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Inotersen, an antisense oligonucleotide inhibitor of hepatic TTR production, demonstrated a favorable efficacy and safety profile in patients with the polyneuropathy associated with hATTR in the NEURO-TTR (NCT01737398) study. We report longer-term efficacy and safety data for inotersen, with a median treatment exposure of 3\u00a0years.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients who satisfactorily completed NEURO-TTR were enrolled in its open-label extension (OLE) study. Efficacy assessments included the modified Neuropathy Impairment Score\u2009+\u20097 (mNIS\u2009+\u20097), Norfolk Quality of Life\u2013Diabetic Neuropathy (Norfolk QoL-DN) questionnaire total score, and the Short Form 36 (SF-36v2) Health Survey Physical Component Summary score. Safety and tolerability were also assessed. Efficacy is reported for patients living in Europe and North America (this cohort completed the study approximately 9\u00a0months before the remaining group of patients outside these regions); safety is reported for the full safety dataset, comprising patients living in Europe, North America, and Latin America\/Australasia. This study is registered with ClinicalTrials.gov, identifier NCT02175004.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the Europe and North America cohort of the NEURO-TTR study, 113\/141 patients (80.1%) completed the study, and 109 patients participated in the OLE study. A total of 70 patients continued to receive inotersen (inotersen\u2013inotersen) and 39 switched from placebo to inotersen (placebo\u2013inotersen). The placebo\u2013inotersen group demonstrated sustained improvement in neurological disease progression as measured by mNIS\u2009+\u20097, compared with predicted worsening based on projection of the NEURO-TTR placebo data (estimated natural history). The inotersen\u2013inotersen group demonstrated sustained benefit, as measured by mNIS\u2009+\u20097, Norfolk QoL-DN, and SF-36v2, compared with estimated natural history as well as compared with the placebo\u2013inotersen group. With a maximum exposure of 6.2\u00a0years, inotersen was not associated with any additional safety concerns or increased toxicity in the OLE study. Platelet and renal monitoring were effective in reducing the risk of severe adverse events in the OLE study.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Inotersen treatment for &gt; 3\u00a0years slowed progression of the polyneuropathy associated with hATTR, and no new safety signals were observed.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00415-022-11276-8","type":"journal-article","created":{"date-parts":[[2022,7,31]],"date-time":"2022-07-31T08:02:43Z","timestamp":1659254563000},"page":"6416-6427","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Long-term efficacy and safety of inotersen for hereditary transthyretin amyloidosis: NEURO-TTR open-label extension 3-year update"],"prefix":"10.1007","volume":"269","author":[{"given":"Thomas H.","family":"Brannagan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel K.","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael J.","family":"Polydefkis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Dyck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Berk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Drachman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Gorevic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carol","family":"Whelan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Violaine","family":"Plante-Bordeneuve","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giampaolo","family":"Merlini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Obici","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep Maria Campistol","family":"Plana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josep","family":"Gamez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnt V.","family":"Kristen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Mazzeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Gentile","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvind","family":"Narayana","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kemi","family":"Olugemo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Aquino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Merrill D.","family":"Benson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morie","family":"Gertz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for the NEURO-T. 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TC reports receiving financial support to attend scientific meetings from Pfizer, Alnylam, Ionis, Akcea, and Biogen. AKW reports being study investigator, consultant, and speaker for Ionis Pharmaceuticals, Inc.; consultant for Pfizer; and study investigator for Alnylam. MJP reports receiving honoraria from Pfizer and Alnylam Pharmaceuticals, Inc. PJD reports receiving training and consulting honoraria from Ionis Pharmaceuticals, Inc., and Alnylam Pharmaceuticals. JLB reports receiving honoraria from Ionis Pharmaceuticals, Inc., and Alnylam Pharmaceuticals; and being a study investigator for Ionis Pharmaceuticals, Inc., Alnylam Pharmaceuticals, Eidos BridgeBio, and Pfizer. BD reports being a consultant\/advisory board member for Eidos and Alnylam Pharmaceuticals. PG declares no competing interests. CW reports being an advisory board member for Alnylam and Akcea Therapeutics. IC reports being a consultant for Alnylam and Pfizer; receiving honoraria for Alnylam, Pfizer, and Sanofi; and being on speaker bureaus for Alnylam, Pfizer, and Sanofi. VP-B reports receiving consulting honoraria for Alnylam Pharmaceuticals, Ionis, and Pfizer and travel honoraria from Ionis. GM declares no competing interests. LO reports receiving speaker honoraria from Akcea Therapeutics, Alnylam Pharmaceuticals, SOBI, and Pfizer. JMCP declares no competing interests. JG declares no competing interests. AVK reports receiving honoraria and fees for lectures and speakers bureaus from Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer Inc. AM reports receiving speaker fees and consulting honoraria from Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer Inc. LG reports receiving speaker fees and consulting honoraria from Pfizer. AN is a former employee of Akcea Therapeutics, a subsidiary of Ionis Pharmaceuticals, Inc. KO is a former employee of Ionis Pharmaceuticals, Inc. PA is a former employee of Ionis Pharmaceuticals, Inc.\/Akcea Therapeutics. MDB reports being study investigator for Ionis Pharmaceuticals, Inc. MG reports receiving consulting honoraria from Ionis, AbbVie, Alnylam, Amgen, Annexon, Appellis, Celgene, Janssen, Medscape, Physicians Education Resource, Prothena, Research to Practice, Teva, and Spectrum, and grants from Spectrum.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The trial protocol for the OLE study was approved by the relevant institutional review boards or local ethics committees and regulatory authorities. The trial was conducted in accordance with Good Clinical Practice guidelines of the International Conference on Harmonisation and the principles of the Declaration of Helsinki. All patients provided written informed consent to participate in the study.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}]}}