Efficacy and Safety of Inclisiran in Patients with Polyvascular Disease: Pooled, Post Hoc Analysis of the ORION-9, ORION-10, and ORION-11 Phase 3 Randomized Controlled Trials

Abstract

Purpose Patients with polyvascular disease (PVD) are at very high cardiovascular risk and require intensive lipid-lowering therapy. This analysis describes the lipid-lowering efficacy and safety of inclisiran versus placebo in patients with and without PVD. Methods In this post hoc analysis of the ORION-9, ORION-10, and ORION-11 trials, patients were randomized 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on day 1, day 90, and 6-monthly thereafter. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510 and corresponding time-adjusted change from day 90 and up to day 540 were evaluated per patients’ PVD status. Safety was assessed over 540 days. Results Of 3454 patients, 470 (13.6%) had PVD, and 2984 (86.4%) did not. Baseline characteristics were generally balanced between the treatment arms in both cohorts. A greater proportion of patients with PVD had comorbidities versus those without. The mean (95% confidence interval [CI]) placebo-corrected LDL-C percentage change from baseline to day 510 was −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in patients without. Proportions of patients with reported treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events were similar between treatment arms, irrespective of PVD status, except for an excess of mild or moderate clinically relevant TEAEs at the injection site with inclisiran. Conclusion Twice-yearly inclisiran dosing (after the initial and 3-month doses) was well tolerated and provided effective and sustained lipid-lowering in patients, irrespective of PVD status.

Inclisiran—A Revolutionary Addition to a Cholesterol-Lowering Therapy

“…Participants were randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and then every 6 months thereafter for 18 months. [ 93 ] Mean LDL-C level at baseline was 112 mg/dL. At Day 90, the absolute reduction in LDL-C was 53 mg/dL.…”

Inclisiran and cardiovascular events: a comprehensive review of efficacy, safety, and future perspectives

“…Inclisiran has demonstrated its effectiveness as a treatment option for hypercholesterolemia, but there are important aspects to consider. The 4-year safety and efficacy data from the ORION-3 trial support its sustained efficacy with repeated exposure, indicating promising long-term sustained LDL-C lowering [41 ▪ ]. However, more extensive research is still required to assess its effectiveness in diverse patient populations and establish its long-term safety and efficacy profile.…”

“…The evidence for the cardiovascular risk reduction potential of inclisiran has been explored through literature-based meta-analyses, which provide valuable insights into its impact on patient outcomes. Although the ORION-9, ORION-10 and ORION-11 trials primarily focused on lowering LDL-C levels, cardiovascular events were captured as safety outcomes [41 ▪ ], shedding light on the potential benefits of inclisiran beyond its LDL-C-lowering effect. It is important to note that these trials were not specifically designed as cardiovascular outcome trials but rather as LDL-C lowering trials.…”

Small Interfering Ribonucleic Acid as Lipid-Lowering Therapy: Inclisiran in Focus

“…Combining the results from three phase 3 studies gave the opportunity to explore inclisiran’s effect on subgroups of patients with polyvascular disease [ 39 ]. This was a post hoc analysis of 3454 patients from the ORION-9, -10, and -11 trials.…”

“…The lipid-lowering effect of inclisiran was persistent despite the presence or the absence of PVD. The average placebo-corrected LDL cholesterol percentage change from baseline to day 510 was −48.9% in the PVD group and −51.5% in the non-PVD group [ 39 ]. In each group, the effect of inclisiran was significantly greater than in the placebo arms ( p < 0.0001).…”