Novel therapy for the reduction of Lp(a) concentrations
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.
BackgroundLp(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 . 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 .
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 resultsPhase 2 trial of IONIS-APO(a)Rx:
- 64 individuals, most of them on statin therapy with or without ezetimibe or other lipid-lowering agents at baseline, were randomly assigned to IONIS-APO(a)Rx or placebo.
- The fasting concentrations of plasma Lp(a) were significantly reduced in participants who received IONIS-APO(a)Rx, compared with those who received placebo. Mean percentage reduction in Lp(a) for individuals with Lp(a) = 125-437 nmol/L at baseline was 66.8% (SD: 20.6; P < 0.0001) and with Lp(a) ≥ 438 nmol/L at baseline was 71.6% (SD: 13.0; P < 0.0001).
- Mean treatment difference in Lp(a) concentration between the active arm and placebo for individuals with Lp(a) = 125-437 nmol/L at baseline was 62.8% (95% CI: 53.8–71.9) and with Lp(a) ≥ 438 nmol/L at baseline was 67.7% (95% CI: 54.5–80.8).
- The mean percentage changes in concentrations of Lp(a), LDL-C, apoB-100, OxPL-apoB, or OxPL-apo(a) did not differ between individuals on statins and those not on statins.
Phase 1/2a trial of IONIS-APO(a)-LRx:
- 58 healthy volunteers were assigned to the single-ascending-dose phase cohort or to the multiple-ascending-dose phase cohort.
- Dose-response relationships of IONIS-APO(a)Rx versus IONIS-APO(a)-LRx revealed that the 50% of the maximum drug-induced inhibitory effect for plasma Lp(a) was achieved at 122 mg/week for IONIS-APO(a)Rx but at 3.96 mg/week for IONIS-APO(a)-LRx.
- In the single-ascending-dose cohort, significant dose-dependent mean reductions in Lp(a) concentration were achieved at day 30, which were 26.2% (SD: 5.4) in the 10 mg group, 33.2% (SD: 17.5) in the 20 mg group, 43.5% (SD: 14.3) in the 40 mg group, 78.6% (SD: 21.2) in the 80 mg group and 85.3% (SD: 7.1) in the 120 mg group, versus a 2.8% (SD: 21.5) mean increase in the placebo group. The effects were sustained at day 90.
- In the multiple-ascending-dose cohort, significant dose-dependent reductions in Lp(a) concentration were achieved, with treatment difference versus placebo of 59.4% (95% CI: 33.5–79.1) for 10 mg, 72.3% (95% CI: 51.6–87.7) for 20 mg and 82.4% (95% CI: 67.6–99.8) for 40 mg. The effects of IONIS-APO(a)-LRx were sustained at 113 days after the last dose.
- Both study medications were well tolerated.
ConclusionThe 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 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:
- ‘Will the efficacy for clinical events be similar when these ASOs are used alone or in combination with optimum background lipid-lowering therapies?’
- ‘How will Lp(a) assays be standardised in the clinic? At what plasma concentration of Lp(a) should we consider treatment?’
Find this article online at The Lancet
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