Inclisiran for Heterozygous Familial Hypercholesterolemia - ORION-9

Contribution To Literature:

The ORION-9 trial showed that inclisiran is superior to placebo in reducing LDL-C among patients with HeFH who are already on statins and ezetimibe.


The goal of the trial was to assess the safety and efficacy of inclisiran in lowering low-density lipoprotein cholesterol (LDL-C) among patients with heterozygous familial hypercholesterolemia (HeFH).

Study Design

Eligible patients were randomized in a 1:1 fashion to either inclisiran 300 mg (n = 242) or matching placebo (n = 240). All patients were on maximally tolerated statin. The study drug was administered as a subcutaneous injection on day 1, day 90, day 270, and then day 450.

  • Total screened: 617
  • Total number of enrollees: 482
  • Duration of follow-up: 510 days
  • Mean patient age: 56 years
  • Percentage female: 53%

Inclusion criteria:

  • ≥18 years of age
  • HeFH diagnosed by genetic testing and/or Simon Broome criteria
  • LDL-C ≥100 mg/dl
  • Stable on a low-fat diet
  • Maximally tolerated statin dose

Exclusion criteria:

  • Prior or planned use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor
  • Major adverse cardiac event within 3 months
  • New York Heart Association class III/IV or left ventricular ejection fraction ≤30%
  • Uncontrolled hypertension
  • Severe concomitant noncardiovascular disease
  • Fasting triglycerides  >400 mg/dl

Other salient features/characteristics:

  • Known atherosclerotic cardiovascular disease: 27%
  • High-intensity statins: 82%, any statin: 91%
  • Baseline LDL-C: 153 mg/dl

Principal Findings:

The primary outcome, % LDL-C change, for inclisiran vs. placebo, was: -41% vs. 8% (p < 0.0001). Absolute difference: 70.6 mg/dl. Results were independent of baseline genotype.

Secondary outcomes for inclisiran vs. placebo:

  • Nasopharyngitis: 12% vs. 8%
  • Protocol-defined event (reaction, erythema, rash, pruritus, hypersensitivity): 13.7% vs. 0.4% (p < 0.05)
  • Transaminitis: 1.2% vs. 0.4%
  • All-cause mortality: 0.4% vs. 0.4%

Pooled analysis of ORION-9, ORION-10, and ORION-11:

  • Mean percent change in LDL-C at 510 days: -51 in the inclisiran group compared with 4 in the placebo group (p < 0.0001). This was a time-averaged 52% reduction in LDL-C for inclisiran vs. placebo.
  • At least one treatment-emergent adverse event: 78.0% with inclisiran vs. 77.3% with placebo
  • At least one serious treatment-emergent adverse event: 20.4% with inclisiran vs. 23.0% with placebo
  • Prespecified exploratory cardiovascular event: 7.1% with inclisiran vs. 9.4% with placebo


The results of this trial indicate that inclisiran is superior to placebo in reducing LDL-C among patients with HeFH who are already on statins and ezetimibe. Inclisiran is a long-acting, small interfering double-stranded RNA agent, which affects the production of PCSK9 in the liver. Cardiovascular outcome trials are awaited – the magnitude of benefit in LDL-C seems to be similar to what was observed with PCSK9 inhibitors.


Presented by Dr. R. Scott Wright at the American College of Cardiology Virtual Annual Scientific Session Together With World Congress of Cardiology (ACC 2020/WCC), March 28, 2020.

Presented by Frederick J. Raal at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 18, 2019.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins, Diet

Keywords: acc20, ACC Annual Scientific Session, AHA Annual Scientific Sessions, AHA19, Atherosclerosis, Cholesterol, LDL, Diet, Fat-Restricted, Dyslipidemias, Erythema, Genetic Testing, Genotype, Hypercholesterolemia, Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Nasopharyngitis, Primary Prevention, Proprotein Convertases, Pruritus, RNA, Double-Stranded

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