Subcutaneous administration of Inclisiran, a small-interfering RNA ( siRNA ) directed against proprotein convertase subtilisin/kexin type 9 ( PCSK9 ), was associated with substantial and sustained low-density lipoprotein cholesterol ( LDL-C ) reductions over the 18-month study.
ORION-11 included 1,617 patients with atherosclerotic cardiovascular disease ( ASCVD ), or ASCVD risk equivalents, and elevated LDL-C despite maximally tolerated statins ( with or without Ezetimibe ).
Patients were randomised to a subcutaneous Inclisiran sodium 300 mg injection, a second injection after three months and then injections every six months thereafter, or to placebo injections.
Mean baseline LDL-C levels were 107 mg/dL in the Inclisiran arm and 104 mg/dL in the placebo arm.
Most patients ( 95% ) were on a statin ( 95% on a high-intensity statin ) and around 7% were on Ezetimibe.
For the primary endpoint, placebo-adjusted LDL-C reductions of 54% ( p less than 0.00001 ) were achieved with twice-yearly injections of Inclisiran at 17 months.
The rate of adverse events was similar between the groups and localised injection-site adverse effects, occurring in 4.7% of patients with Inclisiran versus 0.5% with placebo, were mostly mild and transient.
Further, the marked LDL-C reductions with Inclisiran were not accompanied by any signs of liver, kidney, muscle or platelet toxicity.
A similar proportion of Inclisiran- and placebo-treated patients experienced serious adverse effects ( 22.3% vs 22.5%, respectively ) or all-cause mortality ( 1.7% vs 1.9%, respectively ).
During the study, an exploratory cardiovascular endpoint ( cardiac death, any signs or symptoms of cardiac arrest, non-fatal myocardial infarction or stroke ) occurred in 7.8% of patients treated with Inclisiran and 10.3% of patients with placebo.
In conclusion, the advantage of Inclisiran is that it is given via twice-yearly subcutaneous injection, while the other PCSK9-lowering agents are injected every two weeks or monthly. This may lead to better adherence and, potentially, better outcomes.
ORION-9 is ongoing in patients with ASCVD, while the ORION-10 trial is being conducted in patients with heterozygous familial hypercholesterolaemia. ( Xagena )
Source: European Society of Cardiology ( ESC ) Congress, 2019