Lepodisiran Reduces OxPL Tied to Lp(a), With Steven Nissen, MD

A post hoc analysis of the phase 2 ALPACA trial, presented by Steven E. Nissen, MD, of Cleveland Clinic, at the European Society of Cardiology (ESC) Congress 2026 in Munich, Germany, showed lepodisiran produced dose-dependent, durable reductions in Lp(a)-associated oxidized phospholipids (OxPL). Lepodisiran, an investigational small interfering RNA (siRNA) targeting lipoprotein(a) [Lp(a)], lowered OxPL levels by up to 94% at day 240 with the highest studied dose.¹

Lp(a) is a causal, genetically determined risk factor for atherosclerotic cardiovascular disease and aortic stenosis, with much of its harm hypothesized to stem from the OxPL it carries. In the phase 2 ALPACA trial, lepodisiran previously produced up to 95% average Lp(a) reduction over 1 year with 2 doses given 180 days apart, but its effect on OxPL had not been assessed. This post hoc analysis tested whether near-complete pharmacologic suppression of apolipoprotein(a) [apo(a)] lowers OxPL proportionally and whether reductions relate to systemic inflammation.

"In fact, it is the major reservoir of oxidized phospholipids, and that is why it is such a promising target for treatment," Nissen said in an interview with HCPLive at ESC Congress 2026.

Lepodisiran Effects on OxPL-apo(a) and OxPL-apoB by Dose

The randomized, placebo-controlled ALPACA trial enrolled 320 participants aged ≥ 40 years with Lp(a) levels above 175 nmol/L at 66 centers in 10 countries. Participants received lepodisiran 16 mg, 96 mg, or 400 mg subcutaneously at baseline and again at day 180, or placebo. This post hoc sub-study included 213 participants who received 2 active doses or placebo and had OxPL measured at baseline, day 240, and day 360 in stored samples (placebo, n = 59; 16 mg, n = 31; 96 mg, n = 65; 400 mg, n = 58).

Placebo-adjusted geometric mean percent changes in OxPL-apo(a) at day 240 were −21.9% (95% CI, −45.0% to 11.0%), −65.1% (95% CI, −73.8% to −53.6%), and −94.2% (95% CI, −95.7% to −92.2%) for the 16-mg, 96-mg, and 400-mg groups, respectively. OxPL-apoB changes at day 240 were −39.5% (95% CI, −51.2% to −25.0%), −76.9% (95% CI, −80.6% to −72.5%), and −88.5% (95% CI, −90.4% to −86.3%) across the same dose groups.

Lp(a) Correlations and Safety Findings for Lepodisiran

At day 360, placebo-adjusted percent changes in OxPL-apo(a) were −23.7% (95% CI, −47.0% to 9.8%), −41.6% (95% CI, −56.4% to −21.6%), and −80.7% (95% CI, −85.7% to −73.9%) across the 16-mg, 96-mg, and 400-mg groups. OxPL-apoB changes at day 360 were −30.6% (95% CI, −46.4% to −10.2%), −57.1% (95% CI, −65.2% to −47.2%), and −79.9% (95% CI, −83.8% to −75.2%), respectively.

For the 400-mg group, percent change in Lp(a) correlated strongly with percent change in OxPL-apo(a) at day 240 (95% CI, 0.90-0.96; P <.001) and moderately with OxPL-apoB (95% CI, 0.43-0.76; P <.001). By day 360, correlations strengthened for OxPL-apo(a) (95% CI, 0.86-0.95; P <.001) and OxPL-apoB (95% CI, 0.81-0.93; P <.001).

No significant correlation emerged between percent changes in OxPL and high-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation.

"Nobody, including our own study, has been able to demonstrate an anti-inflammatory effect of lowering of lipoprotein(a)," Nissen said. "hsCRP is only one measure of inflammation, and we may not have measured the right measures."

These findings provide additional biological rationale for the ongoing phase 3 ACCLAIM-Lp(a) cardiovascular outcomes trial (NCT06292013), which is evaluating lepodisiran in around 17,300 participants with elevated Lp(a), though the investigators caution the data do not establish clinical benefit.² Similar OxPL reductions have been reported with the antisense oligonucleotide pelacarsen and the siRNA olpasiran, placing lepodisiran among a growing class of Lp(a)-lowering nucleic acid therapies under investigation.¹

References

1. Nissen SE, Navar AM, Krege JH, et al. Effect on Lipoprotein(a) Oxidized Phospholipids of Lepodisiran, an Extended-Duration siRNA Targeting Lipoprotein(a). JACC. Published online 2026. doi:10.1016/j.jacc.2026.07.015

2. A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) - ACCLAIM-Lp(a). ClinicalTrials.gov. Accessed September 4, 2026. https://clinicaltrials.gov/study/NCT06292013