Physicians' Academy for Cardiovascular Education

Novel therapy for the reduction of Lp(a) concentrations

Viney NJ, et al, The Lancet, 2016

Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials

Viney NJ, van Capelleveen JC, Geary RS, et al.
Lancet 2016;388:2239-2253


Lp(a), a particle composed of LDL and apolipoprotein(a) (apo(a)), is a major and independent risk factor for CV disease and calcific aortic valve stenosis [1]. Lp(a) is more atherogenic than LDL-C, but its concentrations are not significantly altered by current lipid-lowering therapies. Statin treatment might even increase Lp(a) concentrations, while niacin, mipomersen and PCSK9 inhibitors lower Lp(a) by only 20-30% [2-4].
However, there are phase 1 data showing that IONIS-APO(a)Rx, previously called ISIS-APO(a)Rx, an antisense oligonucleotide targeting hepatic apo(a) mRNA, causes dose-dependent, potent reductions in plasma Lp(a) concentrations [5].
In this paper, the results of a phase 2 trial with IONIS-APO(a)Rx are reported in individuals with elevated Lp(a) concentrations. Moreover, the results of the first application of IONIS-APO(a)-LRx in healthy volunteers are reported. IONIS-APO(a)-LRx is a modified IONIS-APO(a)Rx antisense oligonucleotide, which is conjugated with a GalNAc3 complex and targets the therapy to the hepatocyte via the asialoglycoprotein receptor. IONIS-APO(a)-LRx is expected to be more potent than IONIS-APO(a)Rx and may therefore allow lower doses an better tolerability.

Main results

Phase 2 trial of IONIS-APO(a)Rx:  
Phase 1/2a trial of IONIS-APO(a)-LRx:    


The proof-of-concept phase 2 trial shows that IONIS-APO(a)Rx ­significantly lowers Lp(a) concentrations. Moreover, IONIS-APO(a)-LRx appeared a novel therapy with superior potency for reducing Lp(a) concentrations. These data introduce a new therapeutic paradigm for the use of antisense oligonucleotide therapy in patients at risk for or with established cardiovascular disease or calcific aortic valve stenosis.


Editorial comment [6]

In his editorial article, Feinberg summarises the results of both studies reported in the Viney et al paper, and notes that: ‘Collectively, these findings demonstrate the most potent reductions so far in people with elevated plasma Lp(a) concentrations, and build on the phase 1 trial for IONIS-APO(a)Rx that showed reductions of Lp(a) in individuals with lower baseline plasma concentrations.’
Furthermore, he raises two important questions worth considering in the near future: And he concludes: ‘The therapeutic opportunity to target Lp(a) calls for rigorous standardisation of these assays and consideration of potential cut offs, as we excitedly await advanced-stage clinical trials that will finally examine if Lp(a) lowering reduces cardiovascular events and potentially aortic stenosis—and that’s no small task.’
Find this article online at The Lancet


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3. Guyton JR. Niacin in cardiovascular prevention: mechanisms, effi cacy, and safety. Curr Opin Lipidol 2007; 18: 415–20.
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5. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 2015; 386: 1472–83.
6. Feinberg MW. No small task: therapeutic targeting of Lp(a) for cardiovascular disease. Lancet 2016;388:2211-2212.