Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease

Abstract

Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) and statins may not be protective in advanced CKD. The reasons for the limited efficacy of statins in advanced CKD are unclear, but statins may increase plasma levels of the highly atherogenic molecule lipoprotein(a), also termed Lp(a), as well as PCSK9 (protein convertase subtilisin/kexin type 9) levels. Lp(a) has also been linked to calcific aortic stenosis, which is common in CKD. Moreover, circulating Lp(a) levels increase in nephrotic syndrome with declining renal function and are highest in patients on peritoneal dialysis. Thus, the recent publication of the Phase 2 randomized controlled trial of pelacarsen [also termed AKCEA-APO(a)-LRx and TQJ230], a hepatocyte-directed antisense oligonucleotide targeting the LPA gene messenger RNA, in persons with CVD should be good news for nephrologists. Pelacarsen safely and dose-dependently decreased Lp(a) levels by 35–80% and a Phase 3 trial [Lp(a)HORIZON, NCT04023552] is planned to run from 2020 to 2024. Unfortunately, patients with estimated glomerular filtration rate <60 mL/min or urinary albumin:creatinine ratio >100 mg/g were excluded from Phase 2 trials and those with ‘significant kidney disease’ will be excluded from the Phase 3 trial. Optimized exclusion criteria for Lp(a)HORIZON would provide insights into the role of Lp(a) in CVD in CKD patients.

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“… [154] The ongoing Lp(a) HORIZON cardiovascular outcome study is evaluating pelacarsen (i.e., antisense oligonucleotide targeting the LPA gene messenger RNA) regarding its effects upon major adverse cardiac events. [ 154 , 155 , 156 ] Until therapies that lower Lp(a) are proven to provide health benefits, a single accurate measure of Lp(a) may be sufficient to inform on CVD risk. [157] Statins are the most recommended drug treatment for hypercholesterolemia due to their cholesterol-lowering efficacy, safety, and ASCVD benefits supported by numerous cardiovascular outcomes trials.…”

“… [154] The ongoing Lp(a) HORIZON cardiovascular outcome study is evaluating pelacarsen (i.e., antisense oligonucleotide targeting the LPA gene messenger RNA) regarding its effects upon major adverse cardiac events. [ 154 , 155 , 156 ] Until therapies that lower Lp(a) are proven to provide health benefits, a single accurate measure of Lp(a) may be sufficient to inform on CVD risk. [157] …”