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 risk 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 few 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 1 and 2 trials showed very substantial decreases of Lp(a) and good tolerability. The hepatospecific variant IONIS-APO(a)-LRx is 30 times more potent. The results of the IONIS-APO(a)-LRx phase 2 trial were presented recently. The highest dosages reduced Lp(a) by 72 and 80%; in about 81 and 98% Lp(a) levels <50 mg/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 3 trial will reproduce these findings and show a reduction of cardiovascular events.
Highlights
In 1963 Berg described the lipoprotein(a) (Lp(a)) system in man, was the first to note that the individual level of Lp(a) is inherited and that high levels are associated with early onset of atherosclerosis [1]
The first outcome trials show that cardiovascular events are reduced as a consequence
If the Lp(a) lowering capacity of PCSK9 inhibitors contributes to this favourable outcome is unclear
Summary
In 1963 Berg described the lipoprotein(a) (Lp(a)) system in man, was the first to note that the individual level of Lp(a) is inherited and that high levels are associated with early onset of atherosclerosis [1]. High doses of nicotinic acid (2000–4000 mg) are needed to reduce Lp(a) significantly [21] This effect has not yet been shown in patients with high baseline levels of Lp(a) with regard to the inclusion criterion. In a phase 1 trial in healthy volunteers (Lp(a) levels ≥25 nmol/l) IONIS-APO(a)Rx significantly lowered Lp(a) in a dose-dependent manner. Secondary endpoints were effects on other lipoproteins and risk factors In both cohorts Lp(a) was reduced significantly: cohort A—66.8%, cohort B—71.6% at day 85/99. Injection site reactions occurred in 10% in cohort A and in 19% in cohort B (one participant stopped treatment) Another phase 1/2a first-in-man trial [51] was done with the GalNAc3 modified IONIS-APO(a)-LRx0 in healthy volunteers with levels of Lp(a) ≥75 nmol/l. Injection site reactions were the most common (26%) with one patient discontinuing
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