HORIZON trial: pelacarsen lowered Lp(a) but showed no benefit in secondary prevention patients

At the AHA Scientific Sessions in Chicago, Karol Watson, MD, PhD, professor of cardiology and codirector of the UCLA Preventive Cardiology Program, discussed late-breaking results of the HORIZON trial of pelacarsen. The interview was published on endocrinologyadvisor.com thecardiologyadvisor.comendocrinologyadvisor.comthecardiologyadvisor.comOpen source ↗. The trial tested lowering of lipoprotein(a), or Lp(a), in patients in secondary prevention. According to Watson, it showed no benefit.

Trial design and population

All HORIZON participants had previously had a cardiovascular event. Watson said they received excellent background therapy: blood pressure was low, LDL was very low, and all were on antiplatelet agents. Half of the patients received pelacarsen and half received matching placebo.

Watson said pelacarsen lowers Lp(a) cleanly, and the reduction in this population was dramatic. Average LDL in the population was 62.

The trial was event-driven, so it continued until the required number of events had occurred. It was expected to report in 2024, but the report moved to 2025 and then to 2026 because too few events had accrued. Watson noted that, despite the high-risk population, event rates were much lower than expected thecardiologyadvisor.comendocrinologyadvisor.comthecardiologyadvisor.comOpen source ↗.

Neutral result and open questions

According to Watson, the Kaplan-Meier curves superimpose in every respect. There was no benefit in the primary outcome or in the subgroups.

Watson said this does not mean the Lp(a) hypothesis is wrong. In her view, the result may reflect the choice of population, the type of drug (drugs exist that lower Lp(a) more and for longer), a start that was not early enough, or the inclusion of secondary prevention patients rather than primary prevention patients. She said other ongoing Lp(a)-lowering trials can address these questions.

On clinical practice, Watson said the investigators drove LDL down. In her discussion she showed data suggesting that once LDL is that low, the risk associated with Lp(a) seems to mitigate or drop out thecardiologyadvisor.comendocrinologyadvisor.comthecardiologyadvisor.comOpen source ↗. Asked whether other trials show that addressing Lp(a) changes outcomes, she answered that there is no such evidence yet.