Vutrisiran: HELIOS-B Study

Vutrisiran: HELIOS-B Study

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 Summary

Index

Study Design – Patient Demographics and Baseline Characteristics – Primary Endpoint – Secondary Endpoint: All Cause Mortality – Other Secondary Endpoints – Select Exploratory Endpoints – Pharmacodynamic Endpoint – Safety Results – Abbreviations – References

 Study Design

HELIOS-B was a phase 3, global, randomized, double-blind, placebo-controlled, multicenter study designed to evaluate the efficacy and safety of vutrisiran in patients with ATTR-CM, including both hATTR and wtATTR. Patients were randomized (1:1) to receive either vutrisiran 25 mg (n=326) or placebo (n=329) every 3 months by subcutaneous injection for up to 36 months. After the double-blind treatment period, all remaining eligible patients were allowed to receive vutrisiran in an OLE.1

The primary endpoint was the composite outcome of all-cause mortality and recurrent CV events (CV hospitalizations and urgent HF visits) at the end of the double-blind period (up to Month 33–36) in the overall population and in the monotherapy population (patients not receiving tafamidis at baseline).1

This endpoint was tested in parallel between the overall population and the monotherapy population and was analyzed using a modified Andersen-Gill model with a robust variance estimator (LWYY model). Heart transplantation or implantation of a left ventricular assist device, or both, were treated as deaths from any cause. Sensitivity analysis was performed using a Mantel-Haenszel-type stratified win ratio method, stratified by baseline NT-proBNP. Predefined subgroups were stratified according to age at baseline, tafamidis use at baseline, ATTR disease type (hATTR vs wtATTR), and NYHA class.1,3

The secondary endpoints assessed mortality, functional capacity, patient-reported health status and health-related quality of life, and the severity of clinical HF symptoms, including1:

      All-cause mortality up to Month 42 (double-blind period and up to 6 months of OLE data)

      Change from baseline in 6 MWT at Month 30

      Change from baseline in KCCQ-OS at Month 30

      Change from baseline in NYHA class at Month 30

The exploratory endpoints included1:

      Change from baseline in cardiac biomarkers (NT-proBNP and troponin I)

      Change from baseline in peak longitudinal strain, assessed by echocardiogram

      Change from baseline in quality of life, assessed by the EuroQol-5D-5L questionnaire

The pharmacodynamic endpoint was the change from baseline in serum TTR levels at Month 30.1

Safety was monitored throughout the study, including assessments of1:

      AEs

      Clinical laboratory measures

      Vital signs

Inclusion and Exclusion Criteria

Select inclusion and exclusion criteria for HELIOS-B are presented in Table 1.1

Table 1. HELIOS-B Key Inclusion and Exclusion Criteria.1

 Patient Demographics and Baseline Characteristics

A total of 655 patients were enrolled and randomly assigned to receive vutrisiran (n=326) or placebo (n=329). The median age of study participants was 77 years, 93% were male, 88% had wtATTR, and 78% had NYHA Class II heart failure. The patient demographic and clinical characteristics at baseline were similar between the vutrisiran and placebo groups, except that NT-proBNP and troponin I levels were higher in the vutrisiran group than the placebo group in the monotherapy population; and they were not substantially different between the overall and monotherapy populations (Table 2).1

At baseline, concomitant tafamidis use was 40% and 39% in the vutrisiran and placebo groups, respectively. Baseline use of SGLT2 inhibitors was 3% in both treatment groups, and baseline use of diuretics was 80% and 79% in the vutrisiran and placebo groups, respectively.3

Table 2. Baseline Patient Demographics and Clinical Characteristics.1

 Primary Endpoint

Treatment with vutrisiran reduced the risk of the primary composite of all-cause mortality and recurrent CV events, in both the overall population (HR 0.72; 95% CI 0.56, 0.93; P=0.01) and monotherapy population (HR 0.67, 95% CI 0.49, 0.93; P=0.02) (Table 3).1

Table 3. Primary Endpoint and Patients With At Least One Event.1

In both the overall population and monotherapy population, similar effects were observed in all-cause mortality and recurrent CV events across all prespecified subgroups: age at baseline (<75 years vs ≥75 years), tafamidis use at baseline (yes vs no), ATTR disease type (hATTR vs wtATTR), NYHA class (I or II vs III), and baseline NT-proBNP level (≤2000 pg/ml vs >2000 pg/ml).1

