Apo(a) antisense oligonucleotides safely and effectively reduces Lp(a) in patients with CVD

AHA 2018 A randomized phase 2b trial showed safety and efficacy of the antisense nucleotide AKCEA-APO(a)-Lrx at reducing Lp(a) levels in patients with CVD.

Safety and Efficacy of AKCEA-APO(a)-LRx to Lower Lipoprotein(a) Levels in Patients with Established Cardiovascular Disease: A Phase 2 Dose-Ranging Trial

Presented at the AHA congress 2018 by: Sotirios Tsimikas (San Diego, California)

Introduction and methods

Lipoprotein(a) [Lp(a)] is an independent, genetic and likely causal risk factor for CVD and aortic stenosis. Lp(a) >50 mg/dL is associated with an increased risk of recurrent CV events in patients on statin therapy. The increased risk is mediated through three main mechanisms: 1) atherogenicity of its LDL-like moiety, 2) anti-fibrinolytic effects of its apo(a) moiety and 3) pro-inflammatory effects of its content of oxidized phospholipids (OxPL).

Antisense oligonucleotides (AO) have been shown to decrease apo(a) protein production in hepatocytes, which is the primary source of circulating Lp(a). The AKCEA-APO(a)-Lrx is an AO that contains a GalNac ligand. AKCEA-APO(a)-Lrx has a 30-fold higher potency than non-GalNac ASOs, allowing lower doses and dose intervals for similar therapeutic efficacy. A prior phase 1 trial with AKCEA-APO(a)-Lrx showed a dose dependent mean 68-92% reduction in plasma Lp(a) in healthy volunteers with elevated Lp(a) levels.

The AKCEA-APO(a)-Lrx was a multicenter, international, randomized, blinded, placebo-controlled, dose-ranging phase 2b trial, including 270 subjects with pre-existing CVD (CAD, MI, PAD, stroke/TIA) and baseline Lp(a) levels of ≥60 mg/dL (~≥150 mmol/L). Exclusion criteria included revascularization or lipoprotein apheresis within three months of screening, ACS, major cardiac surgery or stroke/TIA within six months of screening, NYHA class IV, uncontrolled hypertension (>160/100 mmHg) or use of oral anticoagulants. Eligible participants were divided into five cohorts and randomized 5:1 to receive either AKCEA-APO(a)-Lrx or placebo (20 mg, 40 mg, 60 mg or placebo Q4W, 20 mg or placebo Q2W, or 20 mg or placebo QW).

The primary endpoint was the mean % change in Lp(a) from baseline to week 25-27 depending on dose regimen. Secondary endpoints included mean percentage change in OxPL-apoB, OxPL-apo(a), LDL-c, apoB, and the percentage of patients reaching Lp(a) <50 mg/dL (<125 mmol/L).

Main results

• LSmean% change in Lp(a) was -35% (P=0.0032), -56% (P<0.0001), -58% (P<0.0001), -72% (P<0.0001) and -80% (P<0.0001) with administration of AKCEA-APO(a)-Lrx 20 mg/Q4W, 40 mg/Q4W, 20 mg/Q2W, 60 mg/Q4W and 20 mg/QW, respectively, compared to -6% with placebo.
• Absolute change in Lp(a) from baseline to week 25-27 was highest with AKCEA-APO(a)-Lrx 20 mg/QW, showing a reduction of 75.1 mg/dL (SD: 32.1), compared to -6.1 mg/dL (SD: 13.8) with placebo.
• 25.0% of patients treated with AKCEA-APO(a)-Lrx 20 mg/Q4W achieved Lp(a) ≤50mg/dL (≤125 mmol/L) (P=0.029), 62.5% with 40 mg/Q4W (P<0.0001), 64.6% with 20 mg/Q2W (P<0.0001), 80.9% with 60 mg/Q4W (P<0.0001) and 97.7% with 20 mg/QW (P<0.0001), compared to 6.4% of patients treated with placebo.
• Treatment with AKCEA-APO(a)-Lrx 20 mg/QW resulted in greatest reduction in OxPL-apoB (-81.8% vs. 22.4%, P<0.001), OxPL-apo(a) (-61.2% vs. -17.6%, P<0.001), LDL-c (-20.5% vs. 1.2%, P<0.01) and apoB (-14.5% vs. 2.0%, P<0.001), compared to placebo.
• Pooled AKCEA-APO(a)-Lrx dose regimen resulted in more treatment emergent adverse events (TEAE), compared to placebo. The intervention group showed more often ≥1 TEAE (213 [89.1%] vs. 39 [83.0%]), ≥1 serious TEAE (25 [10.5%] vs. 1 [2.1%]), ≥1 related serious TEAE (2 [0.8%] vs. 0 [0.0%]), ≥1 TEAE leading to treatment discontinuation (11 [4.6%] vs. 2 [4.3%]), and TEAE leading to death (2 [0.8%] vs. 0 [0.0%]).
• Pooled AKCEA-APO(a)-Lrx dose regimen resulted in more platelets (25 [10.5%] vs. 7 [14.9%), LFTs (1 [0.4%] vs. 0 [0.0%]), and 24 hr CrCl decrease >40% from baseline (2 [0.8%] vs. 0 [0.0%], compared to placebo, but without safety concerns.

Conclusion

This randomized trial achieved its primary endpoint and all of its secondary endpoints, showing that AKCEA-APO(a)-Lrx significantly reduced Lp(a), OxPL-apoB, OxPL-apo(a), LDL-c and apoB levels. Moreover, 98% of treated patients achieved Lp(a) levels of ≤50 mg/dL at the highest dose. No safety concerns were observed related to platelet count, liver function or renal function.

Discussion

Brian A. Ference discussed the main results of the study of Tsimikas et al. and called the results ‘very exciting’. He argued that the highest dose is most likely the most effective one and pointed to the need of further research into the 20-mg weekly dose in individuals with median Lp(a) levels of ≥100 mg/dL in a phase II trial. According to this trial, the 20-mg weekly dose would result in ~75 mg/dL reduction in Lp(a) levels, which should translate into a CV proportional risk reduction of ~15% after four years of treatment. When future trials are conducted with lower doses, absolute risk reductions in Lp(a) may not be high enough to observe a clinically meaningful benefit. However, how large that absolute reduction in Lp(a) should be, remains unknown, commented the audience on Ference. Moreover, the target population for future trials on Lp(a) reduction with antisense oligonucleotides is currently hotly debated. ‘The 80th percentile - used for dose-efficacy testing - was based on a healthy population, while we know that baseline Lp(a) levels will be much higher in high-risk patients with ASCVD’. The discussion was ended with the comment that ‘until the magnitude of the benefit has been established, we should include high-risk patients who show larger absolute reductions in Lp(a) with this antisense oligonucleotide’.

- Our reporting is based on the information provided at the AHA congress -