Inclisiran for Subjects With ASCVD and Elevated Low-Density Lipoprotein Cholesterol - ORION-10

Contribution To Literature:

The ORION-10 trial showed that twice yearly inclisiran injection reduced LDL-C by 56%.


The goal of the trial was to evaluate inclisiran compared with placebo among patients with atherosclerotic cardiovascular disease (ASCVD). Inclisiran is a small interfering double-stranded RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) production.

Study Design

  • Randomized
  • Parallel
  • Double-blind

Patients with ASCVD on maximum tolerated statin therapy were randomized to inclisiran 300 mg daily (n = 781) versus placebo (n = 780). Study drug injection was administered on day 1, day 90, day 270, and day 450.

  • Total number of enrollees: 1,561
  • Duration of follow-up: 18 months
  • Mean patient age: 66 years
  • Percentage female: 30%
  • Percentage with diabetes: 42%

Inclusion criteria:

  • ≥18 years of age
  • Stable ASCVD
  • Elevated low-density lipoprotein cholesterol (LDL-C ≥70 mg/dl)
  • Maximum tolerated or intolerance to statin therapy

Exclusion criteria:

  • Prior or planned use of PCSK9 inhibitor
  • Major adverse cardiac event within the last 3 months
  • Left ventricular ejection fraction ≤30% or New York Heart Association class III-IV symptoms
  • Uncontrolled hypertension
  • Severe concomitant noncardiovascular disease
  • Use of another investigational drug
  • Fasting triglyceride >400 mg/ml

Principal Findings:

The primary outcome, mean percent change in LDL-C at 510 days, was -56 in the inclisiran group compared with 1 in the placebo group (p < 0.0001). This was a time-averaged 56% reduction in LDL-C for inclisiran versus placebo.

Secondary outcomes:

  • Exploratory cardiovascular endpoint: 7.4% with inclisiran vs. 10.2% with placebo
  • Treatment-emergent adverse event: 74% with inclisiran vs. 75% with placebo
  • Serious adverse event: 22% with inclisiran vs. 26% with placebo
  • Protocol-defined skin event: 2.6% with inclisiran vs. 0.9% with placebo
  • No sign of liver, kidney, or muscle toxicity

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


Among patients with ASCVD on maximum tolerated statin therapy, twice yearly inclisiran injection resulted in a significant reduction in LDL-C. This was well tolerated with no sign of liver, muscle, or kidney toxicity. The use of a small interfering double-stranded RNA is a novel approach to management of LDL-C. Clinical event-powered randomized trials are needed.


Ray KK, Wright RS, Kallend D, et al., on behalf of the ORION-10 and ORION-11 Investigators. Two Phase 3 Trials of Inclisiran in Patients With Elevated LDL Cholesterol. N Engl J Med 2020;382:1507-19.

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 Dr. R. Scott Wright at the American Heart Association Annual Scientific Sessions (AHA 2019), Philadelphia, PA, November 16, 2019.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: acc20, ACC Annual Scientific Session, AHA19, AHA Annual Scientific Sessions, Atherosclerosis, Cholesterol, LDL, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Myocardial Ischemia, Primary Prevention, Proprotein Convertases, RNA, Double-Stranded, RNA, Small Interfering, Subtilisins

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