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

One-year results: Reduction in LDL-C at 1 year was -30% with a single dose of 200 mg, -37% with a single dose of 300 mg, -39% with a single dose of 500 mg inclisiran, -30% with a 2-dose 100 mg, -40% with a 2-dose 200 mg, and -46% with a 2-dose 300 mg inclisiran.

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. The results were sustained to 1 year, with the 2-dose 300 mg regimen resulting in the greatest reduction in LDL-C (nearly 50% reduction).

References:

Presented by Dr. Kausik K. Ray at the European Society of Cardiology Congress, Barcelona, Spain, August 28, 2017.

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: ESC Congress, ESC2017, 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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