4945Inclisiran-mediated reductions in Lp(a) in the ORION-1 trial

Abstract

Abstract Background PCSK9 inhibitors and statins both lower LDL-C by increasing LDL-receptor (LDLR) function. PCSK9 inhibitors lower Lp(a) by 20–30%, whereas statins do not lower Lp(a). The mechanism by which PCSK9 inhibitors lower Lp(a) is unclear. We assessed the role of the LDLR in Lp(a) reductions produced by inclisiran, an siRNA which prevents hepatic synthesis of PCSK9. Methods ORION-1 was a phase 2 trial of inclisiran in subjects at high ASCVD risk with elevated LDL-C on optimized statin therapy. Subjects received one dose of inclisiran (200, 300, or 500 mg) or two doses at days 1 and 90 (100, 200, or 300 mg). We assessed the correlations between % change in Lp(a) and LDL-C at Day 180 for the inclisiran groups using Spearman correlation coefficients. We additionally assessed the correlation between % change in Lp(a) and absolute change in LDL-C as a proxy for LDLR expression. Lp(a) was measured using an isoform-independent assay and LDL-C with β-quantification. Results ORION-1 included 501 subjects; mean age 63; 65% male; 73% on statins. Median baseline Lp(a) was 37.0 nmol/l (IQR: 11.5–142.0 nmol/l), median LDL-C was 117.0 (IQR: 92.5–149.5 mg/dL). Inclisiran dose-dependently lowered Lp(a) by 14% to 26%. Overall, there was a significant but weak correlation between % change in Lp(a) LDL-C (Spearman coefficient 0.35, p<0.001). This correlation appeared to be stronger at higher inclisiran doses and with repeat dosing (table), as well as in statin-users versus non-users (Spearman coefficient 0.37 vs. 0.21). The correlation between % Lp(a) change and absolute LDL-C change was weaker (0.27, p<0.001). Correlation coefficients LDL-C – Lp(a) Single-dose groups Two-dose groups Inclisiran overall 200 mg (n=60) 300 mg (n=60) 500 mg (n=60) 100 mg (n=59) 200 mg (n=60) 300 mg (n=59) Lp(a) ∼ % change LDL-C 0.22 0.26 0.22 0.29 0.47 0.51 0.35 Lp(a) ∼ absolute change LDL-C 0.35 0.12 0.04 0.22 0.45 0.24 0.27 Lp(a) ∼ % change LDL-C - Statin users 0.16 0.28 0.28 0.31 0.45 0.55 0.37 Lp(a) ∼ % change LDL-C - Non statin users 0.80 -0.08 0.09 0.10 0.63 0.09 0.21 Conclusion The dose-dependent correlation between % changes in LDL-C and Lp(a) suggests that the LDLR may be partially responsible for Lp(a) reductions produced by inclisiran. The numerically stronger correlation in statin-users supports the idea that LDL-C may compete with Lp(a) for LDLR binding especially at low LDL-C levels. Acknowledgement/Funding The Medicines Company