TIMI Study Group, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (B.A.B., N.A.M., A.J., J.F.K., J.-G.P., S.A.M., M.S.S., S.D.W.).
Pfizer, Inc, New York, NY (C.R.B., M.C., V.R., S.G.T.).
Circulation. 2022 May 3;145(18):1377-1386. doi: 10.1161/CIRCULATIONAHA.122.059266. Epub 2022 Apr 3.
Genetic loss-of-function variants in are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.
Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.
Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all <0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all <0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all <0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%).
Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction.
URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.
是一种与血浆脂质水平降低相关的基因功能丧失变异。Vupanorsen 是一种肝脏靶向的反义寡核苷酸，可抑制血管生成素样 3（ANGPTL3）蛋白合成。
在他汀类药物治疗的非高密度脂蛋白胆固醇（non-HDL-C）≥100mg/dL 和甘油三酯 150-500mg/dL 的成年人中，采用双盲方式随机分配至安慰剂或 7 种 vupanorsen 剂量方案（80、120 或 160mg SC，每 4 周一次，或 60、80、120 或 160mg SC，每 2 周一次）。主要终点是 24 周时非-HDL-C 与基线相比的安慰剂调整百分比变化。次要终点包括与基线相比，甘油三酯、低密度脂蛋白胆固醇（LDL-C）、载脂蛋白 B（ApoB）和 ANGPTL3 的安慰剂调整百分比变化。
286 名受试者被随机分配：44 名至安慰剂组，242 名至 vupanorsen 组。中位年龄为 64 岁（四分位间距，58-69），44%为女性，中位非-HDL-C 为 132.4（四分位间距，118.0-154.1）mg/dL，中位甘油三酯为 216.2（四分位间距，181.4-270.4）mg/dL。与安慰剂相比，vupanorsen 导致非-HDL-C从基线显著降低，范围从 60mg 每 2 周组的 22.0%到 80mg 每 2 周组的 27.7%（所有剂量均<0.001）。甘油三酯的降低幅度较大，从 41.3%到 56.8%（均<0.001）。对 LDL-C 和 ApoB 的影响较小（分别为 7.9%-16.0%和 6.0%-15.1%），且没有明确的剂量反应关系，只有较高的降低幅度达到统计学意义。ANGPTL3 水平呈剂量依赖性降低，幅度为 69.9%-95.2%（均<0.001）。vupanorsen 治疗未导致肾功能或血小板计数显著下降。注射部位反应和丙氨酸氨基转移酶或天冬氨酸氨基转移酶升高超过 3 倍的情况在较高的总月剂量时更为常见（分别为 33.3%和 44.4%），肝脂肪分数也呈剂量依赖性增加（最高达 76%）。
每月等效剂量为 80-320mg 的 vupanorsen 可显著降低非-HDL-C 和其他脂质参数。在较高剂量时，注射部位反应和肝酶升高更为常见，且肝脂肪分数呈剂量依赖性增加。
