A phase II randomized clinical trial has found that olpasiran, a small interfering RNA therapy, significantly reduces oxidized phospholipids on apolipoprotein B in patients with atherosclerotic cardiovascular disease and elevated lipoprotein(a) levels.
The findings, published in JAMA Cardiology, indicate that olpasiran effectively lowers oxidized phospholipids on apolipoprotein B (OxPL-apoB) levels but does not significantly impact systemic inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) and high-sensitivity interleukin 6 (hs-IL-6).
The OCEAN(a)-DOSE trial was a placebo-controlled, multicenter study conducted between July 2020 and November 2022. The trial included 281 patients with atherosclerotic cardiovascular disease and lipoprotein(a) [Lp(a)] levels greater than 150 nmol/L, who were randomized to receive one of four olpasiran regimens:
- 10 mg every 12 weeks (Q12W)
- 75 mg Q12W
- 225 mg Q12W
- 225 mg every 24 weeks (Q24W)
OxPL-apoB and hs-IL-6 levels were assessed at baseline, week 36, and week 48. hs-CRP was measured at baseline and at weeks 4, 12, 24, 36, and 48 in 277 patients.
Among the 272 participants included in the final analysis, the median (interquartile range [IQR]) age was 62 years (56-69), and 31.6% were female. The baseline median Lp(a) concentration was 260.3 nmol/L (IQR = 198.1-352.4), and OxPL-apoB was 26.5 nmol/L (IQR = 19.7-33.9).
Led by Robert S. Rosenson, MD, of the Metabolism and Lipids Program at the Icahn School of Medicine, Mount Sinai Hospital in New York, the researchers found the following reductions in OxPL-apoB in each dosing group (P < .001 for all dose groups compared with placebo):
- 10 mg Q12W: −51.6% (95% confidence interval [CI] = −64.9% to −38.2%)
- 75 mg Q12W: −89.7% (95% CI = −103.0% to −76.4%)
- 225 mg Q12W: −92.3% (95% CI = −105.6% to −78.9%)
- 225 mg Q24W: −93.7% (95% CI = −107.1% to −80.3%)
Olpasiran did not significantly impact hs-CRP or hs-IL-6 levels at weeks 36 or 48 compared with placebo (P > .05), but a strong correlation was observed between Lp(a) and OxPL-apoB reduction (r = 0.79, P < .001).
The study further supported Lp(a) as a major carrier of OxPL-apoB, which contributes to inflammation and atherosclerosis. However, the absence of a significant effect on hs-CRP and hs-IL-6 suggests that the broader inflammatory impact of OxPL reduction remains uncertain.
The trial was limited to a phase II, dose-finding design, and long-term clinical outcomes related to cardiovascular events remain unknown. Future research will be needed to determine whether OxPL-apoB reductions translate into reduced cardiovascular risk.
The researchers concluded, "observational studies report that Lp(a) and OxPL-apoB are both independent predictors of coronary atherosclerosis, as well as myocardial infarction and stroke, with the association for major adverse cardiovascular events reported to be stronger for OxPL-apoB than Lp(a) in many studies. Thus, studying the efficacy of selective Lp(a)-lowering therapy on OxPL-apoB and inflammatory pathways provides potential mechanistic support for ongoing cardiovascular outcomes trials."
The study was sponsored by Amgen. Full disclosures can be found in the study.
