Antisense Oligonucleotides Targeting Apolipoprotein(a) in People with Raised Lipoprotein(a): Two Dose-Ranging Trials

These two dose-ranging randomized controlled trials evaluated two antisense oligonucleotides (ASOs) targeting apolipoprotein(a) synthesis: IONIS-APO(a)Rx (earlier-generation, unconjugated) and IONIS-APO(a)-LRx (GalNAc-conjugated, selectively targeting hepatic uptake) in patients with elevated Lp(a). A total of 122 patients were enrolled across both trials.

IONIS-APO(a)-LRx — the GalNAc-conjugated formulation enabling much lower doses through liver-specific delivery — achieved up to 92% reduction in Lp(a) at the highest dose tested, compared with 68% reduction for the unconjugated predecessor at comparable doses. Both were well tolerated. The GalNAc conjugation technology represented a major advance: by directing the ASO specifically to hepatocytes, the required dose was reduced approximately 10-fold, improving the therapeutic index substantially.

This pair of trials established the two key results that shaped subsequent Lp(a)-lowering drug development. First, the GalNAc conjugation strategy dramatically improved potency for hepatic LPA targeting. Second, Lp(a) reductions of 80–92% are achievable with acceptable tolerability — a magnitude of reduction far exceeding any existing approved therapy and sufficient to test the cardiovascular outcome hypothesis in the Phase 3 HORIZON trial (pelacarsen, the approved-IND successor to IONIS-APO(a)-LRx).

These trials were the direct prelude to tsimikas-et-al-2020 (Phase 2 RCT with pelacarsen) and informed the dose selection for HORIZON.

We rate the evidence strong for dose-ranging trials. Two rigorously designed randomized trials establishing that GalNAc-conjugated ASO targeting apo(a) achieves up to 92% Lp(a) reduction — the foundational dose-ranging evidence for pelacarsen and the HORIZON outcome trial.