Inclisiran safely halves LDL-Cholesterol

Prof. R. Scott Wright (Mayo Clinic, Rochester, USA) presented the latest data from the phase 3, randomised, placebo-controlled, double-blinded ORION-10 trial, testing the effect of the small interfering RNA (siRNA) inclisiran in patients with atherosclerotic cardiovascular disease (ASCVD) and elevated low-density lipoprotein cholesterol (LDL-C) [1]. With a follow-up of 18 months, inclisiran halved LDL-C levels compared with placebo. The safety profile was favourable.

ORION-10 randomised 1,561 ASCVD patients with elevated LDL-C (≥70 mg/mL) who were already taking maximum tolerated statins to receive either 4 injections (at 0, 3, 9, and 15 months) of placebo or of 300 mg inclisiran with a follow-up of 18 months. The co-primary endpoints were percentage of LDL-C change from baseline at day 510 and the average percentage change from day 90 to day 540.

At the study end at day 510, LDL-C was 58% lower in the inclisiran arm versus the placebo arm, and the time-averaged reduction was similar at 56% reduction (both P<0.00001; see Figure). 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 detected toxicities in liver or kidney function or in prespecified exploratory cardiovascular endpoint of CV death, fatal or non-fatal MI, or stroke.

Figure: Percentage change in LDL-C from baseline in ITT population [1]



CI, confidence interval; ITT, intention-to-treat; LDL-C, low-density lipoprotein cholesterol.

The invited discussant, Prof. Karol E. Watson (David Geffen School of Medicine at UCLA, USA) pointed out that although these data are very promising, it is still not clear how inclisiran affects HDL-C, triglycerides, and lipoprotein(a) levels. A further limitation in this study was that it did not use clinical events as a primary outcome. In conclusion, in patients with ASCVD on maximum tolerated statin therapy, inclisiran injections twice a year generated a significant and durable reduction in LDL-C while being well tolerated. The use of a siRNA is a novel approach to management of LDL-C.

 

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. LBS01, AHA Scientific Sessions 2019, 14-18 November, Philadelphia, USA.

 



Posted on 26 February 202013 June 2024