 Secondary Endpoint: All-Cause Mortality

Treatment with vutrisiran reduced the risk of all-cause mortality through Month 42, as shown in Table 4, in both the overall population (HR 0.65; 95% CI 0.46, 0.90; P=0.01; Figure 1) and monotherapy population (HR 0.66, 95% CI 0.44, 0.97; P=0.045; Figure 2).1

Table 4. Secondary End Point and Patients Who Died.1

Figure 1. Overall Population: Death from Any Cause.1

Figure 2. Monotherapy Population: Death from Any Cause.1

In both the overall population and monotherapy population, similar effects were observed in all-cause mortality across all prespecified subgroups: age at baseline (<75 years vs ≥75 years), tafamidis use at baseline (yes vs no), ATTR disease type (hATTR vs wtATTR), NYHA class (I or II vs III), and baseline NT‑proBNP level (≤2000 pg/ml vs >2000 pg/ml). Sensitivity analyses of the secondary endpoint were consistent with the secondary endpoint analysis.1

Analyses of All-Cause Mortality and CV Mortality Through Month 42

Analyses of all-cause mortality and CV mortality were conducted through Month 42 (i.e., 33–36 months of the double-blind period and up to 6 additional months of follow-up in the OLE, resulting in 39-42 months total) using a data cut of November 22, 2024. The analyses were not controlled for multiplicity, and as such, p-values are nominal. The endpoint of all-cause mortality from the primary analysis was conducted based on a data cut of May 8, 2024. As compared to 42.4% of patients from the primary data cut, 96.3% of patients had follow-up through Month 42 with the updated data cut.2

Treatment with vutrisiran reduced the risk of all-cause mortality through Month 42 in both the overall population (HR 0.64; 95% CI 0.46, 0.88; nominal P=0.01; event rates at Month 42 [SE]: placebo 28.95 [2.55], vutrisiran 18.36 [2.21]) and monotherapy population (HR 0.61; 95% CI 0.42, 0.90; nominal P=0.02).2

Treatment with vutrisiran reduced the risk of CV mortality through Month 42 in both the overall population (HR 0.67; 95% CI 0.47, 0.96; nominal P=0.04; event rates at Month 42 [SE]: placebo 22.70 [2.40], vutrisiran 14.96 [2.07]) and monotherapy population (HR 0.64; 95% CI 0.41, 0.98; nominal P=0.05).2

 Other Secondary Endpoints

A summary of the other secondary endpoints related to the effect of vutrisiran on functional capacity, patient-reported health status and health-related quality of life, and severity of clinical HF symptoms are presented in Table 5.1

Table 5. Other Secondary Endpoints: 6-MWT, KCCQ-OS, and NYHA Class.1

Analyses of 6-MWT and KCCQ-OS

6-MWT

At Month 30, the proportion of patients who had maintained or improved 6-MWT distance (i.e., did not have a decrease from baseline of more than the cutoff values of >7 m, >15 m, or >35 m) was significantly greater compared with placebo across the cutoff values in both the overall population (7 m [49.6% vs 33.2%], 15 m [55.5% vs 38.6%], and 35 m [68.5% vs 51.6%]) and monotherapy population (7 m [46.9% vs 28.2%], 15 m [53.1% vs 31.5%], and 35 m [62.3% vs 42.7%]).8

KCCQ-OS

At Month 30, the proportion of patients who had maintained or improved KCCQ-OS (i.e., did not have a decrease from baseline of more than the cutoff values of >5 points or >10 points) was significantly greater compared with placebo across the cutoff values in both the overall population (>5 points [63.5% vs 46.6%] and >10 points [74.6% vs 60.7%]) and monotherapy population (>5 points [64.7% vs 38.2%] and >10 points [73.4% vs 51.9%]).8

 Select Exploratory Endpoints

Cardiac Biomarkers

Treatment with vutrisiran led to a 32% relative reduction from baseline in NT‑proBNP and troponin I (geometric mean fold-change ratio: 0.68) at Month 30 when compared with placebo in the overall population (Table 6). The treatment effect of vutrisiran on NT-proBNP and troponin I was observed at Month 6 and increased over time. NT-proBNP and troponin I results were consistent across all prespecified subgroups in both the overall population and monotherapy population.4

Table 6. Change from Baseline in Cardiac Biomarkers at Month 30.3,4

Echocardiographic Parameters

The changes from baseline in select echocardiographic parameters at 30 months are shown in Table 7.5

Table 7. Change from Baseline in Select Echocardiographic Parameters at Month 30.5

