Effect of inclisiran, the siRNA against PCSK9, on platelets, immune cells and immunological biomarkers - a pre-specified analysis from ORION-1
File(s)
Accepted version
Author(s)
Type
Journal Article
Abstract
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-α) 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-α) 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.
Date Issued
2021-01-01
Date Acceptance
2020-03-16
Citation
Cardiovascular Research, 2021, 117 (1), pp.284-291
ISSN
0008-6363
Publisher
Oxford University Press (OUP)
Start Page
284
End Page
291
Journal / Book Title
Cardiovascular Research
Volume
117
Issue
1
Copyright Statement
© The Author(s) 2020. For permissions please email: journals.permissions@oup.com.
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). This is a pre-copy-editing, author-produced version of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version Ulf Landmesser, Arash Haghikia, Lawrence A Leiter, R Scott Wright, David Kallend, Peter Wijngaard, Robert Stoekenbroek, John J P Kastelein, Kausik K Ray, Effect of inclisiran, the siRNA against PCSK9, on platelets, immune cells and immunological biomarkers - a pre-specified analysis from ORION-1, Cardiovascular Research, , cvaa077 is available online at: https://doi.org/10.1093/cvr/cvaa077
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model). This is a pre-copy-editing, author-produced version of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version Ulf Landmesser, Arash Haghikia, Lawrence A Leiter, R Scott Wright, David Kallend, Peter Wijngaard, Robert Stoekenbroek, John J P Kastelein, Kausik K Ray, Effect of inclisiran, the siRNA against PCSK9, on platelets, immune cells and immunological biomarkers - a pre-specified analysis from ORION-1, Cardiovascular Research, , cvaa077 is available online at: https://doi.org/10.1093/cvr/cvaa077
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/32243492
PII: 5815561
Subjects
Inclisiran
PCSK9
safety analysis
siRNA
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2020-04-03