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6 November 2015
Novel antisense apolipoprotein(a) agent offers new potential for targeting lipid-related residual cardiovascular risk
Lipoprotein(a) (Lp[a]), established as a risk factor for cardiovascular disease and calcific aortic valve stenosis, is also a contributor to lipid-related cardiovascular risk. ISIS-APO(a)Rx, a second-generation antisense drug targeting apolipoprotein(a), a component of Lp(a), may offer potential in reducing elevated Lp(a) concentration.
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.
Objective: To investigate the safety, pharmacokinetics, and pharmacodynamics of ISIS?APO(a)Rx.
Study design:

Randomised double-blind placebo-controlled Phase I trial. The trial was conducted in two parts:

  • A single-dose study, in which patients were randomly allocated to a single subcutaneous injection of ISIS-APO(a)Rx (50 mg, 100 mg, 200 mg, or 400 mg) or placebo (3:1)
  • A multi-dose study, in which patients were randomly allocated to six subcutaneous injections of ISIS-APO(a)Rx (100 mg, 200 mg, or 300 mg, for a total dose exposure of 600 mg, 1200 mg, or 1800 mg) or placebo (4:1) during a 4 week period.
Study population: Healthy adults aged 18–65 years, with a body-mass index < 32.0 kg/m², and Lp(a) concentration ³25 nmol/L (100 mg/L). 47 (23%) of 206 screened subjects were randomly assigned to receive ISIS-APO(a)Rx, either as single - or multiple-dosing, or placebo.
Primary variable:

Safety: incidence, severity, and dose relation of adverse events and changes in laboratory variables

Efficacy: percentage change from baseline in Lp(a) concentration at 30 days in the single-dose cohorts and at 36 days for the multi-dose cohorts


In the single-dose study, 16 subjects (all male, mean Lp(a) in each group ranging from 8.2 to 65.7 nmol/L) were included, receiving each dose of  ISIS-APO(a)Rx (3 subjects at each dose level), or placebo (n=4). All subjects completed treatment and follow-up and were included in the pharmacodynamics, pharmacokinetics, and safety analyses.

In the multi-dose study, 8 subjects were allocated to 100 mg ISIS-APO(a)Rx, 9 to 200 mg ISIS-APO(a)Rx, 8 to 300 mg ISIS-APO(a)Rx, and 6 to placebo. Al, subjects were male, and mean Lp(a) ranged from 82.2 to 152.3 nmol/L).

Main results:


  • There were no serious or severe adverse events. Mild injection site reactions were the most common adverse events.
  • There were no significant changes in liver function tests or other safety variables across the dose cohorts.

Single-dose study

  • Single doses of ISIS-APO(a)Rx (50–400 mg) did not decrease Lp(a) concentrations at day 30.

Multi-dose study

  • Administration of ISIS-APO(a)Rx (100–300 mg) led to dose-dependent, mean percentage decreases from baseline in plasma Lp(a) concentration of 39.6% in the 100 mg group (p=0.005), 59.0% in the 200 mg group (p=0.001), and 77.8% in the 300 mg group (p=0.001).
  • The largest decrease was 88.8% at day 36 after multiple doses of 300 mg ISIS-APO(a)Rx.
  • Reduction in Lp(a) persisted to day 106, 84 days after the last dose in all dose groups
  • Total cholesterol, apolipoprotein (apo)B, low-density lipoprotein (LDL), high-density lipoprotein (HDL) or very low-density lipoprotein (VLDL) cholesterol, or triglycerides were not influenced by ISIS-APO(a)Rx administration.
Authors’ conclusion: ISIS-APO(a)Rx results in potent, dose-dependent, selective reductions of plasma Lp(a). The safety and tolerability support continued clinical development of ISIS-APO(a)Rx as a potential therapeutic drug to reduce the risk of cardiovascular disease and calcific aortic valve stenosis in patients with elevated Lp(a) concentration.


Lipoprotein(a) is an apo B100 containing LDL-like plasma lipoprotein rich in cholesterol, which differs from LDL as it contains an additional plasminogen-like protein, apo(a), attached to the apoB moiety of LDL via a single disulphide bond. Lp(a) levels are stable in a given individual over time, and under strict genetic control (1).

Lp(a) is now established as a cardiovascular risk factor, based on evidence from meta-analyses, Mendelian randomisation studies and genetic analyses (1,2). Additionally, Lp(a) is a contributor to lipid-related residual cardiovascular risk in statin-treated patients (3). Analyses from the JUPITER study in a low-risk group characterised by low LDL cholesterol levels, showed that elevated Lp(a) (³50 mg/dL) was associated with 67% increase in cardiovascular risk  (4). However, the lack of effective treatments specifically targeting Lp(a) has been a major stumbling block for development. Niacin (nicotinic acid) lowers Lp(a) by up to 40% (5); however, beyond the Americas, this agent is no longer available to clinicians. The PCSK9 monoclonal antibodies alirocumab and evolocumab have been shown to reduce Lp(a) by 25-30% (6,7), although the mechanism underlying this effect has been contentious (8). Moreover, the main effect of these treatments is to substantially lower LDL cholesterol. Lipoprotein apheresis is undoubtedly highly efficient in removing circulating Lp(a) but is neither noninvasive nor cheap.

Antisense agents offer a novel approach to directly inhibit synthesis of apo(a) in the liver, and thus reduce plasma levels of Lp(a). This study has shown that multiple doses of this second generation antisense inhibitor of apo(a) results in substantial lowering of plasma Lp(a) in subjects with levels at baseline >25 nmol/L (approximately equivalent to 100 mg/L). This agent also appeared to be well tolerated, supporting further clinical development.

In conclusion, if shown to be safe and effective in further clinical development, ISIS-APO(a)Rx offers the possibility of testing the hypothesis that targeting Lp(a) specifically will provide therapeutic benefit. Additionally, this agent may also offer the opportunity to investigate the relative contribution of elevated Lp(a) to residual cardiovascular risk.


1. Kronenberg F. Lipoprotein(a): there's life in the old dog yet. Circulation 2014;129:619-21.

2. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.

3. Cai A, Li L, Zhang Y et al. Lipoprotein(a): a promising marker for residual cardiovascular risk assessment. Dis Markers 2013;35:551-9.

4. Khera AV, Everett BM, Caulfield MP et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin).Circulation 2014;129:635-42.

5. Bodor ET, Offermanns S. Nicotinic acid: an old drug with a promising future. Br J Pharmacol 2008;153(Suppl 1): S68–S75.

6. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278–88.

7. Gaudet D, Kereiakes DJ, McKenney JM et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014; 114:711–5.

8. Romagnuolo R, Scipione C, Boffa MB et al. Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem 2015; 290:11649–62.

Key words lipoprotein(a); cardiovascular risk factor; antisense therapy targeting apolipoprotein(a); Phase I trial