Olpasiran Effectively Reduces Lp(a)-apoB Without Increasing Other apoB Particles: JAMA
Brazil: Researchers have found in a new study that inhibition of apo(a) synthesis with olpasiran significantly lowered Lp(a)-apoB levels without a compensatory rise in non–Lp(a)-apoB, resulting in an overall reduction of total apoB-containing particle concentrations.
The findings, published as a research letter in JAMA Cardiology by Dr. André Zimerman from Hospital Moinhos de Vento, Porto Alegre, Brazil, and colleagues, provide fresh insights into how olpasiran—a small-interfering RNA (siRNA)—influences apolipoprotein B (apoB) particles and their role in atherosclerotic cardiovascular disease (ASCVD).
Apolipoprotein B–containing lipoproteins are key contributors to atherosclerosis. Lipoprotein(a), or Lp(a), is a complex molecule comprising an apoB component attached to apolipoprotein(a) [apo(a)]. Earlier studies have shown that olpasiran can reduce Lp(a) levels by more than 95% at higher doses, along with a 15–20% reduction in total apoB concentrations. However, since this effect on apoB was not dose-dependent, researchers aimed to determine how olpasiran affects apoB particles bound to apo(a) (Lp[a]-apoB) versus those not bound (non–Lp[a]-apoB).
The data were derived from the OCEAN(a)-DOSE trial (Olpasiran Trials of Cardiovascular Events and Lipoprotein[a] Reduction), a randomized, double-blind, placebo-controlled, dose-ranging clinical study. The trial enrolled patients with established atherosclerotic cardiovascular disease and elevated Lp(a) concentrations above 150 nmol/L. Changes in apoB levels were analyzed as a prespecified secondary outcome using a linear mixed-effects model.
The study led to the following notable findings:
- The study included 281 participants with a baseline median total apoB concentration of 1306 nmol/L (67 mg/dL).
- Baseline Lp(a)-apoB levels were 260 nmol/L.
- Olpasiran treatment led to a dose-dependent reduction in Lp(a)-apoB levels (P<0.001 for all doses).
- Higher doses of olpasiran achieved more than a 95% decrease in Lp(a)-apoB.
- The absolute reduction in Lp(a)-apoB ranged from 211 to 307 nmol/L.
- A compensatory rise in non–Lp(a)-apoB levels was expected but was minimal, limited to 12% or less across all doses.
- Total apoB concentrations decreased by 16.7% to 18.9% compared with placebo.
- This corresponded to an absolute reduction in apoB levels of 201–228 nmol/L (10–11 mg/dL).
The authors explained that olpasiran likely reduces total apoB by preventing the entry of apoB particles into circulation or enhancing their clearance from the bloodstream. Since Lp(a)-apoB particles have a longer half-life and lower affinity for the LDL receptor than non–Lp(a)-apoB, shifting the balance toward non–Lp(a) particles may promote faster clearance.
The results align with prior findings from studies on pelacarsen, an antisense oligonucleotide targeting apo(a), though olpasiran demonstrated a greater overall reduction in total apoB. This appears to stem from a more pronounced decrease in Lp(a) concentrations, while the effects on non–Lp(a)-apoB were similar for both agents.
"Inhibition of apo(a) synthesis with olpasiran substantially decreased Lp(a)-apoB without triggering a rise in non–Lp(a)-apoB, leading to an overall decline in total apoB-containing lipoproteins. These results reinforce olpasiran’s potential as a promising therapy to reduce atherogenic particle burden and cardiovascular risk," the authors concluded.
Reference:
Zimerman A, López JAG, Rosenson RS, et al. Small-Interfering RNA Olpasiran and Apolipoprotein B Particles. JAMA Cardiol. Published online November 05, 2025. doi:10.1001/jamacardio.2025.4105
Next Story