Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

Adams D 1 , Tournev IL 2 , Taylor MS 3 , Coelho T 4 , Planté-Bordeneuve V 5 , Berk JL 6 Show all authors , González-Duarte A 7 , Gillmore JD 8 , Low SC 9 , Sekijima Y 10 , Obici L 11 , Chen C 12 , Badri P 12 , Arum SM 12 , Vest J 12 , Polydefkis M 13 , HELIOS-A Collaborators

Affiliations 

  • 1 Neurology Department, CHU Bicêtre, APHP, Université Paris-Saclay, Le Kremlin Bicêtre Cedex, France
  • 2 Department of Neurology, Clinic of Nervous Diseases, University Hospital Aleksandrovska, Medical University, Sofia, Bulgaria
  • 3 Department of Clinical Immunology and Allergy, Westmead Hospital and Westmead Clinical School, University of Sydney, Sydney, NSW, Australia
  • 4 Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
  • 5 Neurology - Amyloid Network, CHU Henri Mondor, APHP, University Paris Est - Créteil, Créteil, France
  • 6 Boston Medical Center, Boston University, Boston, Massachusetts, USA
  • 7 Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., México
  • 8 National Amyloidosis Centre, University College London, Royal Free Hospital, London, UK
  • 9 Department of Medicine, Division of Neurology, University Malaya Medical Centre, Kuala Lumpur, Malaysia
  • 10 Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
  • 11 Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy
  • 12 Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA
  • 13 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Amyloid, 2023 Mar;30(1):1-9.
PMID: 35875890 DOI: 10.1080/13506129.2022.2091985

Abstract

BACKGROUND: The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy.

METHODS: HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months.

RESULTS: HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10-12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths.

CONCLUSIONS: Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile.

CLINICALTRIALS.GOV: NCT03759379.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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