This activity was funded by Alnylam Pharmaceuticals. The medical content was developed independently by M3 and Professor Violaine Planté-Bordeneuve.

Highlights from

AAN 2021, EAN 2021, ESC-HF 2021 & PNS 2021


Amyloidosis Conference Highlights

HELIOS-A: positive 9-month results with an investigational RNAi for patients with hATTR amyloidosis and polyneuropathy

Take-home messages
  • hATTR amyloidosis is a debilitating, multisystem disease caused by misfolded TRR variants that accumulate as amyloid deposits
  • Vutrisiran is an investigational, subcutaneous RNAi therapeutic that rapidly and sustainably reduces serum TRR levels in hATTR amyloidosis patients, improving neuropathy, quality of life and gait speed (versus placebo)
  • Vutrisiran has the potential to become a new therapeutic option for polyneuropathy of hATTR, with a reduced dosing burden versus patisiran

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, underdiagnosed, debilitating disease, caused by mutations in the TTR gene that result in expression of misfolded TTR protein. Misfolded TTR monomers aggregate to form amyloid fibrils that are deposited throughout a patient's organs and tissues, affecting multiple systems and often causing a mixed phenotype of polyneuropathy and cardiomyopathy.1,2 Patisiran, an RNAi therapeutic that targets both wild-type and variant TTR to reduce the number of unstable circulating TTR aggregates, has been approved for the treatment of polyneuropathy of hATTR amyloidosis following positive results in the phase III placebo-controlled APOLLO trial. Patisiran is administered by IV infusion, once every 3 weeks.3,4

Vutrisiran is an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis. Vutrisiran also targets the production of wild-type and variant TTR, but utilisation of the ESC-GalNAc platform means it can be administered by subcutaneous injection once every 3 months.5

At this year's American Academy of Neurology (AAN) Annual Virtual Meeting, David Adams, Head of the Department of Neurology, presented 9-month results of HELIOS, a phase III open-label study evaluating the efficacy and safety of vutrisiran in adult patients with hATTR amyloidosis and polyneuropathy (N=164), randomised 3:1 to receive vutrisiran or patisiran.

At 9 months, efficacy analyses were conducted against an external placebo group (placebo arm of APOLLO). The primary endpoint was change from baseline in modified Neuropathy Impairment Score (mNIS)+7 (higher scores indicate more neuropathy impairment; range: 0-304). The secondary endpoints were change from baseline in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN; higher scores of indicate worse quality of life; range: -4 to 136) and 10-metre walk test (10-MWT; mean time (seconds) taken to complete two x 10 metre walks at each visit, imputed as 0 for patients unable to perform the walk; lower speeds indicate worse ambulatory function).

All primary and secondary endpoints were met, with statistically significant improvements in the modified intent-to-treat population with vutrisiran versus placebo in mNIS+7 (LS mean change from baseline: -2.24 vs 14.76; p=3.54x10-12), Norfolk QOL-DN (LS mean change from baseline: -3.3 vs 12.9; p=5.43x10-9) and 10-MWT (LS mean change from baseline: -0.001 vs -0.133; p=3.10x10-5), and treatment effects that were consistent with the patisiran group. Exploratory endpoints, including the impact of vutrisiran on the cardiac stress marker NT-proBNP, also demonstrated improvements with vutrisiran versus placebo. Vutrisiran treatment reduced serum TRR levels from baseline by a mean of >60% after just 3 weeks, and achieved a mean steady-state (measured using samples at Day 211) serum TRR reduction of 83%, similar to the reduction seen in patients receiving patisiran.

Vutrisiran demonstrated an acceptable safety profile; the majority of adverse events were mild or moderate in severity and there were no drug-related discontinuations, deaths or safety signals regarding liver function tests, haematology or renal function.

The 9-month results from the HELIOS phase III study have shown that vutrisiran is effective in improving neuropathy impairment, quality of life and gait speed versus placebo in patients with hATTR amyloidosis, with efficacy comparable to patisiran and a positive risk-benefit profile. These results highlight the potential of vutrisiran as a new treatment option for patients with hATTR amyloidosis with polyneuropathy, offering 3-monthly subcutaneous administration, and provide further evidence for the efficacy of RNAi therapeutics.

ESC-GalNAc: enhanced stabilisation chemistry N-acetylgalactosamine; LS: least squares; NT-proBNP: N-terminal pro–brain natriuretic peptide; RNAi: ribonucleic acid interference; TTR: transthyretin

Based on: Adams D, Tournev I L et al. HELIOS-A: 9-month results from the phase 3 study of vutrisiran in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Presented at the American Academy of Neurology (AAN) Virtual Annual Meeting, April 17-22, 2021

  1. Hawkins P, Ando Y et al. Evolving landscape in the management of transthyretin amyloidosis. Annals of Medicine 2015;47:625-638
  2. Benson M D, Dasgupta N R, Rao P. Diagnosis and screening of patients with hereditary transthyretin amyloidosis (hATTR): current strategies and guidelines. Ther Clin Risk Manag 2020;16:749-758
  3. Patisiran Summary of Product Characteristics. Available from: Accessed May 2021
  4. Adams D, Gonzalez-Duarte et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med 2018;379(1):11-21
  5. Nair J K, Willoughby J L S et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc 2014;136(49):16958-16961

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The content and interpretation of these conference highlights are the views and comments of the speakers/authors.

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