Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen. (May 2021)

• Record Type: Journal Article
• Authors: Karwatowska-Prokopczuk, Ewa; Clouet-Foraison, Noemie; Xia, Shuting; Viney, Nicholas J.; Witztum, Joseph L.; Marcovina, Santica M.; Tsimikas, Sotirios
• Is Part Of: Atherosclerosis. Volume 324(2021)
• Page Start: 102
• Page End: 108
• Publication Date: 2021-05
• Subjects: Lipoprotein(a) -- Pathophysiology -- Cardiovascular disease -- Metabolism -- Therapy -- Antisense; Arteriosclerosis -- Periodicals; Electronic journals; 616.136
• DOI: 10.1016/j.atherosclerosis.2021.03.036
• Languages: English
• ISSNs: 0021-9150

Abstract

Abstract: Background and aims: Antisense oligonucleotides (ASOs) targeting LPA to lower lipoprotein(a) [Lp(a]] are in clinical trials. Patients have been recruited according to various Lp(a) thresholds, but the prevalence of LPA genetic variants and their effect on efficacy of these ASOs are not well described. Methods: We analyzed data from 4 clinical trials of the ASO pelacarsen targeting apolipoprotein(a) that included 455 patients. Common LPA genetic variants rs10455872 and rs3798220, major and minor isoform size, and changes in Lp(a), LDL-C, apoB, OxPL-apoB and OxPL-apo(a) were analyzed according to categories of baseline Lp(a). Results: The prevalence of carrier status for rs10455872 and rs3798220 combined ranged from 25.9% in patients with Lp(a) in the 75 - <125 nmol/L range to 77.1% at Lp(a) ≥375 nmol/L. The prevalence of homozygosity for rs3798220, rs10455872 and for double heterozygosity in category of Lp(a) ≥375 nmol/L was 6.3%, 14.6% and 12.5%, respectively. Isoform size decreased with increasing Lp(a) plasma levels, with 99.3% of patients with Lp(a) ≥175 nmol/L having ≤20 KIV repeats in the major isoform. The mean percent reduction from baseline in Lp(a), OxPL-apoB and OxPL-apo(a) in response to pelacarsen was not affected by the presence of rs10455872 and rs3798220, isoform size or baseline Lp(a) at all doses studied. Conclusions: In patients randomized to Lp(a) lowering trials, LPA genetic variants are common, but a sizable proportion do not carry common variants associated with elevated Lp(a). In contrast, the major isoform size was almost uniformly ≤20 KIV repeats in patients with Lp(a) ≥175 nmol/L. The Lp(a) and OxPL lowering effects of pelacarsen were independent of both LPA genetic variants and isoform size. Graphical abstract: Image 1 Highlights: We analyzed 4 clinical trials of antisense oligonucleotides (ASOs) targeting apo(a) including 455 subjects. 99.3% of patients with Lp(a) ≥175 nmol/L had ≤20 KIV repeats in the major isoform. Isoform size decreased with increasing Lp(a) plasma levels. rs10455872 and rs3798220 combined were present in 77.1% at Lp(a) ≥375 nmol/L. The mean percent reduction in Lp(a) was not affected by LPA genetics.