Physicians' Academy for Cardiovascular Education

LDL-c lowering by RNAi against PCKS9 similar across HeFH genotype subgroups

News - Oct. 6, 2020

Inclisiran reduces LDL-cholesterol independent of genotype in subjects with heterozygous familial hypercholesterolemia

Presented at the virtual EAS 2020 by Frederick Raal (University of the Witwatersrand, Johannesburg, South Africa)

Introduction and methods

Heterozygous familial hypercholesterolemia (HeFH) is mainly caused by mutation in the LDLR (in over 90% of cases), APOB, and PCSK9 genes. There may be great overlap between severe HeFH genotypes and homozygous FH (HoFH), as some subjects diagnosed clinically with HeFH may carry two mutations. Those with compound HeFH have different mutations in both alleles of one gene and those with double HeFH have mutations in one allele of two different genes. Causative mutations are characterized by pathogenicity and LDL receptor (LDLR) functional deficiency, and severity of FH depends on residual LDLR function.

The small interfering RNA inclisiran has demonstrated to potently reduce LDL-c in patients with HeFH. It is however unknown what the treatment effect of inclisiran across FH genotypes is.

The ORION-9 trial was a phase III, randomized, double-blind, placebo-controlled trial enrolling HeFH patients with LDL-c ≥2.6 mmol/L despite maximally tolerated statin dose with/without ezetimibe. 482 Participants were randomized in 1:1 ratio to inclisiran 300 mg or placebo. Injections were given at day 1, day 90 and then every 6 months until day 540.

In this substudy, 293 subjects with mutations in the LDLR gene were included. 37 Subjects had two variants: 18 had compound HeFH and 19 had double HeFH. 256 subjects had a single mutation in the LDLR gene. These subjects were divided based on LDLR functionality (negative n=168, defective n=28, unknown n=60) or pathogenicity (pathogenic n=231, likely pathogenic n=17, uncertain significance n=8). Patients in the double HeFH group or those who had LDLR/negative or pathogenic mutations had more often atherosclerotic CVD

Main results


These findings from a subanalysis of ORION-9 suggest that treatment effect of inclisiran in HeFH patients is similar across genotypes of HeFH and that upregulation of residual LDLR function across HeFH genotypes by inclisiran is sufficient for uptake of LDL-c in these patients. Inclisiran may provide benefit in HeFH patients regardless of the causative mutation.


Although ORION-9 was relatively small, it was one of the largest studies conducted in patients with FH who were genotyped. Similar analyses of subgroups of FH patients in the RUTHERFORD program and the ODYSSEY program showed similar treatment effect of a PCSK9 inhibitor across genotypes. So, althought some of the subgroups were small, Raal is confident that the mechanim of action of these drugs is to increase the LDLR function and that is why they work effectively, unlike in homozygous FH patients.

- Our reporting is based on the information provided at the EAS 2019 congress -

Watch a video about this study by prof. Raal

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