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

David Adams, Ivailo L Tournev, Mark S Taylor, Teresa Coelho, Violaine Planté-Bordeneuve, John L Berk, Alejandra González-Duarte, Julian D Gillmore, Soon-Chai Low, Yoshiki Sekijima, Laura Obici, Chongshu Chen, Prajakta Badri, Seth M Arum, John Vest, Michael Polydefkis

Journal: Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 2023;30(1):1-9

PMID: 35875890

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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, = 122; patisiran reference group, = 42); external placebo, = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months ( = 3.54 × 10), 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.

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

DOI: 10.1080/13506129.2022.2091985