Vutrisiran: HELIOS-A Study

Vutrisiran: HELIOS-A Study

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 Summary

Index

Study Design – Patient Demographics and Baseline Characteristics – Efficacy Results – Safety Results – Abbreviations – References

 Study Design

HELIOS-A was a phase 3, global, randomized, open-label study designed to evaluate the efficacy and safety of vutrisiran in patients with hATTR-PN. Patients were randomized (3:1) to receive either vutrisiran 25 mg every 3 months by subcutaneous injection (n=122) or patisiran 0.3 mg/kg every 3 weeks by IV infusion (as a reference group, n=42) for 18 months. This study used the placebo arm of the APOLLO study as an external control arm (n=77) for the primary endpoint and most other efficacy endpoints.1

Endpoints

The primary endpoint was the change from baseline in mNIS+7 at Month 9.1

Secondary endpoints assessed neuropathy impairment, quality of life, functional capacity, nutritional status, disability, and serum TTR levels, including1:

      Change from baseline in mNIS+7 at Month 18

      Change from baseline in Norfolk QOL-DN score at Months 9 and 18

      Change from baseline in 10-MWT at Months 9 and 18

      Change from baseline in mBMI at Month 18

      Change from baseline in R-ODS score at Month 18

      Percentage reduction from baseline in serum TTR levels through Month 18

Select exploratory endpoints assessed the cardiac biomarker NT-proBNP, echocardiographic parameters, and technetium-99m scintigraphy imaging.2

Inclusion and Exclusion Criteria

Select inclusion and exclusion criteria for HELIOS-A are presented in Table 1.1,3

Table 1. HELIOS-A Inclusion and Exclusion Criteria.1,3

Patient Demographics and Baseline Characteristics

Baseline patient demographics and clinical characteristics were comparable among the vutrisiran, patisiran, and APOLLO-placebo arms (Table 2).1

Table 2. Baseline Patient Demographics and Clinical Characteristics.1

Efficacy Results

Primary Endpoint

Neuropathy Impairment (mNIS+7) at Month 9

At Month 9, a statistically significant improvement in mNIS+7 was observed with vutrisiran treatment when compared with external placebo. The LS mean change from baseline showed a 2.24-point decrease in the vutrisiran arm compared with a 14.76-point increase in the external placebo arm, resulting in a LSMD of ‑17.00 points (95% CI -21.78, -12.22; p<0.001). Improvement from baseline in mNIS+7 at Month 9 was observed in 50.4% of patients in the vutrisiran arm compared with 18.2% in the external placebo arm.1

Secondary Endpoints

Neuropathy Impairment (mNIS+7) at Month 18

At Month 18, a statistically significant improvement in mNIS+7 was observed with vutrisiran treatment compared with external placebo. The LS mean change from baseline showed a 0.46‑point decrease in the vutrisiran arm compared with a 28.1-point increase in the external placebo arm, resulting in a LSMD of -28.55 points (95% CI -34.00, -23.10; p<0.001). Improvement in mNIS+7 from baseline was observed in 48.3% of patients in the vutrisiran arm compared with 3.9% of patients in the external placebo arm.1

Quality of Life (Norfolk QOL-DN)

At Months 9 and 18, a statistically significant improvement in quality of life as measured by the Norfolk QOL-DN was observed with vutrisiran treatment when compared with external placebo. At Month 9, the LSMD between the two arms was -16.2 points (95% CI -21.7, -10.8; p<0.001), and improvement from baseline was observed in 53.4% of patients in the vutrisiran arm compared with 23.4% in the external placebo arm. At Month 18, the LSMD between the two arms was -21.0 points (95% CI -27.1, -14.9; p<0.001), and improvement from baseline was observed in 56.8% of patients in the vutrisiran arm compared with 10.4% of patients in the external placebo arm.1

Gait Speed (10-MWT), Nutritional Status (mBMI), and Disability (R-ODS)

Treatment with vutrisiran resulted in improvements for all secondary endpoints, including 10‑MWT at Months 9 and 18, mBMI at Month 18, and R-ODS at Month 18, compared with external placebo.1

A summary of efficacy results at Months 9 and 18 are shown in Table 3.1

Table 3. Summary of Efficacy Results at Months 9 and 18.1

Serum TTR Reduction

Steady-state mean (SD) peak and trough percent reductions from baseline in serum TTR level at Month 18 were 87.6% (15.7%) and 81.0% (21.0%), respectively, in the vutrisiran arm. TTR reduction with vutrisiran was statistically non-inferior to within-study patisiran in the TTR per-protocol population, assessed by mean trough serum TTR levels over 18 months. The fluctuation between median steady-state peak and trough values was lower with vutrisiran (peak-trough=Δ; 91.6%‑86.2%=5.4%) compared with patisiran (88.3%‑78.2%=10.1%).1

