Lp(a) Hypthesis Survives HORIZON Trial Failure as Pipeline Drugs Show Stronger Reductions
The disappointing results of the Lp(a)HORIZON trial, which showed that the drug pelacarsen did not reduce major cardiovascular events despite lowering lipoprotein(a) levels, have not ended the search for Lp(a)-targeted therapies. Experts argue that differences in drug potency and trial design mean that other phase 3 trials, such as Amgen’s OCEAN(a) and Eli Lilly’s ACCLAIM-Lp(a), may still succeed. While pelacarsen reduced Lp(a) by 80%, newer small interfering RNA therapies achieve reductions exceeding 90%. Although the HORIZON failure raises questions about whether Lp(a) is a viable treatment target or merely a risk marker, clinicians emphasize that Lp(a) remains a crucial diagnostic tool for assessing cardiovascular risk.
Key points
- The Lp(a)HORIZON trial, involving over 8,000 patients, found that pelacarsen did not reduce the risk of major adverse cardiovascular events despite lowering Lp(a) levels.
- Pelacarsen, an antisense oligonucleotide, reduced Lp(a) by 80%, whereas newer therapies like Amgen’s olpasiran and Eli Lilly’s lepodisiran achieve reductions of over 90% and 93.9%, respectively.
- Experts suggest the HORIZON trial may have failed because the patient population had well-controlled risk factors, leaving little residual risk for Lp(a) to impact, or because the drug’s potency was insufficient.
- The American Heart Association recommends that all adults get an Lp(a) test at least once in their lifetime to assess cardiovascular risk, particularly those with a family history of heart disease.
- Despite the HORIZON failure, Lp(a) remains a significant marker for cardiovascular risk, and managing it through lifestyle changes and other lipid-lowering agents is still recommended for patients with high levels.
Background
Lp(a) has been linked to coronary artery disease since 1981, with multiple studies confirming a causal association between genetically determined Lp(a) levels and heart attack risk. The HORIZON trial was seen as the final piece of evidence needed to confirm that lowering Lp(a) yields cardiovascular benefits. Previous trials, such as the ODYSSEY Outcomes trial, showed that reductions in Lp(a) via PCSK9 inhibitors were associated with lower cardiovascular risk, independent of LDL cholesterol levels. The recent failure of Novo Nordisk’s ziltivekimab, which also failed to reduce MACE despite lowering inflammatory markers, has drawn parallels to the Lp(a) situation, highlighting the challenges in translating biomarker reductions into clinical benefits.
Why it matters
The HORIZON trial failure has cast doubt on the Lp(a) hypothesis, but it has not dismissed the potential of Lp(a)-targeted therapies. The continued development of more potent drugs and the emphasis on Lp(a) as a risk marker underscore the importance of understanding the mechanisms of Lp(a) in cardiovascular disease. For patients, this means that while Lp(a)-lowering drugs may not yet be approved, measuring Lp(a) remains a critical part of cardiovascular prevention and risk management.
What to watch
Detailed results from the Lp(a)HORIZON trial will be presented at the American Heart Association’s Scientific Sessions in November. Phase 3 trials for Amgen’s olpasiran and Eli Lilly’s lepodisiran are ongoing, with results expected to provide further insights into the efficacy of Lp(a)-lowering therapies. Researchers are also investigating whether Lp(a) plays a role in the early or later stages of atherosclerosis development, which could inform future treatment strategies.
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