Vutrisiran: HELIOS-B Results by Baseline Heart Failure Disease Severity

Vutrisiran: HELIOS-B Results by Baseline Heart Failure Disease Severity

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 Summary

Index

Study Design – Patient Demographics & Baseline Characteristics – Efficacy Results – 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. The primary endpoint was the composite endpoint of all-cause mortality and recurrent CV events (CV hospitalizations and urgent heart failure visits) at the end of the double-blind period in the overall population and in the monotherapy population (patients not receiving tafamidis at baseline). After the double-blind period, all eligible patients remaining in the study were allowed to receive vutrisiran in an OLE.2

Patients aged 18 to 85 years with a diagnosis of ATTR-CM and NT-proBNP levels of >300 ng/L and <8,500 ng/L were eligible to be included in the study. Patients were excluded from the study if they had NYHA class IV or NYHA class III with NAC ATTR Stage 3 (defined as NT-proBNP >3,000 ng/L and eGFR <45 mL/min/1.73m2).1

Exploratory subgroup analyses of the HELIOS-B study were conducted to evaluate the efficacy and safety of vutrisiran compared with placebo in patients with different heart failure severities at baseline including patients with NYHA class I (no symptoms with ordinary physical activity), class II (symptoms with ordinary physical activity), or class III (symptoms with less than ordinary physical activity) and with NT-proBNP levels of >300 ng/L to ≤2,000 ng/L (referred to as the ≤2,000 ng/L group) or >2,000 ng/L to <8,500 ng/L (referred to as the >2,000 ng/L group). Baseline disease severity group analyses were conducted in the overall population and in the monotherapy population.1

Treatment effects for the primary composite endpoint and secondary endpoint of all-cause mortality were also evaluated across subgroups defined by other measures of disease severity, including NAC stage 1 or 2/3, Columbia early stage (score 1-3) or intermediate/late stage (score 4‑9), and baseline NT‑proBNP tertiles (<1,368 ng/L, ≥1,368 and <2,691 ng/L, and ≥2,691 ng/L).1

 Patient Demographics & Baseline Characteristics

A total of 654 patients with ATTR-CM who received vutrisiran (n=326) or placebo (n=328) were assessed in groups by NYHA class I, II, and III and NT-proBNP ≤2,000 ng/L and >2,000 ng/L. In the overall population, 84 patients (12.8%) were NYHA class I, 508 patients (77.7%) were NYHA class II, and 62 patients (9.5%) were NYHA class III; 342 patients (52.3%) had NT-proBNP levels ≤2,000 ng/L and 312 patients (47.7%) had NT-proBNP levels >2,000 ng/L. A summary of the baseline demographics and disease characteristics in the overall population are shown in Tables 1 and 2.1

In both the overall and monotherapy populations, baseline demographics were generally similar between the vutrisiran and placebo arms across the NYHA functional class and NT-proBNP groups, although there were some differences in tafamidis use between the groups in the overall population and more patients had a baseline NT-proBNP >2,000 ng/L in the vutrisiran arm in the monotherapy population. Baseline 6-MWT and KCCQ-OS decreased with increasing baseline NYHA class, and NT‑proBNP levels were generally higher with increasing baseline NYHA class.1

Table 1. Baseline Characteristics by Baseline NYHA Class in the Overall Population.1,a

Table 2. Baseline Characteristics by Baseline NT-proBNP Levels in the Overall Population.1,a

Efficacy Results

Composite of All-Cause Mortality and Recurrent CV Events During the Double-Blind Period

In the overall population, the HRs (95% CI) for the composite of all-cause mortality and recurrent CV events in patients treated with vutrisiran compared with placebo were 0.54 (0.27, 1.10), 0.77 (0.57, 1.03), and 0.68 (0.33, 1.41) in the baseline NYHA class I, II, and III groups, respectively; and 0.53 (0.35-0.79) and 0.80 (0.56-1.13) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively (Figure 1).1

In the monotherapy population, the HRs (95% CI) for the composite of all-cause mortality and recurrent CV events in patients treated with vutrisiran compared with placebo were 0.32 (0.12, 0.87), 0.79 (0.55, 1.12), and 0.31 (0.09, 1.02) in the baseline NYHA class I, II, and III groups, respectively; and 0.50 (0.28-0.92) and 0.71 (0.47-1.07) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively (Figure 1).1

Figure 1. Composite Endpoint of All-Cause Mortality and Recurrent CV Events by Baseline Heart Failure Severity.1,a

Additional analyses on all-cause mortality and recurrent CV events were conducted based on additional measures of baseline heart failure severity including Columbia stage, NAC stage, and NT‑proBNP tertile at baseline, as shown in Table 3.1

Table 3. All-Cause Mortality and Recurrent CV Events by Additional Measures of Baseline Heart Failure Severity.1,a

All-Cause Mortality Through 42 Months

In the overall population, the HRs (95% CI) for all-cause mortality through 42 months in patients treated with vutrisiran compared with placebo were 0.32 (0.11, 0.94), 0.73 (0.50, 1.06), and 0.58 (0.20, 1.69) in the baseline NYHA class I, II, and III groups, respectively; and 0.35 (0.18-0.66) and 0.83 (0.55‑1.24) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

