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A highly anticipated cardiovascular trial came up empty. Pelacarsen, the first drug specifically targeting lipoprotein(a) [Lp(a)] to complete a major outcomes trial, failed to reduce heart attacks, strokes, or CV deaths compared to placebo — despite slashing Lp(a) levels by nearly 78%. Experts say the Lp(a) hypothesis isn't dead yet, with several next-generation therapies still in the pipeline.
The Lp(a)HORIZON trial delivered a major disappointment for the cardiovascular world. Pelacarsen — an antisense oligonucleotide developed by Ionis and Novartis — dramatically reduced lipoprotein(a) [Lp(a)] levels in patients with established heart disease, but that didn't translate into fewer heart attacks, strokes, or cardiovascular deaths. Full results were presented at the American Heart Association Scientific Sessions and published simultaneously in The New England Journal of Medicine.
Experts caution against abandoning the Lp(a) hypothesis entirely. The trial population had unusually well-controlled LDL cholesterol and blood pressure, which may have left too little residual cardiovascular risk for pelacarsen to overcome. Additionally, the drug's mechanism (antisense oligonucleotide) and patient population (secondary prevention) differ from upcoming trials testing more potent siRNA therapies like olpasiran (Amgen) and lepodisiran (Eli Lilly), which have shown Lp(a) reductions exceeding 93–100%.
By the Numbers:
Why it matters: This is the first major CV outcomes trial for an Lp(a)-targeted therapy, and its neutral result raises fundamental questions about whether lowering Lp(a) actually reduces cardiovascular risk — or whether Lp(a) is simply a marker rather than a modifiable target. The answer may hinge on upcoming trials with more potent agents.
