Efficacy and safety of PCSK9 siRNA in primary prevention cohort

Effect of inclisiran on lipids in primary prevention: the ORION-11 trial

Literature - Ray KK, Kallend D, Leiter LA, et al. - Eur Heart J. 2022;ehac615. doi:10.1093/eurheartj/ehac615

Introduction and methods


The majority of CV events occur in individuals without a prior history of ASCVD [1,2, 3]. Lipid-lowering therapy, with statins being the first choice, is used to reduce the risk of ASCVD in primary prevention patients. However, other lipid-lowering therapies are often needed when the lowering of LDL-c with statins is inadequate, and when other lipid mediators, such as non-HDL-c and apoB, also should be reduced.

Inclisiran is an siRNA therapeutic that inhibits the translation of PCSK9 mRNA in hepatocytes reducing circulating PCSK9 levels, and ultimately lowering plasma LDL-c levels. The ORION-11 study showed that inclisiran subcutaneous injection, twice yearly as maintenance dosing, resulted in effective and sustained reductions in LDL-c in a mixed population of primary and secondary prevention patients [4,5].

Aim of the study

The study objectives were to assess the efficacy and safety of inclisiran in high-risk patients with elevated LDL-c levels receiving maximally tolerated lipid-lowering therapy. These primary prevention patients were a subgroup from ORION-11.


This prespecified substudy of the randomized, double-blind, placebo-controlled phase 3 ORION-11 trial included patients at risk of, but without prior CV events and with LDL-c ≥2.6 mmol/L (≥100 mg/dL), despite maximally tolerated lipid-lowering therapy.

Overall 2381 patients were screened, and 1617 were randomized in ORION-11. Of those randomized, 203 were identified as primary prevention patients of whom 98 received inclisiran, and 105 placebo. Inclisiran, 284 mg or placebo, was administered on days 1, 90, and thereafter every 6 months up to 540 days.


The primary endpoints were percentage LDL-c change from baseline to day 510, and time-adjusted percentage change from baseline after day 90 up to day 540. Safety was assessed over 540 days.

Main results

Efficacy outcomes

  • At day 510, the placebo-corrected percentage LDL-c change with inclisiran was −43.7% (95%CI: −52.8 to −34.6) with a corresponding time-adjusted change of −41.0% (95%CI: −47.8 to −34.2); (P<0.0001).
  • At day 510, the placebo-corrected absolute change in LDL-c change with inclisiran was−1.5 mmol/L (95%CI: −1.8 to −1.2) with a respective time-adjusted change of −1.3 mmol/L (95%CI: −1.6 to −1.1).
  • At day 510, the placebo-corrected percentage change in non-HDL-c with inclisiran was −39.5% (95%CI: −47.3 to −31.7) with a corresponding time-adjusted change of −35.3% (95%CI: −41.6 to −29.0); (P<0.0001).
  • At Day 510, the placebo-corrected percentage apoB change with inclisiran was −35.8% (95%CI: −42.6 to −29.0) with a corresponding time-adjusted change of −34.8% (95%CI: −40.3 to −29.3); (P<0.0001).
  • At day 540, the placebo-corrected percentage Lp(a) change with inclisiran was −28.5% (95%CI: −42.0 to −15.0) with a corresponding time-adjusted change of −28.9% (95%CI: −40.9 to −16.9); (P<0.0001).
  • At day 510, PCSK9 decreased by 65.2% with inclisiran and increased by 15.7% with placebo representing a between-group difference of −80.8% (95%CI:−87.4 to −74.3).


  • Inclisiran was generally well-tolerated, but clinically relevant reactions at the injection site were more frequent in the inclisiran group [(4/98) (4.1%) than in the placebo group (0); none of these reactions were severe or persistent.


This prespecified analysis of ORION-11 shows that twice-yearly maintenance dosing of subcutaneous treatment with inclisiran – compared with placebo – reduces atherogenic lipoproteins in high-risk primary prevention patients with elevated LDL-c levels, despite statins, effectively and sustainably. Injection site reactions were more frequent in the inclisiran group than in the placebo group.


1. Canto JG, Kiefe CI, Rogers WJ, Peterson ED, Frederick PD, French WJ, et al. Number of coronary heart disease risk factors and mortality in patients with first myocardial infarction. JAMA 2011;306:2120–2127.

2. Szummer K, Wallentin L, Lindhagen L, Alfredsson J, Erlinge D, Held C, et al. Relations between implementation of new treatments and improved outcomes in patients with non-ST-elevation myocardial infarction during the last 20 years: experiences from SWEDEHEART registry 1995 to 2014. Eur Heart J 2018;39:3766–3776.

3. Pender A, Lloyd-Jones DM, Stone NJ, Greenland P. Refining statin prescribing in lowerrisk

individuals: informing risk/benefit decisions. J Am Coll Cardiol 2016;68:1690–1697.

4. Raal FJ, Kallend D, Ray KK, Turner T, Koenig W, Wright RS, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med 2020;382: 1520–1530.

5. Ray KK, Wright RS, Kallend D, Koenig W, Leiter LA, Raal FJ, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020;382:1507–1519.

Find this article online at Eur Heart J

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