Physicians' Academy for Cardiovascular Education

PCSK9 siRNA does not affect inflammation measures or hematological parameters

Effect of inclisiran, the siRNA against PCSK9, on platelets, immune cells and immunological biomarkers - a pre-specified analysis from ORION-1

Literature - Landmesser U, Haghikia A, Leiter LA et al., - Cardiovasc Res. 2020. doi: 10.1093/cvr/cvaa077.

Introduction and methods

The ORION-1 trial has demonstrated that treatment with inclisiran, a RNA-targeted therapeutic agent lowering PCSK9 levels, lowered LDL-c levels with a long-lasting effect in patients with high CV risk [1]. Previous studies with earlier RNA-based therapies have observed possible adverse effects, including thrombocytopenia [2], activation of the immune system and induction of pro-inflammatory cytokines [3, 4].

The present study was a prespecified safety analysis of the ORION-1 trial and evaluated the effects of inclisiran treatment on hematological and inflammatory parameters in patients (n=501) with high CV risk and elevated LDL-c levels. Also, an analysis of immunogenicity regarding anti-drug-antibodies (ADAs) in >6000 study samples was reported. The ORION-1 trial was part of an RNA-targeted therapy study program in humans [1], and included patients with ASCVD (LDL-c >1.8 mmol/L) or ASCVD risk equivalents (LDL-c >2.5 mmol/L) despite maximally tolerated statin therapy. They were randomly assigned to a single dose (n=252) of inclisiran sodium 200 mg, 300 mg, 500 mg or placebo on day 1, or two doses (n=248) of inclisiran sodium 100 mg, 200 mg, 300 mg or placebo on day 1 and day 90. Primary endpoint of the ORION-1 trial was percentage change in LDL-c from baseline to day 180.

Endpoints of the present analysis were effects of inclisiran on changes in TNF-α, IL-6, monocyte counts, lymphocyte counts, platelet counts and formation of anti-drug antibodies (ADAs) from baseline to 180 days.

Main results


In this prespecified analysis of the ORION-1 trial, no significant effects were observed of 6-month treatment with inclisiran on inflammatory markers, platelets or clinical immunogenicity AEs in patients with high CV risk and elevated LDL-c levels. These findings suggest that inclisiran treatment in these patients is safe.


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