Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol

Background: Laboratory methods that report low-density lipoprotein Cholesterol (LDL-C) include both LDL-C and lipoprotein(a) Cholesterol [Lp(a)-C] content.

Objectives: The purpose of this study was to assess the effect of pelacarsen on directly measured Lp(a)-C and LDL-C corrected for its Lp(a)-C content.

Methods: The authors evaluated subjects with a history of Cardiovascular Disease and elevated Lp(a) randomized to 5 groups of cumulative monthly doses of 20-80 mg pelacarsen vs placebo. Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apolipoprotein(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-C_corr = laboratory-reported LDL-C - direct Lp(a)-C; and 3) LDL-C_corrDahlén = laboratory LDL-C - [Lp(a) mass × 0.30] estimated by the Dahlén formula.

Results: The baseline median Lp(a)-C values in the groups ranged from 11.9 to 15.6 mg/dL. Compared with placebo, pelacarsen resulted in dose-dependent decreases in Lp(a)-C (2% vs -29% to -67%; P = 0.001-<0.0001). Baseline laboratory-reported mean LDL-C ranged from 68.5 to 89.5 mg/dL, whereas LDL-C_corr ranged from 55 to 74 mg/dL. Pelacarsen resulted in mean percent/absolute changes of -2% to -19%/-0.7 to -8.0 mg/dL (P = 0.95-0.05) in LDL-C_corr, -7% to -26%/-5.4 to -9.4 mg/dL (P = 0.44-<0.0001) in laboratory-reported LDL-C, and 3.1% to 28.3%/0.1 to 9.5 mg/dL (P = 0.006-0.50) increases in LDL-C_corrDahlén. Total apoB declined by 3%-16% (P = 0.40-<0.0001), but non-Lp(a) apoB was not significantly changed.

Conclusions: Pelacarsen significantly lowers direct Lp(a)-C and has neutral to mild lowering of LDL-C_corr. In patients with elevated Lp(a), LDL-C_corr provides a more accurate reflection of changes in LDL-C than either laboratory-reported LDL-C or the Dahlén formula.

antisense; cardiovascular disease; cholesterol; lipoprotein(a); therapy.