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First potential drug to reduce Lp(a) concentrations to lower CV risk

Tsimikas S et al., Lancet 2015

Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study

 
Tsimikas S., Viney NJ, Hughes SG et al.,
Lancet 2015. 386(10002), p1472–1483
 

Background

Lipoprotein(a) [Lp(a)] is built up from apolipoprotein(a) [apo(a)] covalently linked to apolipoprotein B-100 [ApoB]. The LPA gene is the main determinant of plasma Lp(a) concentration. The specific subtypes of kringle domains (K) in the LPA gene determine the heterogeneity of Lp(a) molecular size and plasma concentration [1]. Lp(a) concentration is inversely associated with the number of repeats of subtype KIV2 and positively correlated with two SNPs [2,3]. Environmental and dietary factors generally have limited effect on Lp(a) concentrations.
A physiological role of Lp(a) has not been revealed, but several lines of evidence suggest a causal, independent role in myocardial infarction, stroke, peripheral arterial disease and calcific aortic valve stenosis [3-6]. It appears that the increased CV risk originates in increased plasma Lp(a) levels rather than independent effects of LPA genotypes. No clinical trials have been conducted to assess the effect of lowering Lp(a) levels, because to date no agents were available to specifically lower Lp(a) without affecting other lipid parameters.
ISIS-APO(a)Rx is a second generation antisense oligonucleotide, specifically designed to reduce the synthesis of apo(a) in the liver, thereby lowering Lp(a) plasma concentration. This study evaluated the safety, pharmacokinetics and pharmacological effects of ISIS-APO(a)Rx in healthy volunteers.
In a single-dose regimen, 16 participants were randomly assigned in a 3:1 ratio to either ISIS-APO(a)Rx (50mg, 100mg, 200mg, or 400mg) or placebo, administered as a subcutaneous injection. In the multi-dose regimen, 31 participants were assigned in a 4:1 ratio to six doses of either ISIS-APO(a)Rx (100mg, 200mg, or 300mg) or placebo, on day 1, 3, 5, 8, 15 and 22. Lp(a) concentrations were measured, as well as oxidised phospholipids on apoB (OxPL-apoB), to assess the proinflammatory potential of Lp(a), since oxidised phospholipids are preferentially carried by Lp(a) and are strongly associated with Lp(a)-mediated risk. Oxidised phospholipids on apo(a) (OxPL-apo[a]), apolipoprotein AI (OxPL-apoAI), and plasminogen (OxPL-PLG) were also measured.
 

Main results

 

Conclusion

ISIS-APO(a)Rx, an antisense oligonucleotide directed at hepatic apo(a) mRNA, selectively and potently reduces plasma Lp(a) concentrations, in a dose-dependent manner, without serious or severe adverse events. OxPL-apoB and OxPL-apo(a), which mediate the pro-inflammatory potential of Lp(a), were also reduced, while other lipoproteins were unaffected. The findings of this phase 1 study encourage clinical development of targeted Lp(a) therapies, to assess the CV benefit of lowering Lp(a). ISIS-APO(a)Rx represents the first potential drug with which the hypothesis can be tested that specific lowering of plasma Lp(a) will reduce CV disease events and slow down progression of calcific aortic valve stenosis.
 

Editorial comment [7]

Several existing LDL-lowering interventions also lower Lp(a), but not specifically, nor potently. This study reports the exciting results of a phase 1 trial of a second-generation antisense oligonucleotide targeting apo(a), thereby lowering Lp(a). “A simultaneous reduction of Lp(a) particles and their associated OxPL implies that apo(a) antisense reduces not only the atherogenic capacity of Lp(a) but also the pro-inflammatory potential of OxPL.”
Tolerability is of utmost importance, since CV prevention treatment must be taken for life, therefore it is comforting that only two out of 37 participants discontinued due to side-effects after receiving
ISIS-APO(a)Rx. The observed prolonged Lp(a) reductions after the last dose make a biweekly to monthly dosing regimen feasible, which facilitates adherence. “Following an era in which Lp(a) was merely a potent but non-modifiable cardiovascular risk factor, the advent of a selective Lp(a)-lowering strategy is very exciting. While waiting for further data on apo(a) antisense, now would be the time to revisit the existing consensus statements by the European Atherosclerosis Society and the National Lipid Association advising active measurement of Lp(a) in patients with intermediate or high risk of cardiovascular disease. With an estimated 20% of the world’s population with raised Lp(a) concentrations and a large, unaddressed cardiovascular disease burden, it is tempting to speculate that in the near future raised Lp(a) will not only be measured but actually treated to reduce further
the residual cardiovascular risk in these patients.”
 
Find this article online at The Lancet
 

References

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2 Luke MM, Kane JP, Liu DM, et al. A polymorphism in the proteaselike domain of apolipoprotein(a) is associated with severe coronary artery disease. Arterioscler Thromb Vasc Biol 2007; 27: 2030–36.
3 Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361: 2518–28.
4 Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302: 412–23.
5 Kamstrup PR, Tybjaerg-Hansen A, Steff ensen R, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301: 2331–39.
6 Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcifi cation and aortic stenosis. N Engl J Med 2013; 368: 503–12.
7. Stroes ES., Van der Valk FM. A sense of excitement for a specific Lp(a)-lowering therapy. The Lancet. Volume 386, No. 10002, p1427–1429