AHA 2019 — Inclisiran offers potent LDL reduction with twice yearly injection


  • Daniel M. Keller, Ph.D
  • Conference Reports
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Takeaway

  • ORION-10 trial showed that semiannual inclisiran, a small interfering ribonucleic acid, produced potent, durable, low-density-lipoprotein cholesterol (LDL-C) reductions in patients with high-risk atherosclerotic cardiovascular disease (ASCVD) taking lipid-lowering therapies.

Why this matters

  • Inclisiran's mechanism of action, different from current medications, suggests it may be good adjunctive therapy when additional LDL-C reduction is required.
  • Semiannual injection may improve adherence.

Study design

  • Patients 18 years, ASCVD with LDL-C ≥70 mg/dL on maximally tolerated statin doses ± ezetimibe.
  • Randomly assigned to inclisiran 300 mg (n=781) or placebo (n=780) injection on days 1, 90, 270, 450.

Key results

  • Groups well-balanced at baseline for age (median 66-67 years), LDL-C (105 mg/dL), sex, comorbidities, LDL-C-lowering medications.
  • At day 540 (90 days after last dose), mean LDL-C decreased 56 mg/dL on inclisiran vs 1 mg/dL increase on placebo (P<.00001>
  • LDL-C-lowering of >50 mg/dL at 3 months and durable through 18 months. Inclisiran vs placebo, P<.00001 at all time points.>
  • Safety equivalent to placebo.
  • Adverse events (AEs):
    • Diabetes: inclisiran, 15%; placebo, 14%.
    • Transient injection-site reactions: inclisiran, 2.6%; placebo, 0.9%.
    • No differences in serious AEs.
    • No liver, kidney, muscle, or platelet toxicity.
  • Study funded by The Medicines Company.

Limitations

  • Inclisiran effect on other lipids unknown.
  • Unknown adherence with infrequent dosing.
  • Unknown long-term safety and effectiveness.
  • Unknown clinical outcome rates with or vs statins alone.