LDL-C Reduction From 6 to 9 Months Following Single or Second Injection of Inclisiran a Novel siRNA Compound: Primary - ORION-1

Contribution To Literature:

The ORION-1 trial showed that inclisiran was superior to placebo at reducing LDL-C levels.

Description:

The goal of the trial was to evaluate if inclisiran, which is designed to target PCSK9 messenger RNA, could result in sustained reductions in low-density lipoprotein cholesterol (LDL-C) compared with placebo among patients with elevated cardiovascular risk.

Study Design

  • Randomized
  • Parallel
  • Double-blind
  • Placebo

Patients at elevated cardiovascular risk were randomized to a subcutaneous injection inclisiran versus placebo. Patients were randomly assigned to one of eight study groups: a single dose of inclisiran 200 mg, 300 mg, 500 mg, or placebo on day 1 or two doses of inclisiran 100 mg, 200 mg, 300 mg, or placebo on days 1 and 90.

  • Total number of enrollees: 501 patients
  • Duration of follow-up: 180 days
  • Mean patient age: 62 years
  • Percentage female: 35%

Inclusion criteria:

  • Men and woman ≥18 years with LDL-C >70 mg/dl (for patients with history of atherosclerotic cardiovascular disease [ASCVD]) or >100 mg/dl (for patients without history of ASCVD) at screening
  • Patients receiving the maximum possible dose of a statin with or without additional lipid-lowering therapy at stable doses for ≥30 days before screening

Exclusion criteria:

  • Any use at any time of a monoclonal antibody drug targeting PCSK9
  • Any uncontrolled or serious disease, or any medical or surgical  condition that may either interfere with participation or put subject at significant risk
  • New York Heart Association class II, III, or IV heart failure or last known left ventricular ejection fraction <30%
  • Cardiac arrhythmia within 3 months prior to randomization that was not controlled by medication or via ablation
  • Any history of hemorrhagic stroke
  • Major adverse cardiac event within 6 months prior to randomization

Principal Findings:

The primary outcome, percent reduction in LDL-C at 180 days, was -27.9% with single dose 200 mg inclisiran, -38.4% with single dose 300 mg inclisiran, -41.9% with single dose 500 mg inclisiran, 2.1% with single dose placebo, -35.5% with double dose 100 mg inclisiran, -44.9% with double dose 200 mg inclisiran, -52.6% with double dose 300 mg inclisiran, and 1.8% with double dose placebo (p < 0.001 for all comparisons vs. placebo).

Secondary outcomes:

  • Serious adverse events: 11% for inclisiran versus 8% for placebo

Interpretation:

Among patients with elevated cardiovascular risk, inclisiran was superior to placebo at lowering LDL-C. The greatest reduction in LDL-C occurred in the inclisiran 300 mg double dose group. Serious adverse events were similar between treatment groups. Studies powered for clinical outcomes are warranted.

References:

Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in Patients at High Cardiovascular Risk with Elevated LDL Cholesterol. N Engl J Med 2017;Mar 17:[Epub ahead of print].

Presented by Dr. Kausik K. Ray at the American College of Cardiology Annual Scientific Session (ACC 2017), Washington, DC, March 17, 2017.

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

Keywords: ACC17, ACC Annual Scientific Session, Atherosclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Cholesterol, LDL, Dyslipidemias, Lipids, Metabolic Syndrome X, Primary Prevention, RNA Interference, RNA, Small Interfering


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