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)-L_Rx in healthy volunteers are reported. IONIS-APO(a)-L_Rx 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)-L_Rx 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:

• 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)-L_Rx:

• 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)-L_Rx 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)-L_Rx.
• 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)-L_Rx were sustained at 113 days after the last dose.

• Both study medications were well tolerated.  

Conclusion

The proof-of-concept phase 2 trial shows that IONIS-APO(a)_{Rx ­}significantly lowers Lp(a) concentrations. Moreover, IONIS-APO(a)-L_Rx 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:

• ‘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?’

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

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