Novartis Lp(a) Drug Pelacarsen Fails Pivotal Trial, Shaking Cardiovascular Field

Key points

• Novartis reported that pelacarsen failed to reduce the risk of cardiovascular death, heart attacks, or strokes in the Phase 3 HORIZON trial.
• The trial enrolled 8,323 patients with elevated Lp(a) levels and prior cardiovascular events or established cardiovascular disease.
• Pelacarsen, an antisense oligonucleotide developed with Ionis, lowered Lp(a) levels by approximately 72% but did not translate this into reduced clinical events.
• The failure shocked the cardiology community, with Dr. David Maron of the American Society for Preventive Cardiology calling it a 'huge blow.'
• Competitors Amgen and Eli Lilly are developing RNA interference therapies that lower Lp(a) by over 90%, potentially offering a different approach than pelacarsen.

Background

Lp(a), or lipoprotein(a), is a genetic risk factor for heart disease affecting approximately 20% of the global population. Prior to this failure, the Lp(a) drug race was seen as a potential multi-billion dollar market, with no approved therapies available. Recent setbacks in cardiovascular drug development, such as Novo Nordisk’s failed Phase 3 trial for an anti-inflammatory drug in August 2026, had already raised concerns about the efficacy of novel cardiovascular approaches. The HORIZON trial was the first late-stage test specifically targeting Lp(a) reduction to prevent cardiovascular events.

How outlets are covering it

STAT and The New York Times emphasized the shock and disappointment within the cardiology community, highlighting the drug's previous promise as a vanguard for heart disease prevention. Fierce Biotech focused on the technical aspects, noting that pelacarsen lowered Lp(a) by 72% but failed to reduce clinical events, and contrasted this with competitors Amgen and Eli Lilly, whose RNA interference therapies achieve over 90% reduction. Analysts from William Blair and Citi suggested that deeper Lp(a) inhibition might be necessary to achieve cardiovascular benefits, indicating that the mechanism is not necessarily 'dead' but requires further refinement. Yahoo Finance reported on the market reaction, noting stock drops for Novartis and Ionis following the announcement.

Why it matters

The failure of pelacarsen represents a significant setback for the development of Lp(a)-targeting therapies, which were seen as a potential breakthrough in cardiovascular disease prevention. However, the continued development of more potent RNA interference therapies by Amgen and Eli Lilly suggests that the field may still yield successful treatments. The outcome underscores the complexity of translating biomarker reduction into clinical benefit and may influence future trial designs and therapeutic strategies in cardiology.

What to watch

Novartis plans to share full results from the HORIZON trial at an upcoming medical meeting. Amgen and Eli Lilly are expected to continue their clinical development of RNA interference therapies for Lp(a), potentially with different trial designs or patient populations. The cardiology community will await detailed data to determine whether the failure is due to insufficient Lp(a) reduction or other factors, which may guide future research directions.