From the Metabolism and Lipids Program, Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York (R.S.R.); Université de Montréal, Montreal (D.G.), and Robarts Research Institute, London, ON (R.A.H.) - both in Canada; Baylor College of Medicine and the Texas Heart Institute - both in Houston (C.M.B.); Monash Victorian Heart Institute, Monash University, Melbourne, VIC (S.J.N.), and the School of Medicine, University of Western Australia, and the Department of Cardiology, Royal Perth Hospital, Perth (G.F.W.) - all in Australia; Lucas Research, Morehead City, NC (K.J.L.); and Arrowhead Pharmaceuticals, Pasadena, CA (J.S.M., R.Z., M.M., T.C., J.H.).
N Engl J Med. 2024 Sep 12;391(10):913-925. doi: 10.1056/NEJMoa2404147. Epub 2024 May 29.
Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of in the liver.
We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.
A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.
In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).
血管生成素样 3（ANGPTL3）抑制脂蛋白和内皮脂肪酶，并抑制肝脏摄取富含甘油三酯的脂蛋白残粒。功能丧失型携带者的甘油三酯、低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇和非高密度脂蛋白胆固醇水平较低，患动脉粥样硬化性心血管疾病的风险也较低。Zodasiran 是一种针对肝脏中表达的 RNA 干扰（RNAi）疗法。
我们进行了一项双盲、安慰剂对照、剂量范围的 2b 期试验，以评估 zodasiran 治疗混合性高脂血症（空腹甘油三酯水平为 150 至 499mg/dL，且 LDL 胆固醇水平≥70mg/dL 或非高密度脂蛋白胆固醇水平≥100mg/dL）成人的安全性和疗效。符合条件的患者按 3:1 的比例随机分配，接受皮下注射 zodasiran（50、100 或 200mg）或安慰剂，于第 1 天和第 12 周给药，并随访至第 36 周。主要终点是从基线到第 24 周时甘油三酯水平的变化百分比。
共有 204 名患者接受了随机分组。在第 24 周时，观察到 zodasiran 与基线相比具有显著的剂量依赖性降低 ANGPTL3 水平（与安慰剂相比的变化差异，50mg 时为-54 个百分点，100mg 时为-70 个百分点，200mg 时为-74 个百分点），并且观察到甘油三酯水平显著的剂量依赖性降低（与安慰剂相比的变化差异，分别为-51、-57 和-63 个百分点）（所有比较均 P<0.001）。与安慰剂相比，其他基线变化的差异包括：非高密度脂蛋白胆固醇水平，50mg 时为-29 个百分点，100mg 时为-29 个百分点，200mg 时为-36 个百分点；载脂蛋白 B 水平，分别为-19、-15 和-22 个百分点；LDL 胆固醇水平，分别为-16、-14 和-20 个百分点。我们观察到接受最高剂量 zodasiran 的伴发糖尿病患者的糖化血红蛋白水平短暂升高。
在混合性高脂血症患者中，zodasiran 可在 24 周时显著降低甘油三酯水平。（由 Arrowhead 制药公司资助；ARCHES-2 ClinicalTrials.gov 编号，NCT04832971.）
