Effect on Lipoprotein(a) Oxidized Phospholipids of Lepodisiran, an Extended-Duration siRNA Targeting Lipoprotein(a).

BACKGROUND: Lipoprotein(a) [Lp(a)] is a largely genetically determined causal risk factor for atherosclerotic cardiovascular disease and aortic stenosis, likely mediated in part by oxidized phospholipids (OxPL) bound to apolipoprotein(a) [apo(a)] and apolipoprotein B (apoB). Lepodisiran, an extended-duration small interfering RNA demonstrated large and durable reductions in Lp(a) in a phase 2 trial. OBJECTIVES: The purpose of this study was to assess effects of lepodisiran on OxPL-apo(a) and -apoB levels, their relationship to Lp(a) and apoB lowering, whether reductions are proportional to particle reduction, and whether changes correlate with biomarkers of systemic inflammation. METHODS: The randomized, placebo-controlled phase 2 trial enrolled 320 participants at 66 global centers. The current post hoc analysis included 213 of 320 participants who received placebo or lepodisiran 16, 96, or 400 mg at baseline and day 180 and had OxPL levels measured at baseline, day 240, and day 360. Placebo-adjusted percent change from baseline in OxPL-apo(a) and -apoB were assessed. Correlations between percent change in Lp(a), OxPL-apo(a), and -apoB were also determined. RESULTS: Median baseline OxPL-apo(a) and -apoB levels were 122.0 nmol/L (Q1, Q3: 105.1, 137.7 nmol/L) and 27.7 nmol/L (Q1, Q3: 22.5, 36.2 nmol/L) for all participants. 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%) in the 16-, 96-, and 400-mg dose groups, respectively. Percent changes in OxPL-apoB at day 240 in these dose groups 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%), respectively. The percent change in OxPL-apo(a) at day 360 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%) in the 16-, 96-, and 400-mg dose groups, respectively. The percent changes in OxPL-apoB at day 360 in these dose groups 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. Percent change in OxPL-apo(a) correlated more closely than OxPL-apoB with percent change in Lp(a) than did OxPL-apoB. There was no significant correlation between changes in high-sensitivity C-reactive protein and OxPL. CONCLUSIONS: Lepodisiran produced sustained reductions in OxPL-apoB and OxPL-apo(a) levels that correlated with Lp(a) lowering. These findings provide additional biological rationale for the ongoing lepodisiran phase 3 cardiovascular outcomes trial, but do not establish clinical benefit. (A Study of LY3819469 in Participants With Elevated Lipoprotein(a) [Lp(a)]; NCT05565742).