Physicians' Academy for Cardiovascular Education

PCSK9 RNA interference causes significant and sustained lipid reductions

Effect of an siRNA Therapeutic Targeting PCSK9 on Atherogenic Lipoproteins: Pre-Specified Secondary End Point in ORION 1

Literature - Ray KK, Stoekenbroek RM, Kallend D, et al. - Circulation 2018; published online ahead of print

Introduction and methods

Inclisiran, a chemically modified small interfering RNA (siRNA) conjugated to triantennary N-acetylgalactosamine (GalNAc), targets PCSK9 messenger RNA (mRNA) in hepatocytes, and inhibits PCSK9 synthesis. ORION-1 was a phase 2, randomized, double-blind, placebo-controlled trial that evaluated the efficacy, safety and tolerability of 6 different inclisiran doses, in 501 patients with documented atherosclerotic cardiovascular disease (ASCVD) and increased LDL-c levels despite maximum tolerated statin doses. The ORION-1 study showed that it is possible to reduce LDL-c with inclisiran, to similar levels as with currently available PCSK9 inhibitors, and with fewer injections [5,6].

This analysis of the ORION-1 study reports the effect of inclisiran on pre-specified secondary lipid and lipoprotein outcomes over time, for up to 180 days, which was the primary efficacy time-point. The pre-specified secondary lipid and lipoprotein outcomes include HDL-c, non-HDL-c, very low density lipoprotein cholesterol (VLDL-c), apolipoprotein B (apoB), and lipoprotein(a) [Lp(a)]. Moreover, the individual variation in response in these measures was assessed.

Main results


Inhibition of hepatic PCSK9 synthesis with inclisiran led to significant reductions in non-HDL-c and apoB, as well as to increases of HDL-c. The reductions were sustained up to day 180, and are similar to those achieved with currently available PCSK9 inhibitors.


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