These findings from the ORION-11 trial were presented by principal investigator, Professor Kausik Ray (Imperial College London, London, UK) at a Late Breaking Science Session on Monday.
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<0.00001) were achieved with twice-yearly injections of inclisiran at 17 months. The rate of adverse events (AEs) was similar between the groups and localised injection-site AEs—occurring in 4.7% of patients with inclisiran vs 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 AEs (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.
Prof. Ray concludes, “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. We believe 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. Both will report in due course.