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: -39.7% vs. +8.2% (p < 0.0001). Absolute difference: 70.6 mg/dl. Between days 90 and 510, difference was -38.1% vs. +6.2% (p < 0.0001).

Results were independent of baseline genotype (monogenic variants noted in 73.4% of 432 patients who underwent genetic testing; 80.8% had single LDL receptor [LDLR] causative variants).

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.


Raal FJ, Kallend D, Ray KK, et al., on behalf of the ORION-9 Investigators. Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. N Engl J Med 2020;382:1520-30.

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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