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

Publication Details

Amyloid

July 2022

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Author(s)

David Adams¹, Ivailo L Tournev ^{2 3}, Mark S Taylor⁴, Teresa Coelho⁵, Violaine Planté-Bordeneuve⁶, John L Berk⁷, Alejandra González-Duarte⁸, Julian D Gillmore⁹, Soon-Chai Low¹⁰, Yoshiki Sekijima¹¹, Laura Obici¹², Chongshu Chen¹³, Prajakta Badri¹³, Seth M Arum¹³, John Vest¹³, Michael Polydefkis¹⁴; HELIOS-A Collaborators

Affiliations

¹Neurology Department, CHU Bicêtre, APHP, Université Paris-Saclay, Le Kremlin Bicêtre Cedex, France; ²Department of Neurology, Clinic of Nervous Diseases, University Hospital Aleksandrovska, Medical University, Sofia, Bulgaria; ³Department of Cognitive Sciences, New Bulgarian University, Sofia, Bulgaria; ⁴Department of Clinical Immunology and Allergy, Westmead Hospital and Westmead Clinical School, University of Sydney, Sydney, NSW, Australia; ⁵Hospital de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal; ⁶Neurology - Amyloid Network, CHU Henri Mondor, APHP, University Paris Est - Créteil, Créteil, France;⁷Boston Medical Center, Boston University, Boston, Massachusetts, USA; ⁸Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México, D.F., México; ⁹National Amyloidosis Centre, University College London, Royal Free Hospital, London, UK; ¹⁰Department of Medicine, Division of Neurology, University Malaya Medical Centre, Kuala Lumpur, Malaysia; ¹¹Department of Medicine (Neurology & Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan; ¹²Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy; ¹³Alnylam Pharmaceuticals, Cambridge, Massachusetts, USA; ¹⁴Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

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.