Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs

Kohei Takata; Stephen J. Nicholls


Am J Cardiovasc Drugs. 2019;19(2):113-131. 

In This Article

Novel Drugs Targeting Lp(a)

Apolipoprotein (a) Inhibitor: IONIS-APO(a)-LRX

Lp(a) is a pro-atherogenic LDL-like particle that contains apo(a) (≈ 46% of the total protein) bound to apolipoprotein B-100.[178] Although Lp(a) is discouraged as a target of screening for ASCVD,[4] epidemiological and genetic studies have suggested Lp(a) is an independent causal factor of ASCVD.[179–181] Moreover, elevated Lp(a) was a determinant of high CV risk in two statin RCTs.[182,183] Although several drugs have the capacity to reduce Lp(a) levels,[184] there is thus far no clear evidence that lowering Lp(a) reduces ASCVD risk. Recently, a Mendelian randomization study revealed key findings to explain these failures: a 101.5 mg/dl reduction in Lp(a) is required to produce comparable benefits on ASCVD risk reductions to those of a 38.7 mg/dl lowering of LDL-C levels.[185] Accordingly, the study suggested that the benefits are likely to be observed only in patients with very high Lp(a) levels (90–100 mg/dl or more). In these patients, an 80–90% Lp(a) reduction should result in a 70–90 mg/dl Lp(a) reduction, which is supposed to produce a ≈ 15–20% ASCVD risk reduction. Effective agents with high selectivity for Lp(a) lowering are awaited, as well as screening for individuals with extremely elevated Lp(a).

IONIS-APO(a)-LRX, an apo(a)-targeting ASO, has improved on IONIS-APO(a)RX through the modification of the delivery plat form to increase the potency (more than 30 times) for reducing doses and frequencies.[142,186] In a phase 1/2a trial, IONIS-APO(a)-LRX was examined in healthy volunteers with elevated Lp(a) levels.[186] Subcutaneous multiple doses of IONIS-APO(a)-LRX resulted in dose-dependent Lp(a) reductions up to 92% at the highest dose, with good tolerance and safety profile, including liver function. The sustained effect (over 3 months in 58% of the highest-dose group) is of considerable interest. This promising drug has been assessed in a phase 2 trial including 286 established ASCVD patients with hyperlipoproteinemia [baseline mean Lp(a) levels ≈ 100 mg/dl].[187] Recently, the result was presented at American Heart Association Scientific Sessions 2018. All IONIS-APO(a)-LRX treatment with different doses showed significant Lp(a) reductions in a dose-dependent manner, with good safety profiles: 20 mg Q4W [absolute mean change in Lp(a) levels 38.4 mg/dl], 40 mg Q4W (46.8 mg/dl), 60 mg Q4W (59.8 mg/dl), 20 mg Q2W (52.1 mg/dl), and 20 mg QW (75.1 mg/dl). Notably, 98% of patients in the 20-mg QW group achieved the recommended Lp(a) levels for preventing CVD.[188] In addition, given the required absolute change in Lp(a) to generate clinical benefits as aforementioned, 20 mg QW may have the most favorable potential to be tested in the planned phase 3 CVOT.