Efficacy and safety of PCSK9 siRNA in primary prevention
Effect of inclisiran on lipids in primary prevention: the ORION-11 trial
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.
- 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.