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

• No serious or severe adverse events occurred. Mild injection site reactions were most commonly reported adverse event, which was the reason to discontinue in 1 out of 37 participants. No significant changes in liver function tests or other safety assessments were observed.
• The single-dose regime (50-400mg) did not decrease Lp(a) concentration at day 30. OxPL-apoB, OxPL-apo(a), OxPL-apoAI, OxPL-PLG, or plasminogen were not significantly altered.
• In multi-dose regimens, ISIS-APO(a)Rx caused significant dose-dependent decreases in Lp(a) from baseline to day 36 (100mg: 39.6%, 200mg: 59.0%, 300mg: 77.8% vs. placebo).
  At day 106, Lp(a) was still decreased from baseline in all multi-dose groups.
• In multi-dose cohorts, OxPL-apoB was also significantly decreased in a dose-dependent manner at day 36 vs. baseline (100mg: 26.1%, 200mg: 55.1%, 300mg: 61.3% vs. placebo).
  At day 106, OxPL-apoB remained lower than baseline in the 200 and 300 mg groups.
• OxPL-apo[a] was also dose-dependently reduced at day 36 as compared with baseline, while no changes in OxPL-apoAI, OxPL-PLG, plasminogen and Lp-PLA2 mass were seen.
• Size of the predominantly expressed apo(a) isoform was inversely correlated to baseline plasma Lp(a) and OxPL-apoB concentrations, but no significant correlation was seen with mean percent change from baseline to day 36 in Lp(a) or OxPL-apoB concentrations.
• Levels of total cholesterol, apoB, LDL-c, HDL-c, VLDL-c and triglycerides were not significantly different after treatment with either ISIS-APO(A)Rx or placebo.

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

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