Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers

Importance Lipoprotein(a) (Lp[a]) is thought to be the major carrier of oxidized phospholipids (OxPL). OxPL are believed to be a potent driver of inflammation and atherosclerosis. Olpasiran, a small interfering RNA, blocks Lp(a) production by inducing degradation of apolipoprotein(a) messenger RNA. Olpasiran’s effects on OxPL and systemic markers of inflammation are not well described. Objective To assess the effects of olpasiran on OxPL, high-sensitivity interleukin 6 (hs-IL-6), and hs-C-reactive protein (hs-CRP) in the OCEAN(a)-DOSE randomized clinical trial. Design, Setting, and Participants OCEAN(a)-DOSE was an international, multicenter, placebo-controlled, phase 2, dose-finding randomized clinical trial conducted between July 2020 and November 2022. A total of 281 patients with atherosclerotic cardiovascular disease and Lp(a) levels greater than 150 nmol/L were included. Intervention Participants were randomized to receive 1 of 4 active subcutaneous doses of olpasiran vs placebo: (1) 10 mg, administered every 12 weeks (Q12W); (2) 75 mg, Q12W; (3) 225 mg, Q12W; or (4) 225 mg, administered every 24 weeks (Q24W). OxPL on apolipoprotein B (OxPL-apoB), hs-CRP, and hs-IL-6 were assessed at baseline, week 36, and week 48 in 272 patients. Main Outcomes and Measures The primary outcome was placebo-adjusted change in OxPL-apoB from baseline to week 36. Results Among 272 participants, median (IQR) age was 62 years (56-69), and 86 participants (31.6%) were female. Baseline median (IQR) Lp(a) concentration was 260.3 nmol/L (198.1-352.4) and median (IQR) OxPL-apoB concentration was 26.5 nmol/L (19.7-33.9). The placebo-adjusted mean percentage 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 dose ( P < .001 for all). These effects were maintained to week 48 (−50.8%, −100.2%, −104.7%, and −85.8%, respectively; P < .001 for all). There was a strong correlation between percentage reduction in Lp(a) and OxPL-apoB for patients treated with olpasiran ( r = 0.79; P < .001). Olpasiran did not significantly impact hs-CRP or hs-IL-6 compared with placebo to weeks 36 or 48 ( P > .05). Conclusion and Relevance In the OCEAN(a)-DOSE multicenter randomized clinical trial, olpasiran led to a significant and sustained reduction in OxPL-apoB but no significant effects on hs-CRP or hs-IL-6.