Lipoprotein(a)-antisense therapy.

Abstract

Elevated levels of lipoprotein(a) (Lp(a)) contribute to the risk of early and severe cardiovascular disease (CVD) and Lp(a) is acknowledged as a\xa0risk factor to be included in risk assessment. The established lipid-modifying medical therapies do not lower Lp(a) except niacin but no data of endpoint trials are available. Of the new lipid-modifying drugs a\xa0few have some impact on Lp(a). Whether the Lp(a) lowering effect contributes to the reduction of CVD events would have to be shown in Lp(a) dedicated trials. None of the available agents is indicated to lower Lp(a). Lipoprotein apheresis lowers levels of Lp(a) significantly by >60% per treatment. Trial data and data of the German Lipoprotein Apheresis Registry show that regular apheresis reduces cardiovascular events. The Apo(a) antisense oligonucleotide is the only approach to specifically lower Lp(a). The IONIS-APO(a)Rx phase\xa01 and 2 trials showed very substantial decreases of Lp(a) and good tolerability. The hepatospecific variant IONIS-APO(a)-LRx is 30\xa0times more potent. The results of the IONIS-APO(a)-LRx phase\xa02 trial were presented recently. The highest dosages reduced Lp(a) by 72 and 80%; in about 81 and 98% Lp(a) levels <50\u202fmg/dl were achieved. Tolerability and safety were confirmed, whereby injection site reactions were the most common side effects. This raises hope that the planned phase\xa03 trial will reproduce these findings and show a\xa0reduction of cardiovascular events.