Quality of Life

The change from baseline in quality of life as assessed with EuroQol-5D-5-L index at 30 months is shown in Table 8.3

Table 8. Change from Baseline in EuroQol-5D-5L Index at Month 30.3

 Pharmacodynamic Endpoint

In the overall population, the median (95% CI) trough percent reduction from baseline in serum TTR level at Month 30 was 86.8% (83.7%, 88.2%) in the vutrisiran group (Figure 3). The median percent change from baseline in serum TTR at Month 30 was generally consistent across vutrisiran-treated subgroups regardless of baseline characteristics or baseline disease severity.6

Figure 3. Median Percent Change from Baseline in Serum TTR Level Through Month 30.6,a

 Safety Results

In the overall population, the proportion of patients with at least one AE and the incidence of AEs and cardiac AEs was similar between treatment groups. The majority of AEs were mild or moderate in severity.7 A summary of the safety results during the double-blind period are presented in Table 9.3

Table 9. Safety Summary.3

There were no clinically relevant changes in laboratory measures (including hematologic measures, blood chemistry measures, liver function tests, and renal function tests), vital signs, or electrocardiograms in either treatment group.1

 Abbreviations

6-MWT = 6-minute walk test; AE = adverse event; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; COVID-19 = coronavirus disease 2019; CV = cardiovascular; E/A = ratio of early to late diastolic transmitral inflow velocities; E/e’ = ratio of early mitral inflow velocity to lateral early diastolic mitral annular velocity; eGFR = estimated glomerular filtration rate; EuroQoL-5D-5L = EuroQoL 5-dimensions-5 levels; GLS = global longitudinal strain; hATTR = hereditary transthyretin amyloidosis; HF = heart failure; HR = hazard ratio; IQR = interquartile range; KCCQ‑OS = Kansas City Cardiomyopathy Questionnaire-Overall Summary; LS = least squares; LV = left ventricular; LWYY = Lin‑Wei-Yang-Ying; NAC = National Amyloidosis Centre; NT‑proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; OLE = open-label extension; PND = polyneuropathy disability; RV = right ventricular; RV S’ = right ventricular systolic myocardial velocity; SAE = safety adverse event; SE = standard error; SEM = standard error of the mean; SGLT2 = sodium-glucose cotransporter-2; TDI lateral e’ = lateral peak early diastolic mitral annular tissue velocity; TTR = transthyretin; wtATTR = wild-type transthyretin amyloidosis.

Updated 09 June 2026

 References

1.  Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

2.  Witteles RM, Garcia-Pavia P, Damy T, et al. Vutrisiran improves survival and reduces cardiovascular events in ATTR amyloid cardiomyopathy. J Am Coll Cardiol. 2025;85(20):1959-1970. doi:10.1016/j.jacc.2025.04.008

3.  Supplement to: Fontana M, Berk JL, Gillmore JD, et al. Vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. N Engl J Med. 2025;392(1):33-44. doi:10.1056/NEJMoa2409134

4.  Maurer MS, Berk JL, Damy T, et al. Impact of vutrisiran on cardiac biomarkers in patients with transthyretin amyloidosis with cardiomyopathy from HELIOS-B. J Am Coll Cardiol. 2025;86(6):459-475. doi:10.1016/j.jacc.2025.04.055

5.  Jering KS, Fontana M, Lairez O, et al. Effects of vutrisiran on cardiac structure and function in patients with transthyretin amyloidosis with cardiomyopathy: secondary outcomes of the HELIOS-B trial. Nat Med. 2025:1-9. doi:10.1038/s41591-025-03851-z

6.  Fontana M, Algalarrondo V, Garcia-Pavia P, et al. Vutrisiran-mediated knockdown of transthyretin in patients with ATTR amyloidosis. Clin Pharmacokinet. 2026:1-13. doi:10.1007/s40262-026-01651-3

7.  Fontana M, Berk JL, Gillmore JD, et al. Primary results from HELIOS-B, a phase 3 study of vutrisiran in patients with transthyretin amyloidosis with cardiomyopathy. Presented at: European Society of Cardiology (ESC) Congress; August 30-September 2, 2024; London, UK.

8.  Sheikh FH, Habib G, Tang WHW, et al. Impact of vutrisiran on functional capacity and quality of life in transthyretin amyloidosis with cardiomyopathy. J Am Coll Cardiol. 2025;85(20):1943-1955. doi:10.1016/j.jacc.2025.03.454