Pelacarsen Leads to Robust, Dose-Dependent Reduction in Directly Measured Lp(a)-C

Pelacarsen was found to significantly lower direct lipoprotein(a) cholesterol Lp(a)-C and to be associated with neutral to mild lowering of corrected low-density lipoprotein cholesterol (LDL-C_corr), according to the results of a study published in the Journal of the American College of Cardiology.

Researchers sought to assess the effect of pelacarsen on directly measured Lp(a)-C and on corrected LDL-C without the interference of Lp(a)-C.

Eligible participants had established cardiovascular disease and screening Lp(a) levels ≥60 mg/dL (≥150 nmol/L). They received pelacarsen 20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week (cumulative doses of 20, 40, 60, and 80 mg monthly); or saline placebo subcutaneously for 6 to 12 months.

Measurement of Lp(a)-C was performed at baseline, week 13, weeks 25/27 (the primary analysis time point), and week 69 (final analysis time point). LDL-C was reported as (1) LDL-C 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. The primary endpoint was the percentage change in Lp(a) levels from baseline to month 6 of exposure.

A total of 286 patients were included in the analysis. Baseline Lp(a) levels ranged from approximately 205 to 247 nmol/L, and median Lp(a)-C levels were 11.9 to 15.6 mg/dL. Mean laboratory-reported LDL-C was 68.5 to 89.5 mg/dL, and the LDL-C_corr was approximately 13 to 16 mg/dL lower than the laboratory-reported LDL-C. The LDL-C_corrDahlén was approximately 27 to 33 mg/dL lower than the laboratory-measured LDL-C.

Pelacarsen was associated with statistically significant, dose-dependent mean percentage decreases in Lp(a)-C vs a 2% decrease in pooled placebo (29%-67%; P =.001 to <.0001 at the primary analysis time point). The extent and temporal changes in directly measured Lp(a)-C were consistent with the change in Lp(a) molar concentration. The absolute decline in Lp(a)-C values ranged from -5.4 to -9.4 mg/dL for participants with the lowest to highest cumulative monthly doses.

The reduction in LDL-C_corr ranged from -0.7 to -8.0 mg/dL, laboratory-reported LDL-C decreased from -5.6 to -6.7, and LDL-C_corrDahlén increased by 0.1 to 9.5 mg/dL.

Total apolipoprotein B-100 (apoB) decreased for all doses from -2.3 to -10.8 mg/dL, although variability occurred in the changes in non-Lp(a) apoB with no dose response.

For all patient groups combined at baseline, direct Lp(a)-C correlated strongly with Lp(a) molar concentration (P <.0001).

Among several study limitations, the Lp(a)-C and LDL-C_corr methods have not been validated against a gold standard. Also, the analysis included patients with relatively normal triglyceride levels. Further research is needed to determine whether deriving a corrected LDL-C in patients with increased triglyceride-rich lipoproteins allows for accurate correction of LDL-C.

“Determining LDL-C_corr by directly quantitating Lp(a)-C and subtracting it for the laboratory LDL-C provides a more accurate reflection of the baseline and change in LDL-C following pelacarsen in patients with elevated Lp(a),” stated the investigators.

Disclosure: The clinical trial was funded by Ionis Pharmaceuticals, and the direct Lp(a)-C measurements were funded by Novartis. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Yeang C, Karwatowska-Prokopczuk E, Su F, et al. Effect of pelacarsen on lipoprotein(a) cholesterol and corrected low-density lipoprotein cholesterol. J Am Coll Cardiol. 2022;79(11):1035-1046. doi:10.1016/j.jacc.2021.12.032