Inclisiran for Treatment of Heterozygous Familial Hypercholesterolemia

Study Questions:

Monoclonal antibodies directed against proprotein convertase subtilisin-kexin type 9 (PCSK9) have been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels by >50% but require administration every 2-4 weeks. What is the effect of a twice-yearly injection of inclisiran, a small interfering RNA inhibitor of hepatic PCSK9, in adults with heterozygous familial hypercholesterolemia (HeFH)?


ORION-9, a phase 3 double-blind trial conducted between December 2017 and September 2019, enrolled 482 adults with HeFH who received subcutaneous injections of inclisiran sodium (at a dose of 300 mg) or matching placebo on days 1, 90, 270, and 450 assigned in a 1:1 ratio. The two primary endpoints were the percent change from baseline LDL-C compared to day 510, and the time-adjusted percent change from baseline in the LDL-C level between day 90 and day 540.


Median age was 56 years and 47% were men; the mean baseline level of LDL-C was 153 mg/dl, mean triglycerides 119 mg/dl, and apolipoprotein B 123 mg/dl. About 90% were on statins, 75% high-intensity statins, and >50% on ezetimibe. In the intention-to-treat cohorts, 92% on inclisiran and 96% on placebo completed defined as through day 540. At day 510, the change in the LDL-C was a reduction of 39.7% (95% CI, -43.7 to -35.7) in the inclisiran group and an increase of 8.2% (95% CI, 4.3-12.2) in the placebo group, for a between-group difference of -47.9 percentage points (95% CI, -53.5 to -42.3; p < 0.001). The time-averaged percent change in the LDL-C level between day 90 and day 540 was a reduction of 38.1% (95% CI, -41.1 to -35.1) in the inclisiran group and an increase of 6.2% (95% CI, 3.3-9.2) in the placebo group, for a between-group difference of -44.3 percentage points (95% CI, -48.5 to -40.1; p < 0.001). There were robust reductions in LDL-C in all genotypes of familial hypercholesterolemia. Adverse events and serious adverse events were similar in the two groups.


Amongst adults with HeFH, those who received inclisiran had significantly lower levels of LDL-C than those who received placebo with an infrequent dosing regimen and an acceptable safety profile.


The addition of another agent that can lower the LDL-C by about 50% in maximally treated HeFH patients is welcome. Studies will be needed to further assess clinical benefit, sustainability of effect and a larger cohort to assess side effects. Most placebo-controlled studies of the two available PCSK9 antibody agents in HeFH were limited to those genetically proven. In this study using the RNA inhibitor of hepatic PCSK9, 36% had no genetic variant (115), LDL-R variant of unknown significance (8), or had no genetic testing (50). Interestingly the cohort with no genetic variants had the largest absolute and percent changes and are possibly polygenic hypercholesterolemia.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Genetic Arrhythmic Conditions, Homozygous Familial Hypercholesterolemia, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Apolipoproteins B, Cholesterol, LDL, Dyslipidemias, Genetics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Hyperlipoproteinemia Type II, Proprotein Convertases, Primary Prevention, Triglycerides

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