15289-s-bos

108 | Chapter 7 Anti-sense apo-(a) Recently, the results of a phase 1 study with an anti-sense compoundwas presented (ISIS APO(a)Rx, Gazelle Court Carlsbad, CA, USA) which acts specifically against the mRNA of apo(a),andlowersapo(a)mRNAby90%,andLp(a)levelsupto82%[40] [http://ir.isispharm . com/phoenix.zhtml?c=222170&p=irol-newsArticle&ID=1877550&highlight]. The phase I trials of ISIS APO(a)Rx have been completed, and a phase II trial will soon commence. This trial will assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of ISIS APO(a)Rx administered subcutaneously to patients with high Lipoprotein(a) levels (0,50-1,75 g/L) and very high Lp(a) levels. (>1,75 g/L). It is the first agent which specifically targets Lp(a) and will cast the final verdict whether Lp(a) lowering will lower CVD event rates. Conclusion Multiple agents have shown to have Lp(a) lowering properties. However statins, the most effective drugs in reducing CVD risk, do not modify Lp(a) to a clinical relevant degree. The drugs that do decrease Lp(a) have either no overall effect on CVD risk (estrogens and niacin), are currently investigated in phase 3 trials (CETP inhibitors and PCSK9 inhibitors) or are registered for an orphan population (homozygous FH patients for lomitapide and mipomersen). An overview of all drugs discussed in this study is shown in table 1. The mechanism by which Lp(a) is modified is mostly, as in case of niacin, CETP inhibitors and PCSK9 inhibition, unknown, which may be not surprising since insight into the metabolism of Lp(a) is limited. We created an overview of known and proposedmechanisms by which different drugs lower Lp(a) (figure 2). None of Lp(a) modifying agents which were reviewed, with the exception of antisense Lp(a), solely reduced Lp(a) without the modification of other lipoproteins. To establish whether Lp(a) reduction is a relevant target for CVD prevention this will be an essential piece of the puzzle to be determined in the future. ASO Apo-B, anti-sense oligonucleotide for apolipoprotein B (mipomersen); ASO apo(a), anti-sense oligonucleotide for apolipoprotein (a) (ISIS APO(a)Rx); MTP-inhibitors, microsomal triglyceride transport protein inhibitor (Lomitapide); CETP, cholesterol ester transfer protein; PCSK-9, proprotein convertase subtilisin/kexin type 9; Lp(a), lipoprotein (a); TRβ, the β isoform of the thyroid hormone receptor.