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

Abstract

<h3>Lead Author's Financial Disclosures</h3> Wolfgang Koenig, MD has received consulting fees and lecture fees from AstraZeneca, Novartis and Amgen; consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Genentech, Esperion, OMEICOS, Novo Nordisk, LIB Therapeutics, Kowa, Corvidia Therapeutics and Daiichi Sankyo; lecture fees from Berlin- Chemie, Bristol-Myers Squibb and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr. Beckmann Pharma. <h3>Study Funding</h3> Novartis Pharma AG, Basel, Switzerland. <h3>Background/Synopsis</h3> Approximately 25% of patients with atherosclerotic cardiovascular disease (ASCVD) have polyvascular disease (PVD) involving 2 or more coronary, cerebrovascular, and peripheral artery beds. PVD is an independent predictor of major adverse cardiovascular events (MACE) and death. Agents that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein cholesterol (LDL-C) concentrations and MACE incidence in patients with PVD. Inclisiran is a small interfering RNA agent targeting PCSK9 messenger RNA that is well tolerated and provides effective and sustained LDL-C reductions. <h3>Objective/Purpose</h3> To describe the effect of inclisiran vs placebo in patients with and without PVD. <h3>Methods</h3> This was a post hoc analysis of patients with heterozygous familial hypercholesterolemia or ASCVD or its risk equivalents randomized 1:1 to 300mg inclisiran sodium (equivalent to 284mg inclisiran) or placebo at baseline, Day 90, and 6 monthly thereafter in ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800). Evaluations included LDL-C percentage change from baseline to Day 510 and corresponding time-averaged change from Day 90 to Day 540, with both evaluated by PVD presence or absence, and safety over 540 days. <h3>Results</h3> Baseline characteristics for 470 patients (13.6%) with PVD and 2984 (86.4%) without PVD were generally balanced between treatment arms in both groups, with higher cardiovascular risk factors and lower LDL-C concentrations in patients with PVD (Table 1). Mean (95% CI) placebo-corrected LDL-C percentage changes from baseline to Day 510 with inclisiran were −48.9% (−55.6 to −42.2) in patients with PVD and −51.5% (−53.9 to −49.1) in those without (Table 2). Treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs) were similar between treatment arms irrespective of PVD status, although reported TESAEs trended higher with PVD in both treatment arms (Table 2). Clinically relevant injection site TEAEs were more frequent with inclisiran vs placebo in both groups; all were mild or moderate. Few patients had clinically relevant laboratory measurements (Table 2). <h3>Conclusions</h3> Twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided effective and sustained LDL-C lowering in patients with ASCVD irrespective of their PVD status, with a safety profile similar to that of placebo except for a modest increase in mainly mild TEAEs at the injection site. Notably, TESAEs were reported more frequently in patients with PVD, which was likely due to their more advanced disease. Since patients with PVD are at high risk of cardiovascular events, intensive LDL-C lowering may be beneficial to reduce this risk.