A study led by Dr. Sotirios Tsimikas published in the New England Journal of Medicine showed that the hepatocyte-directed antisense oligonucleotide APO(a)-LRx significantly reduced the blood lipoprotein(a) [Lp(a)] levels in patients with established cardiovascular disease in a dose-dependent manner.
Lp(a) is almost entirely genetically-determined. Former studies suggested that Lp(a) levels > 50 mg/dL (125 nmol/L) are significantly associated with increased risk of cardiovascular disease. This value has been endorsed in both the European and US guidelines. Further, Mendelian randomization studies suggested that Lp(a) levels should be reduced by at least 60-70 mg/dL (normal range is 30 mg/dL) in order to achieve a clinically significant reduction in the risk of coronary artery disease. Former research has shown that antisense oligonucleotides can inhibit the production of Lp(a) in both humans and experimental models.
The authors performed a phase-II, double-blind randomized trial in which they assigned 286 patients with established cardiovascular disease and an elevated plasma Lp(a) level ≥ 60 mg/dL to placebo or APO(a)-LRx at different doses and frequencies (20 mg every 1, 2, or 4 weeks, 40 or 60 mg every 4 weeks) for six months. Patients on stable lipid-lowering medications within 4 weeks prior to screening were included. However, patients were excluded if they had acute coronary syndrome, stroke, heart failure NYHA IV class, uncontrolled hypertension or renal/hepatic dysfunction. The primary efficacy end point was the percent change in Lp(a) level at 6 months of exposure, while the secondary efficacy endpoints included the percent changes in LDL cholesterol, apolipoprotein B, and oxidized phospholipids on apolipoproteins.
At the baseline, the median levels of Lp(a) across all groups ranged between 82 and 99 mg/dL. Treatment with APO(a)-LRx caused dose-dependent reductions in Lp(a) levels (mean percent decreases ranged from 35% in the 20 mg every 4 weeks’ group to 72% in the 60 mg every 4 weeks’ group and 80% in the 20 mg every week group, compared to 6% with placebo (p<0.01). At the highest used cumulative dose (80 mg/4 weeks), 98% of patients achieved Lp(a) levels ≤ 50 mg/dL. Marked reductions were also observed in the APO(a)-LRx with regards to total and LDL cholesterol, apolipoprotein B, and oxidized phospholipids on apolipoproteins. The authors recorded no significant differences between any APO(a)-LRx dose group and placebo in terms of platelet counts or liver and renal function biomarkers. Injection site reactions were the most common adverse events observed (APO(a)-LRx: 27% vs Placebo: 6%).
In conclusion, treatment with APO(a)-LRx significantly reduced Lp(a) levels in patients with cardiovascular disease in a dose-dependent manner. However, the trial only investigated biochemical efficacy outcomes and future studies are encouraged to examined the clinical outcomes of APO(a)-LRx.