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Clinical Trial
. 2025 May 1;10(5):482-486.
doi: 10.1001/jamacardio.2024.5433.

Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers: Results From the OCEAN(a)-DOSE Trial

Robert S Rosenson  1 , J Antonio G López  2 , Daniel Gaudet  3 , Seth J Baum  4   5 , Elmer Stout  6 , Norman E Lepor  7 , Jeong-Gun Park  8 , Sabina A Murphy  8 , Beat Knusel  2 , Jingying Wang  2 , Tomaz Wilmanski  2 , Huei Wang  2 , You Wu  2 , Helina Kassahun  2 , Marc S Sabatine  8 , Michelle L O'Donoghue  8 ; OCEAN(a)-DOSE Trial Investigators
Affiliations
Clinical Trial

Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers: Results From the OCEAN(a)-DOSE Trial

Robert S Rosenson et al. JAMA Cardiol. .

Abstract

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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Rosenson reported grants and personal fees from Amgen during the conduct of the study; grants from 89bio, Arrowhead Pharmaceuticals, Eli Lilly and Company, Merck Sharp & Dohme, Novartis Pharmaceuticals, Novo Nordisk, and the US National Institutes of Health (NIH); personal fees from Arrowhead Pharmaceuticals, CRISPR Therapeutics, Editas Medicine, Eli Lilly and Company, Intercept Pharmaceuticals, Kowa America Corporation, Life Extension, Lipigon, New Amsterdam, Novartis Pharmaceuticals, Organon, Precision Biosciences, Regeneron, Rona Therapeutics, UltraGenyx, Verve Therapeutics, Viatris, and Wolters Kluwer (UpToDate); and holding stock in MediMergent outside the submitted work. Dr López reported being an employee of and shareholder in Amgen during the conduct of the study. Dr Gaudet reported grants and personal fees from Amgen during the conduct of the study; grants from 89bio, Alnylam, Amgen, Arrowhead, AstraZeneca, Chiesi, Eli Lilly and Company, Esperion, Inversago, Ionis, Kowa, Merck, New Amsterdam Therapeutics, Novo Nordisk, Regeneron, Ultragenyx, and Verve Therapeutics; and personal fees from Amgen, Arrowhead, Chiesi, CRISPR Therapeutics, Eli Lilly and Company, Flagship Pioneering, Ionis, Medison, Novartis, Ultragenyx, and Verve Therapeutics outside the submitted work. Dr Baum reported consultant, scientific advisory board membership, or speaker fees from Altimmune, Amgen, Beren Therapeutics, Boehringer Ingelheim, Eli Lilly, Esperion, Ionis, Madrigal, Merck, Novartis, and Regeneron outside the submitted work. Dr Lepor reported speakers bureau grants from Amgen and advisory board grants from Novartis and from Eli Lilly outside the submitted work. Dr Park reported research grants through Brigham Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Saghmos Therapeutics, Siemens Healthcare Diagnostics, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, and Zora Biosciences during the conduct of the study. Dr Murphy reported being a member of the TIMI Study Group, which received institutional research grant support from Amgen to conduct the OCEAN(a) dose-TIMI 67 trial during the conduct of the study and which received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Anthos Therapeutics, ARCA Biopharma, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis Pharmaceuticals, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Regeneron Pharmaceuticals, Roche, Saghmos Therapeutics, Siemens Healthcare Diagnostics, Softcell Medical Limited, The Medicines Company, Verve Therapeutics, and Zora Biosciences. Dr Knusel reported stock ownership in Amgen outside the submitted work. Dr J. Wang reported salary support from Amgen during the conduct of the study. Drs López, Wilmanski, H. Wang, and Wu reported being employees of and owning stock in Amgen. Dr Kassahun reported being an employee of and holding stock in Amgen both during the conduct of the study and outside the submitted work and being a coinventer of a pending patent for Amgen related to the phase 2 study. Dr Sabatine reported being a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abiomed, ARCA Biopharma, Janssen Research and Development, MedImmune, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical Limited, and Zora Biosciences; receiving grant support through Brigham and Women's from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Ionis, Marea, Merck, Novartis, Pfizer, Saghmos Therapeutics, and Verve Therapeutics; and receiving consulting fees from Amgen, AMPEL BioSolutions, Anthos Therapeutics, AstraZeneca, and Boehringer Ingelheim outside the submitted work. Dr O’Donoghue reported grants and personal fees from Amgen during the conduct of the study; grants from AstraZeneca and Novartis; and personal fees from AstraZeneca, Janssen, Novartis, Novo Nordisk, and Verve Therapeutics outside the submitted work. No other disclosures were reported.

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