In the monotherapy population, the HRs (95% CI) for all-cause mortality through 42 months in patients treated with vutrisiran compared with placebo were 0.43 (0.10, 1.82), 0.73 (0.48, 1.12), and 0.19 (0.02, 1.63) in the baseline NYHA class I, II, and III groups, respectively; and 0.43 (0.18-1.01) and 0.75 (0.48-1.18) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

Additional analyses on all-cause mortality were conducted based on additional measures of baseline heart failure severity including Columbia stage, NAC stage, and NT‑proBNP tertile at baseline, as shown in Table 4.1

Table 4. All-Cause Mortality by Additional Measures of Baseline Heart Failure Severity.1,a

Functional Assessments

6-MWT at 30 Months

In the overall population, the LS mean differences (95% CI) between vutrisiran compared with placebo in change from baseline to Month 30 in 6-MWT were 34.8 m (–1.6, 71.2), 22.6 m (7.5, 37.6), and 28.4 m (‑12.1, 68.9) in the baseline NYHA class I, II, and III groups, respectively; and 35.2 m (17.6‑52.8) and 21.7 m (2.8-40.6) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

In the monotherapy population, the LS mean differences (95% CI) between vutrisiran compared with placebo in change from baseline to Month 30 in 6-MWT were 62.9 m (–31.3, 157.2), 29.0 m (9.5, 48.5), and 72.2 m (2.7, 141.7) in the baseline NYHA class I, II, and III groups, respectively; and 44.0 m (17.5-70.6) and 32.1 m (8.6-55.5) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

KCCQ-OS at 30 Months

In the overall population, the LS mean differences (95% CI) between vutrisiran compared with placebo in change from baseline to Month 30 in KCCQ-OS were 6.6 (–2.5, 15.7), 5.9 (2.0, 9.8), and 3.5 (–9.2, 16.3) in the baseline NYHA class I, II, and III groups, respectively; and 8.6 (4.3-12.8) and 3.8 (‑1.5, 9.0) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

In the monotherapy population, the LS mean differences (95% CI) between vutrisiran compared with placebo in change from baseline to Month 30 in KCCQ-OS were 7.9 (–13.7, 29.4), 8.3 (3.2, 13.3), and 17.5 (–3.0, 37.9) in the baseline NYHA class I, II, and III groups, respectively; and 12.1 (5.9, 18.3) and 7.8 (1.1-14.5) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

Cardiac Biomarkers

NT-proBNP at 30 Months

In the overall population, the adjusted geometric mean fold-change ratios (95% CI) from baseline to Month 30 in NT-proBNP between vutrisiran and placebo were 0.74 (0.55, 0.98), 0.68 (0.60, 0.76), and 0.71 (0.49, 1.02) in the baseline NYHA class I, II, and III groups, respectively; and 0.61 (0.53, 0.70) and 0.78 (0.66-0.91) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

In the monotherapy population, the adjusted geometric mean fold-change ratios (95% CI) from baseline to Month 30 in NT-proBNP between vutrisiran and placebo were 0.45 (0.28, 0.72), 0.60 (0.51, 0.71), and 0.36 (0.22, 0.58) in the baseline NYHA class I, II, and III groups, respectively; and 0.49 (0.40‑0.61) and 0.65 (0.53, 0.81) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

Troponin I at 30 Months

In the overall population, the adjusted geometric mean fold-change ratios (95% CI) from baseline to Month 30 in troponin I between vutrisiran and placebo were 0.81 (0.64, 1.02), 0.67 (0.59, 0.75), and 0.71 (0.54, 0.94) in the baseline NYHA class I, II, and III groups, respectively; and 0.65 (0.58, 0.74) and 0.71 (0.61, 0.82) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

In the monotherapy population, the adjusted geometric mean fold-change ratios (95% CI) from baseline to Month 30 in troponin I between vutrisiran and placebo were 0.57 (0.36, 0.89), 0.55 (0.48, 0.64), and 0.46 (0.26, 0.82) in the baseline NYHA class I, II, and III groups, respectively; and 0.52 (0.43, 0.62) and 0.55 (0.44, 0.68) in the baseline NT-proBNP ≤2,000 ng/L and >2,000 ng/L groups, respectively.1

 Safety Results

In the overall population, the proportion of patients with at least one AE was similar between treatment arms, and the majority of AEs with vutrisiran were mild or moderate. A summary of the safety results during the double-blind period are presented in Table 5.2,3

Table 5. HELIOS-B Safety Summary.3

 Abbreviations

6-MWT = 6-minute walk test; AE = adverse event; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; hATTR = hereditary transthyretin amyloidosis; HR = hazard ratio; KCCQ‑OS = Kansas City Cardiomyopathy Questionnaire‑Overall Summary; LS = least squares; NAC = National Amyloidosis Centre; NT-proBNP = N-terminal pro‑B‑type natriuretic peptide; NYHA = New York Heart Association; OLE = open-label extension; SAE = serious adverse event; SD = standard deviation; SGLT2i = sodium-glucose co-transporter-2 inhibitor; wtATTR = wild-type transthyretin amyloidosis.

Updated 02 May 2025

References

1.  Maurer MS, Witteles RM, Garcia-Pavia P, et al. Impact of heart failure severity on vutrisiran efficacy in transthyretin amyloidosis with cardiomyopathy. J Am Coll Cardiol. 2025;85(20):1927-1939. doi:10.1016/j.jacc.2025.03.477

2.  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

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