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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
 

Background

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:    

Conclusion

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
 

References

1. Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Int Med 2013; 273: 6–30.
2. Yeang C, Hung M-Y, Byun Y-S, et al. Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B-100 and lipoprotein(a). J Clin Lipidol 2016; 10: 594–603.
3. Guyton JR. Niacin in cardiovascular prevention: mechanisms, effi cacy, and safety. Curr Opin Lipidol 2007; 18: 415–20.
4. Santos RD, Raal FJ, Catapano AL, et al. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol 2015; 35: 689–99.
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.