Efficacy and safety of inclisiran in patients with established cerebrovascular disease: pooled, post hoc analysis of the ORION-9, ORION-10 and ORION-11, phase 3 randomised clinical trials

Abstract

Background: Patients (pts) with hyperlipidaemia and established cerebrovascular disease (CeVD) are at an increased risk of future strokes or other cardiovascular events.[1] In ischaemic stroke survivors, statins and inhibitors of proprotein convertase subtilisin‐kexin type 9 (PCSK9) reduce recurrent cardiovascular events including stroke.[2‐4] With guidelines increasingly advocating lower LDL‐C goals, add‐on lipid lowering therapies to statins may be needed. Inclisiran, a first‐in‐class small interfering RNA (siRNA) targeting PCSK9 messenger RNA, when added to maximally tolerated statin therapy, may provide further LDL‐C lowering with a convenient, infrequent dosing schedule in pts with established CeVD. Purpose: To assess efficacy and safety of inclisiran in pts with established CeVD. Methods: Pts with HeFH, ASCVD or its risk equivalents from ORION‐9 (NCT03397121]), ORION‐10 (NCT03399370), and ORION‐11 (NCT03400800) were randomised 1:1 to receive inclisiran sodium 300 mg (equivalent to 284 mg inclisiran) or placebo (pbo) at Days 1, 90 and 6‐ monthly thereafter to Day 540. This post hoc analysis included pts with established CeVD (ischaemic stroke, and/or carotid artery stenosis by angiography or ultrasound >70%, and/or prior percutaneous or surgical carotid artery revascularisation). Percentage LDL‐C change from baseline to Day 510 and corresponding time‐averaged percentage change from baseline after Day 90 to Day 540 were evaluated. Safety was assessed over 540 days. Results: Of 202 pts with established CeVD, 110 and 92 received inclisiran and pbo, respectively. At baseline, 90.0% (99/110) of pts in inclisiran and 84.8% (78/92) in pbo group reported prior ischaemic stroke(s); others had carotid artery stenosis and/or carotid revascularisation (Table 1). Mean (95% CI) pbo‐corrected LDL‐C percentage change from baseline at Day 510 with inclisiran was ‐55.2% (‐64.5 to ‐45.9); corresponding time‐averaged change from baseline after Day 90 to Day 540 was ‐55.2% (‐62.4 to ‐47.9) (P<0.0001 for each; Table 2). Treatmentemergent adverse event (TEAE) and treatment‐emergent serious adverse event (TESAE) were more frequent in the inclisiran vs pbo group but were consistent with the overall pooled (N=3655) population of the combined trials. Clinically relevant TEAEs at the injection site were reported more frequently with inclisiran (3.6% [4/110]) vs pbo (0% [0/92]), but none were severe. Percentage of pts with clinically relevant laboratory measurements was low and similar between treatment groups and consistent with the overall pooled population (Table 2). Conclusions: In pts with established CeVD, a twice‐yearly dosing with inclisiran (after the initial and 3‐month doses) provided sustained additional LDL‐C reduction of ∼55%. A modest excess of mild/moderate TEAEs at the injection site were reported with inclisiran. The cardiovascular benefits of inclisiran among patients with established CeVD are being evaluated in ongoing trials.