Oxidized Phospholipids Track Closely With Lp(a) Reductions in Clinical Trial

Oxidized phospholipids attached to lipoprotein(a) appear to be an important mechanism for harm from lipoprotein(a), and pharmacologic reduction of lipoprotein(a) with lepodisiran parallels reductions in oxidized phospholipids bound to lipoprotein(a) moieties.

Those are key findings of a post hoc analysis of the phase 2 ALPACA trial presented in a late-breaking science session at the European Society of Cardiology Congress 2026 and simultaneously published in the Journal of the American College of Cardiology.

“This analysis shows that lepodisiran produces sustained, dose-dependent reductions in oxidized phospholipids associated with lipoprotein(a) [Lp(a)],” says lead author and presenter Steven Nissen, MD, Chief Academic Officer for Cleveland Clinic’s Heart, Vascular & Thoracic Institute. “Reductions of 80% to 95% were achieved up to one year after two injections six months apart at the highest dose given. These findings suggest a possible mechanism for therapeutic benefit of lepodisiran and provide further biological rationale for the ongoing phase 3 trial evaluating the effect of this Lp(a)-lowering therapy on cardiovascular outcomes in 17,300 patients.”

In search of a mechanism for Lp(a)-lowering benefits

The analysis builds on primary results of the ALPACA trial reported in the New England Journal of Medicine (2025;392[17]:1673–1683), a randomized, placebo-controlled study that demonstrated a 95% time-averaged reduction in Lp(a) levels during one-year follow-up in participants given two doses of lepodisiran 400 mg six months apart.

Lepodisiran is a long-acting small interfering RNA (siRNA) that lowers blood levels of Lp(a). It is one of several siRNA agents in development that have shown similar reductions in elevated Lp(a), a genetically determined cardiovascular risk factor linked to atherosclerotic cardiovascular disease and aortic stenosis.

“As much as we know about Lp(a), the precise mechanisms by which it produces harms are not entirely clear,” says Dr. Nissen, principal investigator of the ALPACA trial. “There’s a strong body of biological data to suggest that oxidized phospholipids attached to Lp(a) are among the more noxious elements of this particle. But there’s not much data on what effects these investigational Lp(a)-lowering therapies have on oxidized phospholipids, and these effects were not included in the initial ALPACA analysis. We wanted to know whether the impressive reduction in Lp(a) observed with lepodisiran in ALPACA was paralleled by reductions in oxidized phospholipids attached to Lp(a).”

Analysis at a glance

ALPACA included 320 adults aged 40 or older with Lp(a) serum concentrations of 175 nmol/L or higher randomized to placebo or one of three doses of lepodisiran: 16 mg, 96 mg or 400 mg. All treatments were given by subcutaneous injection in two doses: at baseline and at day 180.

The post hoc analysis included participants who had levels of oxidized phospholipids (OxPL) measured at baseline, day 240 and day 360. Measurements included OxPL carried on apolipoprotein(a) [apo(a)] and those carried on apolipoprotein B (apoB). The analysis focused on participants who received two doses of study drug, so the one study arm that received a single lepodisiran dose of 400 mg was excluded, resulting in a cohort of 213 participants.

Results on the primary end point — placebo-adjusted geometric mean percent change in OxPL levels — showed that lepodisiran reduced OxPL in a dose-dependent manner. The effect remained substantial at 360 days, particularly with the 400-mg dose. Specific results are detailed in the table below.

Waterfall plot analysis showed highly consistent reductions in both OxPL-apo(a) and OxPL-apoB across all patients in the 400-mg dose group but some variability in the 16-mg and 96-mg groups.

Notably, the OxPL reductions tracked closely with Lp(a) reductions, particularly for OxPL-apo(a). For participants in the 400-mg group, correlations of Lp(a) reduction with OxPL reductions were as follows:

• For OxPL-apo(a), r = 0.94 at day 240 and r = 0.92 at day 360 (P < .001 for both)
• For OxPL-apoB, r = 0.62 at day 240 and r = 0.88 at day 360 (P < .001 for both)

Clinical relevance likely to emerge over time

“These findings show that lepodisiran has substantial effects on oxidized phospholipids that are consistent with its effects in lowering Lp(a) and are persistent with two doses out to a full year,” Dr. Nissen observes. He adds that while studies of other nucleic acid-based therapies in development for Lp(a) reduction have shown reductions in OxPL, not all of them evaluated OxPL bound to both apo(a) and apoB or examined correlations with Lp(a) lowering.

Notably, the post hoc analysis found no significant correlation between OxPL levels and changes in high-sensitivity C-reactive protein. “Some have proposed that one of the mechanisms by which Lp(a) promotes cardiovascular events is by inducing inflammation,” Dr. Nissen says, “but this lack of correlation with C-reactive protein is not consistent with a systemic inflammatory mechanism.”

He notes that while the overall results of this analysis support the biological rationale for Lp(a)-lowering therapy and suggest that reducing Lp(a) also reduces potentially harmful OxPL cargo, no clinical thresholds for OxPL values have been established and the clinical relevance of OxPL reductions remains uncertain. “But our understanding of the relevance of these reductions will soon expand as data from the cardiovascular outcomes trials of Lp(a)-lowering therapies start to emerge in the coming months,” he says. “We will find out exactly which parameters are associated with benefit or harm, including oxidized phospholipids.”

Those results from clinical outcomes trials are highly anticipated across the broad cardiology community, notes his colleague Leslie Cho, MD, Section Head of Preventive Cardiology at Cleveland Clinic. “While these are exciting findings, we still await the large cardiovascular outcome trials to determine whether lowering Lp(a) improves outcomes in the era of high-intensity statin and PCSK9 inhibitor therapy,” she says.

Meanwhile, greater insight into the role of OxPL may yield additional utility a bit further down the line. “If we learn that oxidized phospholipids are a strong mediator of outcomes, then we may want to look at oxidized phospholipids as a way to determine optimal dose in dose-finding studies of future drugs,” Dr. Nissen concludes. “There are implications here for therapeutic development.”

The ALPACA study on which this analysis is based was supported by Eli Lilly, which is developing lepodisiran.