise post hoc) na subpopulação brasileira do APOLLO-B. Métodos Pacientes foram randomizados 1:1 para patisirana 0,3 mg/kg ou placebo uma vez a cada 3 semanas por 12 meses. O desfecho primário foi a alteração em relação ao período basal (ARPB) na capacidade funcional (teste de caminhada de 6 minutos [6MWT]) no mês 12. Desfechos secundários incluíram ARPB no mês 12 do escore Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS). Desfechos exploratórios incluíram ARPB em biomarcadores cardíacos e na escala de Perugini durante cintilografia com 99m-Tecnécio pirofosfato. Resultados Quarenta e dois pacientes foram incluídos no Brasil (patisirana, n=20; placebo, n=22). Patisirana demonstrou benefício no 6MWT e nos escores KCCQ-OS vs. placebo; ARPB (intervalo de confiança [IC] de 95%) no 6MWT (mediana) e escores KCCQ-OS (média dos mínimos quadrados) foram -2,0 m (-58,5; 42,9) e 9,37 (1,93; 16,81) pontos com patisirana vs. -30,1 m (-72,2; 3,5) e 2,62 (-4,68; 9,92) pontos para o placebo. Para biomarcadores cardíacos, a alteração média da razão em relação ao período basal (IC 95%) para peptídeo natriurético tipo B pró-hormonal N-terminal e troponina I foi de 1,31 (1,06; 1,61) e 1,12 (0,94; 1,34) para patisirana e 1,71 (1,39; 2,10) e 1,28 (1,08; 1,53) para placebo, respectivamente. A escala de Perugini melhorou em 11/18 (61,1%) pacientes e 0/10 pacientes com patisirana e placebo, respectivamente. Não houve mortes no grupo patisirana vs. 3 mortes no grupo placebo. Conclusão A eficácia e a segurança da patisirana em pacientes brasileiros com ATTR-CM foram consistentes com as da população global do APOLLO-B. Os achados são descritivos devido ao pequeno número de pacientes.

Importance:There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective:To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants:This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention:Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures:Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life-Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results:At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and -3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance:In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration:ClinicalTrials.gov Identifier: NCT02510261.