Physicians' Academy for Cardiovascular Education

Sustained LDL-c-lowering with long-term treatment with PCSK9 siRNA

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

Literature - Ray KK, Troquay RPT, Visseren FLJ, et al. - Lancet Diabetes Endocrinol. 2023 Feb;11(2):109-119

Introduction and methods


Small-interfering ribonucleic acid (siRNA)-based therapies against PCSK9 have emerged as an alternative method to lower LDL-c, which require substantial less injections than therapy with PCSK9 monoclonal antibodies. The siRNA-therapeutic inclisiran reduces hepatic PCSK9 production resulting in reduced circulating PCSK9 levels [1-2]. Twice-yearly administration of inclisiran from second dose onwards was studied up to 18 months in the ORION-9, ORION-10, and ORION-11 trials [3-5].

Aim of the study

The authors investigated the long-term efficacy and safety of twice-yearly inclisiran in patients with high CV risk and elevated LDL-c.



ORION-3 was a 4-year open label extension study of the 1-year, phase 2 ORION-1-trial. ORION-1 was a multicenter, double-blind, placebo-controlled, dose-finding study with subcutaneous injections of inclisiran in patients at high risk of ASCVD or high-risk primary prevention and elevated LDL-c concentrations despite maximally tolerated statins or other LDL-lowering therapies, or with documented statin intolerance [2]. Patients that were treated with inclisiran in ORION-1 received twice-yearly 300 mg subcutaneous inclisiran sodium throughout ORION-3 (inclisiran-only arm, n=290), whereas patients in the placebo group in ORION-1 first started with subcutaneous evolocumab 140 mg every 2 weeks until day 360 and thereafter transitioned to subcutaneous 300 mg inclisiran sodium subcutaneously twice-yearly for the remainder of ORION-3 (switching arm, n=92). Inclisiran was administrated by a health care professional, whereas evolocumab was self-administered. 233 patients in the inclisiran-only arm and 80 patients in the switching arm completed the full 4-year study period.


The primary endpoint was the percentage change in LDL-c from baseline of ORION-1 to day 210 of ORION-3 in the inclisiran-only arm (total observational period of approximately 570 days after first inclisiran exposure). Secondary endpoints were changes in LDL-c and PCSK9 levels over 4 years in each arm, and long-term safety and tolerability.

Main results

Inclisiran-only arm

Switching arm

Adverse events


This study demonstrates that twice-yearly administration of inclisiran is well tolerated in patients, and provided sustained reductions in LDL-c, non-HDL-c, and apoB over a period of 4 years. In contrast to LDL-c lowering with PCSK9 monoclonal antibodies, much less injections are needed with an siRNA therapeutic.


Show references

Find this article online at Lancet Diabetes Endocrinol.

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