Select Exploratory Endpoints: Cardiac Endpoints in the mITT Population

NT-proBNP

Improvement in NT-proBNP levels at Month 9 with continued improvement to Month 18 was observed with vutrisiran compared with external placebo. At Month 18, the adjusted geometric fold change ratio was 0.480 (95% CI 0.383, 0.600; nominal p=9.606×10-10); geometric mean ± SEM NT-proBNP levels decreased from 273.0 ± 42.2 ng/L at baseline to 227.2 ± 37.0 ng/L in the vutrisiran arm and increased from 531.3 ± 86.7 ng/L at baseline to 844.4 ± 167.0 ng/L in the external placebo arm.2

Echocardiographic Parameters

A nominally significant benefit in cardiac output, LV end-diastolic volume, and LV stroke volume was observed in patients receiving vutrisiran compared with external placebo at Month 18, with a LSMD (SE) of 0.587 (0.130) L/min (p=1.144×10−5), 10.489 (2.485) mL (p=4.021×10−5), and 7.837 (1.670) mL (5.754×10−6), respectively. A nonsignificant trend towards improvement in all other prespecified echocardiographic parameters, including mean LV wall thickness (nominal p=0.5228), LV mass (nominal p=0.4456), and global longitudinal strain (nominal p=0.3182), was observed in patients receiving vutrisiran compared with external placebo at Month 18.2  

Technicium-99m Scintigraphy Imaging

In a planned cohort of patients receiving vutrisiran, reduced cardiac uptake of technetium on scintigraphy imaging relative to baseline was observed. At Month 18, 32 (68.1%) evaluable patients improved in technetium uptake as assessed by normalized LV total uptake and 31 (64.6%) patients showed improvement in heart‑to‑contralateral lung ratio. At Month 18, among all evaluable scintigraphy patients, 55 (96%) were stable or improved by ≥1 Perugini grade(s). Of those patients with a Perugini grade ≥1 at baseline, 16 (50%) improved by ≥1 Perugini grade and 5 (16%) patients improved by ≥2 Perugini grades.2

 Safety Results

During the 18-month treatment period, AEs were reported in 119 patients (97.5%) in the vutrisiran arm. The majority of the AEs were mild or moderate in severity (Table 4).1

There were no drug-related discontinuations or deaths. Three patients (2.5%) in the vutrisiran arm discontinued the study due to AEs (2 due to death, 1 due to a non-fatal heart failure event), none of which were considered related to vutrisiran. One death was due to COVID-19 pneumonia, and the other was due to iliac artery occlusion. Two SAEs (dyslipidemia and urinary tract infection) were deemed related to vutrisiran by the Investigators.1

AEs occurring in ≥10% of patients in the vutrisiran arm included fall, pain in extremity, diarrhea, peripheral edema, urinary tract infection, arthralgia, and dizziness; all of these AEs, with the exception of arthralgia and pain in extremity, were reported at a similar or lower frequency than in the external placebo arm. Injection site reactions were reported in 5 patients (4.1%) receiving vutrisiran, all of which were mild and transient. There were no safety concerns regarding liver function tests, hematology, or renal function related to vutrisiran. Four (3.3%) patients in the vutrisiran arm developed ADAs, which were low and transient with no evidence of an effect on clinical efficacy, safety, or pharmacodynamic parameters of vutrisiran.1

Table 4. Safety Summary at Month 18.1

 Abbreviations

10-MWT = 10-meter walk test; ADA = antidrug antibody; AE = adverse event; CI = confidence interval; COVID‑19 = coronavirus disease 2019; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IQR = interquartile range; IV = intravenous; KPS = Karnofsky performance status; LFT = liver function test; LS = least squares; LSMD = least-squares mean difference; m/s = meters/second; mBMI = modified body mass index; mITT = modified intent-to-treat; mNIS+7 = modified Neuropathy Impairment Score +7; NIS = Neuropathy Impairment Score; Norfolk QOL-DN = Norfolk Quality of Life–Diabetic Neuropathy; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; R-ODS = Rasch-built Overall Disability Scale; SAE = serious adverse event; SD = standard deviation; SE = standard error; TTR = transthyretin.

Updated 21 July 2025

References

1.  Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2023;30(1):18-26. doi:10.1080/13506129.2022.2091985

2.  Garcia‐Pavia P, Grogan M, Kale P, et al. Impact of vutrisiran on exploratory cardiac parameters in hereditary transthyretin‐mediated amyloidosis with polyneuropathy. Eur J Heart Fail. 2024;26(2):397-410. doi:10.1002/ejhf.3138

3.  Alnylam Pharmaceuticals, Inc. HELIOS-A: A Study of Vutrisiran (ALN-TTRSC02) in Patients With Hereditary Transthyretin Amyloidosis (hATTR Amyloidosis). ClinicalTrials.gov website. Updated July 17, 2025. Accessed July 21, 2025. ClinicalTrials.gov Identifier: NCT03759379. Alnylam Pharmaceuticals, Inc.