Highlights from

AHA 2019

American Heart Association’s Scientific Sessions

Philadelphia, USA 16 - 18 November 2019

Inclisiran Safely Halves LDL-Cholesterol

Prof. R. Scott Wright (Mayo Clinic, Rochester, Minnesota, USA) presented the latest data on inclisiran from the ORION-10 trial, an investigational, twice-yearly small interfering RNA (siRNA) injectable [1]. Inclisiran halved low-density lipoprotein cholesterol (LDL-C) levels in a population of patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL compared with placebo in a follow-up of 18 months. The safety profile was very favourable.

ORION-10 randomised 1,561 patients with ASCVD and elevated LDL-C (≥ 70 mg/mL) already taking maximum tolerated statins to receive placebo or 4 injections of inclisiran over 18 months (days 1, 90, 270, and 450). Of note, 10% of patients were taking concomitant ezetimibe over the course of the study. At the end of the study, on day 510, LDL cholesterol had been reduced by 56% in the inclisiran arm versus the placebo arm (P<0.00001).

Treatment-emergent adverse event rates were similar between the placebo and inclisiran arms (75% vs 74%), as were the rates of serious adverse events (26.3% vs 22.4%), including those that led to drug discontinuation (2.2% vs 2.4%). There were only 20 instances of an injection site event (2.6%)—13 mild and 7 moderate; but these numbers fell after the protocol switched to a prefilled syringe midway through the study. There were no other differences with regard to liver or kidney function or to the prespecified exploratory cardiovascular endpoint defined as cardiac death, any signs or symptoms of cardiac arrest, nonfatal MI, and/or stroke (10.2% vs 7.4%).

It is not clear how inclisiran affects HDL cholesterol, triglycerides, and lipoprotein(a) levels, or how the safety profile will hold up for a drug intended as a lifelong therapy. In conclusion, in 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 siRNA is a novel approach to management of LDL-C. Clinical event-powered randomised trials are needed.

  1. Wright RS et al. Safety and Efficacy of Inclisiran in Patients With ASCVD and Elevated LDL Cholesterol - Results From the Phase 3 ORION-10 Trial. Session LBS01. American Heart Association Annual Scientific Sessions (AHA 2019), 14-18 November, Philadelphia, PA, USA.

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