Design and rationale of the CORE-TIMI 72a and CORE2-TIMI 72b trials of olezarsen in patients with severe hypertriglyceridemia

IF 3.7 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

American heart journal Pub Date : 2025-03-09 DOI:10.1016/j.ahj.2025.03.003

Nicholas A. Marston MD, MPH , Brian A. Bergmark MD , Veronica J. Alexander PhD , Ewa Karwatowska-Prokopczuk MD, PhD , Yu Mi Kang MD, PhD , Filipe A. Moura MD, PhD , Thomas A. Prohaska MD, PhD , Andre Zimerman MD, PhD , Shuanglu Zhang MPH , Sabina A. Murphy MPH , Sotirios Tsimikas MD , Robert P. Giugliano MD, SM , Marc S. Sabatine MD, MPH

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引用次数: 0

Abstract

Background

Severe hypertriglyceridemia (HTG), defined as a serum triglyceride (TG) concentration ≥500 mg/dl, is present in approximately 1 in every 100 individuals and carries direct clinical consequences, including pancreatitis, which can be life-threatening. Olezarsen is an investigational antisense oligonucleotide targeted to the mRNA for apolipoprotein C-III (apoC-III), a protein known to impair TG clearance by inhibiting lipoprotein lipase and the hepatic uptake of triglyceride-rich remnants. No dedicated trial has tested olezarsen in patients with severe HTG.

Methods

In these 2 pivotal phase 3 trials, CORE-TIMI 72a and CORE2-TIMI 72b, patients with severe HTG were randomized in a 2:1 fashion to either olezarsen (80 mg or 50 mg dose) or matching placebo. Patients will be treated for a total of 12 months and evaluated for the primary endpoint of percent change in TGs from baseline to 6 months compared with placebo. Pooled analyses of CORE and CORE2 will also assess olezarsen's effect on acute pancreatitis events and change in hepatic steatosis.

Results

A total of 617 subjects in CORE-TIMI 72a and 446 subjects in CORE2-TIMI 72b were randomized. In these 2 trials, the median age was 54 and 55 years, women made up 24% and 23% of the study population, and the baseline TGs were 836 mg/dl and 749 mg/dl, respectively. A total of 333 subjects, 129 from CORE-TIMI 72a and 204 from CORE2-TIMI 72b, were enrolled in the hepatic MRI substudy.

Discussion

Together, CORE-TIMI 72a and CORE2-TIMI 72b are designed to establish the efficacy and safety of olezarsen in patients with severe HTG.

Trial Registration

Clinicaltrials.gov: NCT05079919 and NCT05552326.

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Olezarsen治疗严重高甘油三酯血症患者的CORE -TIMI 72a和CORE2 -TIMI 72b试验的设计和基本原理

严重高甘油三酯血症（HTG），定义为血清甘油三酯（TG）浓度≥500 mg/dl，每500人中约有1人存在，并具有直接的临床后果，包括胰腺炎，可危及生命。Olezarsen是一种正在研究的反义寡核苷酸，靶向载脂蛋白C-III (apoC-III) mRNA，载脂蛋白C-III是一种已知通过抑制脂蛋白脂肪酶和肝脏摄取甘油三酯和富含甘油三酯残留物而损害TG清除的蛋白质。Olezarsen在主要为中度HTG （150-499 mg/dl）和罕见遗传病家族性乳糜小铁血症综合征（FCS）的患者中进行了评估，其降低TG的效果分别为53%和44%，并减少了FCS人群中的胰腺炎。然而，没有专门的试验测试olezarsen在严重HTG患者中的作用。在这两项关键的3期试验中，CORE -TIMI 72a （NCT05079919）和CORE2 -TIMI 72b (NCT05552326)，超过1000名严重HTG患者将以2:1的方式随机分配到olezarsen（剂量为80 mg或50 mg）或匹配的安慰剂。患者将接受总共53周的治疗，并评估与安慰剂相比，从基线到6个月的tg变化百分比的主要终点。CORE和CORE2的合并分析也将评估olezarsen对急性胰腺炎事件和肝脂肪变性的影响。CORE -TIMI 72a （NCT05079919）和CORE2 -TIMI 72b （NCT05552326）旨在确定olezarsen在重度HTG患者中的有效性和安全性。

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来源期刊

American heart journal 医学-心血管系统

CiteScore

8.20

自引率

2.10%

发文量

214

审稿时长

38 days

期刊介绍： The American Heart Journal will consider for publication suitable articles on topics pertaining to the broad discipline of cardiovascular disease. Our goal is to provide the reader primary investigation, scholarly review, and opinion concerning the practice of cardiovascular medicine. We especially encourage submission of 3 types of reports that are not frequently seen in cardiovascular journals: negative clinical studies, reports on study designs, and studies involving the organization of medical care. The Journal does not accept individual case reports or original articles involving bench laboratory or animal research.