Antisense oligonucleotide targeting LPA mRNA reduces directly measured Lp(a)-C
Effect of Pelacarsen on Lipoprotein(a) Cholesterol and Corrected Low-Density Lipoprotein Cholesterol
Introduction and methods
In previous studies was shown that the antisense oligonucleotide pelacarsen lowers Lp(a) and also oxidized phospholipids (OxPL) on apo(a) and apoB by 70-88%. Somewhat surprisingly, LDL-C levels were reduced up to 26% and total apoB levels up to 16% [1-4].
It is not known whether changes in LDL-C are real or may be caused by laboratory measures of LDL-C (including both true LDL-C plus Lp(a)-cholesterol).
Recently, a novel quantitative, sensitive, high-throughput method has been reported to directly measure Lp(a)-C on isolated Lp(a) holoparticles .
In this study, the effect of pelacarsen was assessed on directly measured Lp(a)-C an on corrected LDL-C.
A phase 2B trial of pelacarsen was previously reported. This was a randomized, double-blind, placebo-controlled, dose-ranging trial of 286 patients with established CVD and Lp(a) levels ≥60 mg/dL. Patients received pelacarsen at 20, 40 or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week, or they received placebo for 6 to 12 months.
Direct Lp(a)-C was measured on isolated Lp(a) using LPA4-magnetic beads directed to apo(a). LDL-C was reported as: 1) LDL-C as reported by the clinical laboratory; 2) LDL-Ccorr=laboratory-reported LDL-C minus directly measured Lp(a)-C; and 3) LDL-CcorrDahlén=laboratory LDL-C minus [Lp(a) mass x 0.30] estimated by the Dahlén formula. Primary analysis time point was at week 25/27 (dependent on the dose schedule).
Baseline levels of LDL-C
- LDL-Ccorr was ~13 to 16 mg/dL lower than the laboratory reported LDL-C. The LDL-CcorrDahlén was ~27 to 33 mg/dL lower than the laboratory measured LDL-C.
Effect of pelacarsen on Lp(a)-C and LDL-C parameters
- Pelacarsen significantly reduced Lp(a)-C in a dose-dependent manner compared to pooled placebo (29%-67% vs. 2%, P=0.001-<0.0001).
- The extent and temporal changes in directly measured Lp(a)-C are consistent with change in Lp(a) molar concentration.
- LDL-Ccorr trended in the same direction as laboratory-derived LDL-C with pelacarsen from baseline to primary analysis time point, although with a smaller effect and loss of significance in some groups.
- LDL-CcorrDahlén levels were significantly increased from baseline in most cohorts with pelacarsen compared with placebo.
- Total apoB levels were decreased in all pelacarsen cohorts except the lowest dose. However, non-Lp(a) apoB levels were not significantly reduced in any pelacarsan cohort.
Correlations between Lp(a)-related variables
- At baseline, direct Lp(a)-C correlated strongly with Lp(a) molar concentration; modestly with laboratory-reported LDL-C, total apoB, OxPL-apoB and triglycerides; and weakly with LDL-Ccorr.
- Furthermore, at baseline, LDL-Ccorr did not correlate with Lp(a) or direct Lp(a)-C, but did correlate strongly with total apoB and non-Lp(a) apoB.
The antisense oligonucleotide pelacarsen reduced directly measured Lp(a)-C in a dose-dependent manner, consistent with reduction of Lp(a) molar concentration. Pelacarsen had neutral to modest effects on corrected LDL-C. This analysis further demonstrated that corrected LDL-C is ~13 to 16 mg/dL lower than laboratory-reported LDL-C in patients with elevated Lp(a) levels, and LDL-Ccorr provides an accurate reflection of changes in LDL-C. Moreover, this analysis confirmed that the Dahlén formula overestimates the Lp(a)-C and underestimates LDL-C in subjects with elevated Lp(a) levels.