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
{"title":"Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial.","authors":"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","doi":"10.1080/13506129.2022.2091985","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>HELIOS-A enrolled 164 patients (vutrisiran, <i>n</i> = 122; patisiran reference group, <i>n</i> = 42); external placebo, <i>n</i> = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (<i>p</i> = 3.54 × 10<sup>-12</sup>), 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.</p><p><strong>Conclusions: </strong>Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile.</p><p><strong>Clinicaltrials.gov: </strong>NCT03759379.</p>","PeriodicalId":50964,"journal":{"name":"Amyloid-Journal of Protein Folding Disorders","volume":null,"pages":null},"PeriodicalIF":5.2000,"publicationDate":"2023-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"69","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Amyloid-Journal of Protein Folding Disorders","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/13506129.2022.2091985","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 69
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.
期刊介绍:
Amyloid: the Journal of Protein Folding Disorders is dedicated to the study of all aspects of the protein groups and associated disorders that are classified as the amyloidoses as well as other disorders associated with abnormal protein folding. The journals major focus points are:
etiology,
pathogenesis,
histopathology,
chemical structure,
nature of fibrillogenesis;
whilst also publishing papers on the basic and chemical genetic aspects of many of these disorders.
Amyloid is recognised as one of the leading publications on amyloid protein classifications and the associated disorders, as well as clinical studies on all aspects of amyloid related neurodegenerative diseases and major clinical studies on inherited amyloidosis, especially those related to transthyretin. The Journal also publishes book reviews, meeting reports, editorials, thesis abstracts, review articles and symposia in the various areas listed above.