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
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.
- Non-HDL-c changes from baseline to day 180 ranged dose-dependently from -25% to -46% (P<0.001 for all groups vs. placebo).
- Apo-B changes from baseline to day 180 ranged dose-dependently from -23% to -41% (P<0.001 for all groups vs. placebo).
- The effect of inclisiran on HDL-c lasted longer than the effect on other lipid parameters, with percentage changes from baseline to day 180 of +4.74% to +8.69%, depending on the dose.
- VLDL-c, triglyceride, and Lp(a) changes showed broad inter-individual and temporal variability.
- Lp(a) reductions did not reach statistical significance in any of the dosing regimens.
- A single dose of 300mg of inclisiran at baseline and repeated at day 90, provided the best efficacy with the most prolonged effect on lipoproteins.
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.