Vutrisiran efficacy and safety at 18 months: results from the HELIOS-A phase III trial

Take-home messages:

  • Vutrisiran is an investigational RNAi therapeutic that targets hepatic production of variant and wild-type TTR
  • At 18 months, vutrisiran showed improvements versus placebo in neuropathy impairment, gait speed, quality of life, nutritional status and disability, and led to improvements from baseline in exploratory cardiac measures
  • Vutrisiran treatment has an acceptable safety profile at 18 months, with most AEs being mild-to-moderate in severity

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, underdiagnosed, debilitating disease, caused by mutations in the transthyretin (TTR) gene. These mutations destabilise the tetrameric structure of TTR, causing it to dissociate into monomers that aggregate into amyloid fibrils. The deposition of the amyloid fibrils in organs and tissues throughout the body results in a multisystemic disease.1

Treatment options for hATTR include RNAi-mediated gene silencers, such as patisiran - licensed in the UK for adults with hATTR and stage 1 or 2 polyneuropathy2 - and vutrisiran - currently under investigation. Both drugs target hepatic production of variant and wild-type TTR, with the aim to reduce the number of circulating unstable TTR tetramers, but they differ in their mode of administration; patisiran is administered once every 3 weeks via intravenous infusion, while vutrisiran can be given once every 3 months by subcutaneous injection.2

HELIOS-A phase III study

HELIOS-A, a phase III open-label study, evaluated the efficacy and safety of vutrisiran in adult patients with hATTR amyloidosis and polyneuropathy for up to 18 months. Patients were randomised 3:1 to vutrisiran or patisiran. For most endpoints, including the primary efficacy endpoint of modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months, vutrisiran was compared with an external placebo group (from the APOLLO-B phase III study).

IV: intravenous; Q3M: once every 3 months; Q3W: once every 3 weeks; R: randomisation; SC: subcutaneous

The results of HELIOS-A at 9 months have been previously presented, with vutrisiran meeting all endpoints and demonstrating statistical improvements versus placebo in neuropathy impairment (mNIS+7), quality of life (Norfolk Quality of Life-Diabetic Neuropathy; Norfolk QOL-DN) and gait speed (10-minute walk test; 10-MWT). At this year’s American College of Cardiology Scientific Sessions, Dr Alejandra González-Duarte shared the results at 18 months.

HELIOS-A 18-month results

At 18 months, vutrisiran achieved a mean steady-state serum TTR reduction from baseline of 88%. The TTR reduction over 18 months was non-inferior to that of the patisiran reference group, with a median TTR difference for vutrisiran-patisiran of 5.28%.

Vutrisiran continued to show significant improvements in mNIS+7, Norfolk QOL-DN and 10-MWT compared with the external placebo group, as well as in additional analyses of nutritional status (modified body mass index; mBMI) and disability (Rasch-built Overall Disability Scale; R-ODS) (all secondary endpoints).

Characteristic Vutrisiran
Placebo (APOLLO)
Vutrisiran vs placebo
  LS mean (SEM) change from baseline at 18 months LS mean difference
(95% CI)
mNIS+7 -0.46 (1.60) 28.09 (2.28) -28.55 (-34.00, -23.10);
p=6.50 × 10–20
Norfolk QOL-DN -1.2 (1.8) 19.8 (2.6) -21.0 (-27.1, -14.9);
p=1.84 × 10–10
10-MWT -0.024 (0.025) -0.264 (0.036) 0.239 (0.154, 0.325);
p=1.21 × 10-7
mBMI 25.0 (9.5) -115.7 (13.4) 140.7 (108.4, 172.9);
p=4.16 × 10–15
R-ODS -1.5 (0.6) -9.9 (0.8) 8.4 (6.5, 10.4);
p=3.54 × 10–15

CI: confidence interval; LS: least squares; SEM: standard error of the mean

Exploratory and sub-analyses

Patients were only eligible for HELIOS-A inclusion if they had polyneuropathy. However, over one-third of the study population were also identified as having pre-existing evidence of cardiac amyloid involvement (baseline left ventricular (LV) wall thickness ≥1.3 cm and no aortic valve disease or hypertension in medical history). This is not surprising; although hATTR amyloidosis was initially classified according to the main clinical manifestation (polyneuropathy or cardiomyopathy) and certain TTR variants are associated with specific predominating symptoms, the majority of patients develop a mixed phenotype of polyneuropathy and cardiomyopathy.3,4

An exploratory analysis in HELIOS-A assessed the impact of vutrisiran on cardiac stress and function. At Month 18, vutrisiran:  

  • achieved a reduction from baseline in NT-proBNP versus external placebo
  • reduced cardiac uptake of 99mTechnetium on scintigraphy imaging from baseline in most patients compared with a planned cohort*
  • significantly improved cardiac output and LV end-diastolic volume from baseline, and trended toward improvement of mean LV wall thickness and global longitudinal strain versus external placebo

In a subgroup analysis, the efficacy of vutrisiran was assessed in patients with V122I/T60A TTR variants, which are historically associated with cardiomyopathy. In this subgroup vutrisiran led to benefits in mNIS+7, Norfolk QOL-DN and NT-proBNP levels that were similar to those observed in the modified intent-to-treat population

NT-proBNP: N-terminal pro B-type natriuretic peptide
*Patients from a planned cohort for whom the relevant baseline and 18-month data were available.

Safety results:

  • No drug-related discontinuations or deaths were reported in the study
  • Two serious vutrisiran-related adverse events (AEs) were reported (dyslipidaemia and urinary tract infection)
  • AEs occurring in ≥10% of the vutrisiran group included: fall, pain in extremity, diarrhoea, peripheral oedema, urinary tract infection, arthralgia and dizziness
  • No safety signals regarding liver function tests, haematology or renal function related to vutrisiran
Patients experiencing ≥1 event, n (%) Vutrisiran (n=122) Patisiran (n=42) Placebo (n=77)
AEs 119 (97.5) 41 (97.6) 75 (97.4)
Serious AEs 32 (26.2) 18 (42.9) 31 (40.3)
Severe AEs 19 (15.6) 16 (38.1) 28 (36.4)

Based on: González-Duarte A, Adams D et al. HELIOS-A: results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at ACC.22, 2-4 April 2022, Washington, DC, US

Top image: Design Cells
The content and interpretation of these conference highlights are the views and comments of the speakers/ authors.


  1. Hawkins P N, Ando Y et al. Evolving landscape in the management of transthyretin amyloidosis. Ann Med 2015;47(8):625-638
  2. Patisiran Summary of Product Characteristics. Available at: Accessed June 2022
  3. Coelho T, Maurer M S, Suhr O B. THAOS - The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis. Curr Med Res Opin 2013;29(1):63-76
  4. Rapezzi C, Quarta C C et al. Disease profile and differential diagnosis of hereditary transthyretin-related amyloidosis with exclusively cardiac phenotype: an Italian perspective. Eur Heart J 2013;34(7):520-528