{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:58:15Z","timestamp":1790053095230,"version":"4.0.1"},"reference-count":18,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,4,3]],"date-time":"2020-04-03T00:00:00Z","timestamp":1585872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Kowa and the Medicines Company"},{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015237","name":"The Medicines Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015237","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]},{"name":"CIVI Biotechnology"},{"name":"Corvidia"},{"DOI":"10.13039\/100008322","name":"CSL Behring","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002973","name":"Daiichi Sankyo","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100002973","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Draupnir"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims\u2003<\/jats:title>\n                  <jats:p>Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin\/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and results\u2003<\/jats:title>\n                  <jats:p>The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200\u2009mg, n\u2009=\u200960; 300\u2009mg, n\u2009=\u200962 or 500\u2009mg, n\u2009=\u200966) or double-dose starting regimen (DD: 100\u2009mg, n\u2009=\u200962; 200\u2009mg, n\u2009=\u200963; or 300\u2009mg, n\u2009=\u200961 on days 1 and 90) of inclisiran or placebo (SD: n\u2009=\u200965; DD: n\u2009=\u200962). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-\u03b1 (TNF-\u03b1) were examined after 180\u2009days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200\u2009mg: 0.8%; 300\u2009mg: \u22120.5%; 500\u2009mg: \u22121.8%; DD: 100\u2009mg: 1.3%; 200\u2009mg: \u22120.5%; 300\u2009mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-\u03b1) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion\u2003<\/jats:title>\n                  <jats:p>In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/cvr\/cvaa077","type":"journal-article","created":{"date-parts":[[2020,3,30]],"date-time":"2020-03-30T11:07:09Z","timestamp":1585566429000},"page":"284-291","source":"Crossref","is-referenced-by-count":74,"title":["Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin\/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1"],"prefix":"10.1093","volume":"117","author":[{"given":"Ulf","family":"Landmesser","sequence":"first","affiliation":[{"name":"Department of Cardiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, 12203 Berlin, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, 10785 Berlin, Germany"},{"name":"Berlin Institute of Health (BIH), 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5646-3237","authenticated-orcid":false,"given":"Arash","family":"Haghikia","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Charit\u00e9-Universit\u00e4tsmedizin Berlin, 12203 Berlin, Germany"},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, 10785 Berlin, Germany"},{"name":"Berlin Institute of Health (BIH), 10178 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lawrence A","family":"Leiter","sequence":"additional","affiliation":[{"name":"The Li Ka Shing Knowledge Institute, Departments of Medicine and Nutritional Sciences, St. Michael's Hospital, University of Toronto, M5B 1W8 Toronto, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R Scott","family":"Wright","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Mayo Clinic, Rochester, MN 55905, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Kallend","sequence":"additional","affiliation":[{"name":"The Medicines Company, 8001 Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Wijngaard","sequence":"additional","affiliation":[{"name":"The Medicines Company, Parsippany, NJ 07054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Stoekenbroek","sequence":"additional","affiliation":[{"name":"The Medicines Company, Parsippany, NJ 07054, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Jp","family":"Kastelein","sequence":"additional","affiliation":[{"name":"Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kausik K","family":"Ray","sequence":"additional","affiliation":[{"name":"Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, SW7 2AZ London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,3]]},"reference":[{"key":"2021011509544990000_cvaa077-B1","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1038\/nsmb.2931","article-title":"From guide to target: molecular insights into eukaryotic RNA-interference machinery","volume":"22","author":"Ipsaro","year":"2015","journal-title":"Nat Struct Mol Biol"},{"key":"2021011509544990000_cvaa077-B2","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1056\/NEJMoa1615758","article-title":"Inclisiran in patients at high cardiovascular risk with elevated LDL 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