| アブストラクト | INTRODUCTION: siRNA-based targeting of PCSK9 represents a novel therapeutic approach that may provide a convenient, infrequent and safe dosing schedule to robustly lower 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 under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS: The pre-specified safety analysis from ORION-1 was performed in 6 different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single-dose (SD: 200mg, n = 60; 300mg, n = 62 or 500mg, n = 66) or double-dose starting regimen (DD: 100mg, n = 62; 200mg, n = 63; or 300mg, n = 61 on days 1 and 90) of inclisiran or placebo (single-dose: n = 65; double-dose: n = 62). 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 tumor necrosis factor alpha (TNF-alpha) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADA) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity adverse events 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, single dose: 200mg: 0.8%; 300mg: -0.5%; 500mg: -1.8%; double dose: 100mg: 1.3%; 200mg: -0.5%; 300mg: 1.0%; no significant difference for any group as compared to placebo). No significant effects on other immune cells, including leukocytes, monocytes or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-alpha) with either the single or double dose regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity adverse events in none of the treatment regimens. CONCLUSIONS: 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 adverse events were observed over at least 6-months 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. |
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| ジャーナル名 | Cardiovascular research |
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| 投稿日 | 2020/4/4 |
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| 投稿者 | Landmesser, Ulf; Haghikia, Arash; Leiter, Lawrence A; Wright, R Scott; Kallend, David; Wijngaard, Peter; Stoekenbroek, Robert; Kastelein, John J P; Ray, Kausik K |
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| 組織名 | Department of Cardiology, Charite-Universitatsmedizin Berlin, Germany.;German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany.;Berlin Institute of Health (BIH), Berlin, Germany The.;Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto,;Toronto, Canada.;Department of Cardiology, Mayo Clinic, Rochester, MN, USA.;The Medicines Company, Parsippany, NJ, USA.;Department of Vascular Medicine, Academic Medical Center, University of;Amsterdam, Amsterdam, the Netherlands.;Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care;and Public Health, Imperial College London, London, United Kingdom. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/32243492/ |
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