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The Lp(a)HORIZON trial failed to show that lowering lipoprotein(a) with pelacarsen reduces cardiovascular events — a major blow to the field. But cardiologists and researchers say it's too soon to abandon the Lp(a) hypothesis, pointing to trial design issues and more potent therapies still in the pipeline.
The highly anticipated Lp(a)HORIZON phase 3 trial delivered a disappointing result: pelacarsen, Novartis's Lp(a)-lowering drug, failed to reduce major adverse cardiovascular events (MACE) despite meaningfully cutting Lp(a) levels in over 8,000 high-risk patients. The miss has shaken confidence in the "Lp(a) hypothesis" — the idea that lowering this cardiovascular biomarker translates into clinical benefit — and experts say pelacarsen is now "very unlikely to be approved."
Still, many researchers aren't ready to close the book. They point to potential trial design issues, including an aggressively treated patient population with well-controlled LDL, which may have left too little residual risk for Lp(a) lowering to make a measurable difference. Two next-generation siRNA therapies — Amgen's olpasiran and Eli Lilly's lepodisiran — are still in phase 3 trials and have shown far greater Lp(a) reductions (up to 100%+ vs. pelacarsen's ~80%).
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Why it matters: Even with this setback, experts urge clinicians to keep measuring Lp(a) — it remains a meaningful risk marker. The results of the OCEAN(a) and ACCLAIM-Lp(a) trials could still vindicate the hypothesis, and understanding Lp(a)'s role in cardiovascular disease is more important than ever.
