• 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, and HELIOS-A Collaborators.
• Neurology Department, CHU Bicêtre, APHP, Université Paris-Saclay, Le Kremlin Bicêtre Cedex, France.
• Amyloid. 2023 Mar 1; 30 (1): 191-9.

BackgroundThe 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.MethodsHELIOS-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.ResultsHELIOS-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.ConclusionsVutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile.Clinicaltrials.GovNCT03759379.

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