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

IF 14.8 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JAMA cardiology Pub Date : 2025-05-01 DOI:10.1001/jamacardio.2024.5433

Robert S Rosenson, J Antonio G López, Daniel Gaudet, Seth J Baum, Elmer Stout, Norman E Lepor, Jeong-Gun Park, Sabina A Murphy, Beat Knusel, Jingying Wang, Tomaz Wilmanski, Huei Wang, You Wu, Helina Kassahun, Marc S Sabatine, Michelle L O'Donoghue

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引用次数: 0

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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Olpasiran，氧化磷脂和全身炎症生物标志物：来自OCEAN(a)-DOSE试验的结果。

重要性：脂蛋白(a) （Lp[a]）被认为是氧化磷脂（OxPL）的主要载体。OxPL被认为是炎症和动脉粥样硬化的有力驱动因素。Olpasiran是一种小干扰RNA，通过诱导载脂蛋白(a)信使RNA的降解来阻断Lp(a)的产生。奥尔帕西兰对OxPL和全身炎症标志物的影响尚未得到很好的描述。目的：在OCEAN(a)-DOSE随机临床试验中，评价奥帕西兰对OxPL、高敏白介素6 （hs-IL-6）、hs- c反应蛋白（hs-CRP）的影响。设计、环境和参与者：OCEAN(a)-DOSE是一项国际、多中心、安慰剂对照、剂量发现的2期随机临床试验，于2020年7月至2022年11月进行。共纳入281例动脉粥样硬化性心血管疾病且Lp(A)水平大于150 nmol/L的患者。干预：参与者随机接受4种有效皮下剂量的奥帕西兰和安慰剂中的1种：(1)10mg，每12周给药（Q12W）；(2) 75mg, Q12W；(3) 225 mg, Q12W；(4) 225 mg，每24周给药一次（Q24W）。在基线、36周和48周对272例患者的载脂蛋白B （OxPL- apob）、hs-CRP和hs-IL-6的OxPL进行评估。主要结局和测量：主要结局是经安慰剂调整的OxPL-apoB从基线到第36周的变化。结果：272名参与者中位（IQR）年龄为62岁（56-69岁），86名参与者（31.6%）为女性。基线Lp(a)浓度中位数（IQR）为260.3 nmol/L (198.1-352.4)， OxPL-apoB浓度中位数（IQR）为26.5 nmol/L（19.7-33.9）。从基线到第36周，经安慰剂调整后的OxPL-apoB平均百分比变化为：10mg Q12W剂量为-51.6% (95% CI, -64.9%至-38.2%)，75mg Q12W剂量为-89.7% (95% CI, -103.0%至-76.4%)，25mg Q12W剂量为-92.3% (95% CI, -105.6%至-78.9%)，Q24W剂量为-93.7% (95% CI, -107.1%至-80.3%)（P < 0.05）。结论及相关性：在OCEAN(a)-DOSE多中心随机临床试验中，奥帕西兰导致OxPL-apoB显著且持续降低，但对hs-CRP或hs-IL-6无显著影响。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

JAMA cardiology Medicine-Cardiology and Cardiovascular Medicine

CiteScore

45.80

自引率

1.70%

发文量

264

期刊介绍： JAMA Cardiology, an international peer-reviewed journal, serves as the premier publication for clinical investigators, clinicians, and trainees in cardiovascular medicine worldwide. As a member of the JAMA Network, it aligns with a consortium of peer-reviewed general medical and specialty publications. Published online weekly, every Wednesday, and in 12 print/online issues annually, JAMA Cardiology attracts over 4.3 million annual article views and downloads. Research articles become freely accessible online 12 months post-publication without any author fees. Moreover, the online version is readily accessible to institutions in developing countries through the World Health Organization's HINARI program. Positioned at the intersection of clinical investigation, actionable clinical science, and clinical practice, JAMA Cardiology prioritizes traditional and evolving cardiovascular medicine, alongside evidence-based health policy. It places particular emphasis on health equity, especially when grounded in original science, as a top editorial priority.