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
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 . Previous studies with earlier RNA-based therapies have observed possible adverse effects, including thrombocytopenia , 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 , 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.
- As compared to placebo, overall, inclisiran did not significantly affect platelet, leucocyte, monocyte, or neutrophil counts in any of the dosing groups.
- As compared to placebo, inclisiran did not significantly affect TNF-α or IL-6 levels in any of the dosing groups.
- A total of 6068 serum samples were collected and 65 samples from 39 patients were identified as potentially positives for anti-inclisiran antibodies.
- No immune system disorder AEs occurred in the inclisiran or placebo single dose groups. In the two-doses group, two AEs occurred in two subjects (3.2%) on placebo, allergy to an arthropod sting and drug hypersensitivity, and two AEs occurred in two subjects (1.1%) on inclisiran, both of seasonal allergy.
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.