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ORION-9: Inclisiran RNAi halves LDL in familial hypercholesterolaemia patients

Presented by
Prof. Frederick Raal, University of the Witwatersrand, South Africa
AHA 2019
Phase 3, ORION-9
The phase 3 ORION-9 trial data demonstrated that the novel lipid-lowering drug inclisiran halved low-density lipoprotein (LDL) levels in patients with familial hypercholesterolaemia (FH) [1].

Prof. Frederick Raal (University of the Witwatersrand, South Africa) presented the placebo-controlled 18-month follow-up data of 482 patients with diagnosed FH (half had genetic variants of the LDL receptor, 5% had apolipoprotein B variants, 1 patient had a PCSK9 gain-of-function variant, 7% had 2 different gene variants, and 24% had no detected gene variant). All subjects had LDL levels higher than 100 mg/dL (mean 150 mg/dL), and almost all were already taking maximum tolerated doses of statins (90% of patients; 80% were on high-intensity statin treatment) with or without ezetimibe (50% of patients). Participants were randomly assigned to receive subcutaneous injections of inclisiran 300 mg or placebo at day 1 and day 30, thereafter every 6 months for 18 months.

The primary outcome at both prespecified time points (day 510, and time average day 90-540) was LDL reduction. The primary endpoint was met at both timepoints: the absolute mean reduction in LDL in the inclisiran arm was 71 mg/dL at day 510 (50% reduction compared with placebo; P<0.0001) and 63 mg/dL over the time average period (45% reduction compared with placebo; P<0.0001).

The novel mode of action of inclisiran is that it works to interfere with translation of the PCSK9 protein and is selectively taken up by the liver, resulting in an exceptionally long duration of action, requiring dosing only twice yearly. As such, Prof. Raal concluded, "inclisiran shows potential to address the unmet need of high-risk FH patients."

1. Raal F, et al. Safety and efficacy of inclisiran in patients with heterozygous familial hypercholesterolemia. LBS06, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.

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