Michelle O'Donoghue, MD, is the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women's Hospital and associate professor at Harvard Medical School

Michelle O'Donoghue, MD

Olpasiran Lowers Lp(a) Irrespective of Apo(a) Isoform Size, With Michelle O’Donoghue, MD

atherosclerotic cardiovascular disease (ASCVD)

, irrespective of apolipoprotein(a) isoform size, according to results from the OCEAN(a)-DOSE trial.

Lp(a) concentration is predominantly driven by genetics, with a well-documented inverse correlation between it and the number of Kringle IV-2 (KIV-2) repeats on apolipoprotein(a) alleles. However, the relationship between the size of these apo(a) isoforms and the response to Lp(a) lowering via RNA interference via olpasiran has not been studied. To that end, this analysis of the OCEAN(a)-DOSE trial was undertaken.

 spoke with Michelle O’Donoghue, MD, the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital and associate professor at Harvard Medical School, to discuss the implications of this finding, not only for olpasiran, but for apo(a)-targeting ASCVD care at large.

“This is relevant because a lot of studies are looking at participants and individuals who have the highest levels of Lp(a),” O’Donoghue told 

. “We really need to better understand whether all people will have a similar type of response to these therapies, even if we end up pushing down to lower baseline Lp(a) concentrations.”

OCEAN(a)-DOSE was a phase 2, dose-finding randomized clinical trial evaluating 4 active doses of olpasiran – 10 mg every 12 weeks (Q12W), 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W. For inclusion, patients were required to have ASCVD and Lp(a) levels >150 nmol/L. Investigators also measured the number of Kringle IV-2 (KIV-2) repeats, which are inversely correlated to the concentration of Lp(a), in each patient via a gel electrophoresis and immunoblotting system.

A total of 277 patients were enrolled in the trial, with a mean age of 62 years (interquartile range [IQR], 56-69). At baseline, the median Lp(a) concentration was 260.2 (IQR, 197.9-358.5) nmol/L. Lp(a) concentration was generally higher among patients with a lower number of KIV-2 repeats (

 = 0.02). Patients were then randomly assigned to 1 of 4 of the active subcutaneous doses of olpasiran or placebo; the final dose was administered at week 36 for the Q12W arms and at week 24 for the Q24W arm.

By week 36, the placebo-adjusted LSM percent change from baseline in Lp(a) with olpasiran was consistent irrespective of baseline KIV-2 repeat number (

 = .66). Additionally, no significant change was observed over time in the percent expression of the dominant apo(a) isoform with olpasiran versus placebo (mean change from baseline [+/- standard deviation] +1.1 [+/-9.8] % with olpasiran and + 2.1 [+/- 12.8] % with placebo; 

“Most people carry 2 different copies of an apo(a) allele, so they have a variable number of KIV-2 repeats in their blood, reflecting each of those 2 alleles – the dominant isoform is really just determined by what percent expression you have of one or the other,” O’Donoghue said. “We found that olpasiran really seems to target both isoforms equally; it doesn’t seem to matter how many KIV-2 repeats you have. It’s being taken out.”

Editor's Note: O'Donoghue reports disclosures with Amgen, Novartis, AstraZeneca, Janssen, Novo Nordisk, Verve, and others.

Monguillon V, Lopez A, Rosenson R, et al. Efficacy of Olpasiran by Apolipoprotein(a) Isoform Size: Insights from the OCEAN(a)-DOSE Trial. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

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;10(5):482-486. 

Videos

O’Donoghue discusses the results of the recent OCEAN(a)-DOSE trial and addresses the implications for Lp(a)-lowering therapies moving forward.

Michelle O'Donoghue, MD

Articles