新藥AZD8233在降低患者LDL-C和Lp(a)水平上展現前所未有的效果：來自ETESIAN研究的階段2b數據

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在ETESIAN的階段2b臨床試驗中，針對膽固醇管理的新藥物AZD8233對使用他汀類藥物治療的血脂異常患者顯示出顯著的LDL-C和Lp(a)降低效果。 研究顯示，AZD8233能夠有效降低這兩種獨立的心血管風險因素，為進一步降低心血管疾病風險提供了新的可能性。

Alexis Hofherr, Jennifer Schumi, Anna Rudvik, Rick Vega, Tina Ryden-Bergsten, Eva Hurt-Camejo, Per Johanson and Bjorn C Carlsson
Originally published30 Oct 2022

https://doi.org/10.1161/circ.146.suppl_1.11482

Circulation. 2022;146:A11482

Abstract

Elevated blood levels of lipoprotein(a) [Lp(a)] are an independent causal risk factor for atherosclerotic cardiovascular disease. Lp(a) particles are formed by a lipid domain and an apolipoprotein B (apoB) protein that is bound to apolipoprotein(a). Standard low-density lipoprotein cholesterol (LDL-C) and ApoB lowering treatments have minimal Lp(a)-lowering efficacy. We have previously shown that AZD8233 inhibits hepatic PCSK9 synthesis and causes substantial reductions in LDL-C. Here we report the significant effects of AZD8233 on Lp(a) and ApoB.

ETESIAN was a multicenter phase 2b, randomized, double-blind, placebo-controlled, dose-ranging study (NCT04641299). Eligible participants were 18-75 years old, on statin therapy, with LDL-C of ≥ 70 to < 190 mg/dL, and with fasting triglycerides of < 400 mg/dL. Participants were randomized 1:1:1:1 to subcutaneous injections (days 1, 8, 29, and 57) of either 15, 50, or 90 mg AZD8233, or placebo. The primary objective was to evaluate the effect of AZD8233 versus placebo on LDL-C at week 12. Secondary objectives were to assess Lp(a) levels and other lipid parameters.

 A total of 119 patients were enrolled in ETESIAN. AZD8233 was well tolerated and demonstrated dose-dependent and clinically meaningful reductions in LDL-C, Lp(a), and ApoB (Table). The relative distribution of these effects across participant subgroups and the interaction of effects on Lp(a), ApoB, and LDL-C will be presented.

In patients with dyslipidemia on statins, AZD8233 caused substantial reductions in LDL-C and Lp(a), two independent risk factors for major adverse cardiovascular events. The broad lipid-modifying effect of AZD8233 may, hence, provide an opportunity to reduce cardiovascular risk in patients with ASCVD beyond currently available medications.

摘要

血脂蛋白(a) [Lp(a)] 的升高是動脈粥狀硬化心血管疾病的一個獨立的致病風險因子。 Lp(a) 顆粒由脂質區域和與載脂蛋白(a)結合的載脂蛋白B (apoB) 蛋白形成。 標準的低密度脂蛋白膽固醇 (LDL-C) 和 ApoB 降低治療對降低 Lp(a) 的效力很小。 我們先前已經顯示 AZD8233 抑制肝臟 PCSK9 合成並導致 LDL-C 顯著降低。 在這裡，我們報告了 AZD8233 對 Lp(a) 和 ApoB 的顯著影響。

ETESIAN 是一個多中心 2b 期、隨機、雙盲、安慰劑對照、劑量範圍研究 (NCT04641299)。 符合條件的參與者為18-75歲，接受他汀治療，LDL-C ≥ 70 到 < 190 mg/dL，空腹三酸甘油酯 < 400 mg/dL。 參與者隨機分為亞切皮注射組（第1、8、29和57天）接受15、50或90 mg AZD8233，或安慰劑，比例為1:1:1:1。 主要目標是評估 AZD8233 與安慰劑在第12週對 LDL-C 的影響。 次要目標是評估 Lp(a) 水平和其他血脂參數。

共有119名患者参与了 ETESIAN。AZD8233 耐受性良好，并显示出剂量依赖性和临床上有意义的 LDL-C、Lp(a) 和 ApoB 减少（见表）。这些效应在参与者亚组之间的相对分布以及对 Lp(a)、ApoB 和 LDL-C 的影响互动将被呈现。

在接受他汀治療的血脂異常患者中，AZD8233 導致 LDL-C 和 Lp(a) 顯著降低，這兩者是主要不良心血管事件的獨立風險因子。 AZD8233 的廣泛血脂改善效果可能為超出目前可用藥物的 ASCVD 患者降低心血管風險提供機會。