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The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3\u00a0mg\/kg intravenously (<jats:italic>n<\/jats:italic>\u2009=\u2009148) or placebo (<jats:italic>n<\/jats:italic>\u2009=\u200977) once every 3\u00a0weeks for 18\u00a0months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18\u00a0months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference,\u2009\u2212\u20097.5; 95% CI:\u2009\u2212\u200911.9,\u2009\u2212\u20093.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference,\u2009\u2212\u20091.1;\u2009\u2212\u20091.8,\u2009\u2212\u20090.5], nutritional status (modified body mass index, LS mean difference, 115.7;\u2009\u2212\u200982.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference,\u2009\u2212\u20090.3;\u2009\u2212\u20090.5,\u2009\u2212\u20090.1). Patisiran treatment also led to improvement from baseline at 18\u00a0months for COMPASS-31 (LS mean change from baseline,\u2009\u2212\u20095.3; 95% CI:\u2009\u2212\u20097.9,\u2009\u2212\u20092.7) and individual domains, orthostatic intolerance (\u2212\u00a04.6;\u2009\u2212\u20096.3,\u2009\u2212\u20092.9) and gastrointestinal symptoms (\u2212\u00a00.8;\u2009\u2212\u20091.5,\u2009\u2212\u20090.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.<\/jats:p>","DOI":"10.1007\/s00415-019-09602-8","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T22:01:31Z","timestamp":1573768891000},"page":"703-712","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":56,"title":["Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis"],"prefix":"10.1007","volume":"267","author":[{"given":"Alejandra","family":"Gonz\u00e1lez-Duarte","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John L.","family":"Berk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dianna","family":"Quan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Mauermann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hartmut H.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Polydefkis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rcia","family":"Waddington-Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuharu","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel M.","family":"Concei\u00e7\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnt V.","family":"Kristen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Coelho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9cile A.","family":"Cauquil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9line","family":"Tard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madeline","family":"Merkel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emre","family":"Aldinc","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jihong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne T.","family":"Sweetser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"9602_CR1","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1016\/j.acvd.2013.06.051","volume":"106","author":"D Mohty","year":"2013","unstructured":"Mohty D, Damy T, Cosnay P et al (2013) Cardiac amyloidosis: updates in diagnosis and management. 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JB reports compensation for study investigator and coordinator time and hospital services from Alnylam Pharmaceuticals during the study. Outside of the submitted work, JB acknowledges personal fees from Alnylam Pharmaceuticals for visiting professor presentations, from Akcea Therapeutics for attendance at an advisory committee, from Intellia Therapeutics and Corino Therapeutics for scientific advisory boards and also reports study investigator and coordinator compensation from Pfizer Inc. DQ reports grants received from Alnylam Pharmaceuticals. MLM reports research grants from Alnylam Pharmaceuticals and Ionis Pharmaceuticals. HS has nothing to disclose. MP reports receiving personal fees and serving as a principal investigator and consultant for Alnylam Pharmaceuticals during the work. Outside of the study work MP reports personal fees, and serving as a principal investigator and consultant for Alnylam Pharmaceuticals, Ionis Pharmaceuticals, and Pfizer Inc. MWC received honoraria from NHI, Prothena, FoldRx, Akcea Therapeutics, Pfizer Inc., Alnylam Pharmaceuticals, PTC and Genzyme for travel expenses related to presentations at medical meetings, for acting as a consultant and as a principal investigator in clinical trials. MU reports personal fees and non-financial support for travel, participating in advisory boards, and speaker fees from Alnylam Pharmaceuticals and Pfizer Inc. outside of the submitted work. IC reports receiving personal fees and serving as a principal investigator for Alnylam Pharmaceuticals. AVK received honoraria and fees for lectures and speakers bureaus from Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer Inc. TC reports personal fees from Alnylam Pharmaceuticals and personal fees and financial support to attend scientific meetings from Pfizer Inc., outside of the submitted work. CC acknowledges speaker honoraria from Alnylam Pharmaceuticals, Pfizer Inc., and Akcea Therapeutics, outside of the submitted work. CT has nothing to disclose. MM, EA, JC, MS, JJW are all employees of Alnylam Pharmaceuticals and MS reports owning Alnylam Pharmaceutical stock options. DA reports consultancy fees and clinical grants from Alnylam Pharmaceuticals, and clinical grants and symposium speaker fees from Pfizer Inc., outside of the submitted work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflicts of interest"}},{"value":"The protocol was approved by central and local institutional review boards or ethics committees and conducted in accordance with the International Conference on Harmonization for Good Clinical Practice, the Declaration of Helsinki, and the 1996 Health Insurance Portability and Accountability Act.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical standards"}}]}}