Olpasiran Reduces Oxidized Phospholipids on ApoB in OCEAN(a)-DOSE Trial

Olpasiran, a small interfering RNA inhibitor of lipoprotein(a) [Lp(a)], sustained a significant reduction in oxidized phospholipids associated with apoliprotein B (OxPL-apoB), but not high-sensitivity interleukin 6 (hs-IL-6) or C-reactive protein (hs-CRP), in the Phase 2 OCEAN(a)-DOSE trial.1

Olpasiran halts the production of Lp(a) by inducing the degradation of apolipoprotein(a) messenger RNA (mRNA), a major protein component of Lp(a) alongside apoB. In previous results from the OCEAN(a)-DOSE trial, increased doses of olpasiran reduced circulating Lp(a) levels by ≥95% in individuals with atherosclerotic cardiovascular disease (ASCVD).3

“Our study is the first clinical trial to investigate the association between oxidized phospholipids on Lp(a) and inflammatory mediators,” lead trial investigator Robert Rosenson, MD, a professor of cardiology at the Icahn School of Medicine at Mount Sinai, said in a statement.2 “We found that in addition to its beneficial effects on lowering Lp(a), olpasiran reduced levels of oxidized phospholipids, which are presumed to promote atherosclerosis.”

OCEAN(a)-DOSE, a Phase 2 dose-ranging trial, randomized 281 individuals with ASCVD and raised Lp(a) levels ≥150 nmol/L to one of 3 active subcutaneous doses of olpasiran (10 mg, 75 mg, or 225 mg) administered every 12 weeks (Q12W), or an exploratory dose (225 mg) administered every 24 weeks (Q24W), compared with placebo.1

In this prespecified OCEAN(a)-DOSE analysis, investigators assessed the effect of olpasiran on OxPL-apoB and hs-IL-6 at baseline, week 36, and week 48 in 272 participants. Further assessment was performed on hs-CRP levels at baseline and weeks 4, 12, 24, 36, and 48 in 277 patients. The analysis used repeated measures linear mixed-effects models to assess the placebo-adjusted mean percentage changes over this timeline.

“Results of our trial revealed that olpasiran led to a significant and sustained reduction in oxidized phospholipids on apoB,” Rosenson said.2 “We observed no significant effects of olpasiran, however, on the secretion of the proinflammatory cytokine IL-6 or CRP compared to the placebo group.”

At baseline, the median Lp(a) concentration was 260.3 nmol/L and the median OxPL-apoB concentration was 26.5 nmol/L. Across the olpasiran treatment phase, the placebo-adjusted mean percent change in OxPL-apoB from baseline to week 36 was –51.6% (95% CI, –64.9 to –38.2) for the 10 mg Q12W dose, –89.7% (95% CI, –103.0 to –76.4) for the 75-mg Q12W dose, –92.3% (95% CI, –105.6 to –78.9) for the 225 mg Q12W dose, and –93.7% (95% CI, –107.1 to –80.3) for the Q24W exploratory dose (P <.001 for all).1

Further analysis showed these reductions maintained until Week 48 (mean percentage changes, –50.8%, –100.2%, –104.7%, and –85.8%, respectively; P <.001 for all). Rosenson and colleagues identified a strong correlation between the percentage reduction in Lp(a) and OxPL-apoB for patients receiving olpasiran at Q12W dosing (r =.79; P <.001). However, the analysis showed no significant impact of olpasiran on hs-CRP or hs-IL-6 compared with placebo in Weeks 36 or 48 (P >.05).

Based on these findings, Rosenson and colleagues suggested the strong correlation between olpasiran and Lp(a) lowering supports Lp(a) as a key carrier of OxPL. Further evaluation of the impact of selected Lp(a)-lowering therapy on OxPL-apoB could provide mechanistic support for future cardiovascular outcomes trials.1

“Further work is needed in this area, but OCEAN will enable us to more accurately select patients for future trials who are likely to show an anti-inflammatory response from selective RNA inhibitors of Lp(a),” Rosenson added.2

References

1. Rosenson RS, López JAG, Gaudet D, et al. Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers: Results From the OCEAN(a)-DOSE Trial. JAMA Cardiol. Published online February 12, 2025. doi:10.1001/jamacardio.2024.5433

2. O'Donoghue ML, Rosenson RS, Gencer B, et al. Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease. N Engl J Med. 2022;387(20):1855-1864. doi:10.1056/NEJMoa2211023