Olpasiran lowers oxidized phospholipids in patients with ASCVD
In a prespecified analysis of OCEAN(a)-DOSE among patients with ASCVD and elevated Lp(a), the Lp(a) siRNA olpasiran reduced oxidized phospholipids compared with placebo. Olpasiran had a neutral effect on hs-CRP and hs-IL-6 levels.
This summary is based on the publication of Rosenson RS, López JAG, Gaudet D, et al. - Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers: Results From the OCEAN(a)-DOSE Trial. JAMA Cardiol. 2025 Feb 12:e245433. [Online ahead of print] doi: 10.1001/jamacardio.2024.5433.
Introduction and methods
Background
Lp(a) is a major carrier of oxidized phospholipids (OxPLs) among apoB-containing lipoproteins [1]. OxPLs promote inflammation, thrombosis, and plaque destabilization.
In the phase 2 OCEAN(a)-DOSE study, treatment with olpasiran, an siRNA targeting Lp(a), led to a significant reduction in circulating Lp(a) levels in patients with ASCVD [2]. The effects of olpasiran on OxPLs and other markers of inflammation remain unclear.
Aim of the study
In this prespecified analysis of OCEAN(a)-DOSE, the authors evaluated the effects of olpasiran on OxPLs associated with apoB (OxPL-apoB), high-sensitivity IL-6 (hs-IL-6) and hs-CRP.
Methods
OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction-DOSE Finding Study) was an international, multicenter, double-blind, placebo-controlled, dose-finding, phase 2 RCT in which 281 patients with ASCVD and Lp(a) >150 nmol/L were randomized in a 1:1:1:1:1 ratio to subcutaneous olpasiran (10, 75, or 225 mg every 12 weeks (Q12W); or an exploratory dose of 225 mg every 24 weeks (Q24W)) or placebo. Patients in the Q12W groups received their last dose at week 36, whereas patients in the Q24W group received their last dose at week 24. OxPL-apoB and hs-IL-6 measurement data were available for 272 patients. In addition, hs-CRP data were available for 277 patients. At baseline, the median Lp(a) concentration was 260.3 nmol/L (IQR: 198.1–352.4) and the median OxPL-apoB concentration was 26.5 nmol/L (IQR: 19.7–33.9).
Main results
- The placebo-adjusted percent reduction in OxPL-apoB from baseline to 36 weeks with olpasiran 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 225 mg Q24W dose (all P<.001). These effects were maintained to week 48.
- The effects of olpasiran on OxPL-apoB were consistent regardless of age, sex, race, baseline Lp(a), baseline LDL-c, or use of high-potency statin (All P for interaction>0.05).
- In the olpasiran Q12W dose group, there was a correlation between the change in Lp(a) and OxPL-apoB (r= 0.79; P<0.001).
- Compared with placebo, treatment with olpasiran had no significant effect on hs-CRP or hs-IL-6.
Conclusion
In this prespecified analysis of OCEAN(a)-DOSE, treatment with olpasiran led to a significant and sustained reduction in OxPL-apoB in patients with ASCVD and elevated Lp(a) levels. Olpasiran had a neutral effect on hs-CRP and hs-IL-6 levels. The authors conclude that “it remains unknown whether these observed effects may offer incremental benefit beyond olpasiran’s effect of Lp(a) lowering alone.”
References
- Tsimikas S, Witztum JL. Oxidizedphospholipids in cardiovascular disease. Nat Rev Cardiol. 2024;21 (3):170-191. doi:10.1038/s41569-023-00937-4
- O’Donoghue ML, Rosenson RS, Gencer B, et al. OCEAN(a)-DOSETrial Investigators. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med. 2022;387 (20):1855-1864. doi:10.1056/NEJMoa2211023