Physicians' Academy for Cardiovascular Education

Sustained LDL-c lowering with PCSK9 siRNA up to 4 years

News - Nov. 10, 2022

Long-term efficacy and safety of inclisiran in patients with high cardiovascular risk and elevated low-density lipoprotein cholesterol (ORION-3): Results from the 4-year open-label extension of the ORION-1 trial

Presented at the AHA Scientific Sessions 2022 by: Prof. Kausik Ray, MD - London, UK

Introduction and methods

Inclisiran is an siRNA therapeutic that inhibits the translation of PCSK9 mRNA in hepatocytes leading to reduction in circulating PCSK9 levels. Three large phase 3 trials with inclisiran have previously shown that a dosing interval at day 1, 90 and 6-monthly thereafter over 18 months reduced placebo-corrected LDL-c levels by 52%. It is however unknown whether twice-yearly dosing of inclisiran results in sustained lowering of LDL-c beyond 18 months, and whether repeated exposes to a siRNA-based approach by inclisiran has additional safety concerns.

The objective of the ORION-3 study was to assess the 4-year long-term efficacy and safety of inclisiran twice a year in patients with high CV risk and elevated LDL-c (despite maximally-tolerated LLT).

The study population was the population of patients who completed the ORION-1 trial. Patients ≥18 years of age with established ASCVD or ASCVD risk equivalent (high-risk primary prevention). 317 Patients who had been on inclisiran (either single or double dose) in ORION-1 were invited to participate in the open-label extension study; 290 patients were enrolled. The 127 patients in the ORION-1 study who had not been exposed to inclisiran were invited to participate, first in the switching arm – evolocumab every 2 weeks for 1 year- and then transitioning to the inclisiran arm in 2 ways -either sequential, where the last dose of evolocumab was 24 days earlier or at the same time at day 360; a total of 92 patients were enrolled.

The primary endpoint was percentage change in LDL-c from baseline of ORION-1 to day 210 of ORION-3 for the inclisiran-only arm.

Main results

Efficacy outcomes

Exploratory analyses

Safety outcomes


Over 4 years, twice-yearly dosing of inclisiran resulted in effective and sustained reductions in LDL-c by 44.2% from ORION-1 baseline.

Prof. Ray concluded that this study suggests that the siRNA-based therapy of inclisiran with a twice-yearly dosing schedule has a favorable safety and efficacy profile for long-term control of LDL-c levels.

- Our reporting is based on the information provided at the AHA Scientific Sessions 2022 -

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