Novartis Pelacarsen Fails to Reduce Cardiovascular Events in Phase 3 HORIZON Trial Despite Lp(a) Reduction
Pelacarsen lowered Lp(a) substantially but failed to improve cardiovascular outcomes in a large Phase 3 trial. The result raises questions about the causal role of Lp(a) in secondary prevention and increases the evidentiary bar for remaining Lp(a) therapies. Future studies will need to show additive clinical benefit on top of optimized therapy.
The HORIZON trial randomized over 8,000 patients with elevated Lp(a) and established cardiovascular disease to pelacarsen or placebo. Pelacarsen lowered Lp(a) by approximately 90 percent, yet the composite endpoint of cardiovascular death, myocardial infarction, or stroke showed no significant difference versus placebo over a median follow-up of four years. Absolute event rates remained similar between arms.
Competing Lp(a)-lowering programs from Amgen and Eli Lilly continue in earlier phases. The failure highlights that Lp(a) reduction alone may not translate to clinical benefit when added to intensive statin and PCSK9 inhibitor background therapy, echoing patterns seen with other lipid targets where surrogate changes outpace hard outcomes.
Regulatory scrutiny will intensify for remaining Lp(a) assets. Companies must now demonstrate that Lp(a) lowering produces incremental event reduction beyond current standards of care, likely requiring larger, longer trials with stricter endpoint adjudication.
Next steps include full data release at a major cardiology meeting and subgroup analyses to identify any responsive populations before further development decisions.
Novartis: Pelacarsen development will be discontinued by end of 2027 after subgroup review shows no viable path.
Sources (2)
- [1]Primary Source(https://www.statnews.com/2026/09/04/novartis-therapy-pelacarsen-fails-cardiovascular-trial/)
- [2]Supporting Source(https://www.nejm.org/doi/full/10.1056/NEJMoa2402204)