N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels
N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels
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DOI：
10.1093/eurheartj/ehz209
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发表时间：
2019-09-01
影响因子：
39.3
通讯作者：
Tsimikas, Sotirios
中科院分区：
文献类型：
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作者：
Alexander, Veronica J.;Xia, Shuting;Tsimikas, Sotirios
AIM载脂蛋白C-III(apoC-III)水平升高与高甘油三酯血症和冠心病有关。AKCEA-APOCIII-LRx是一种N-乙酰半乳糖胺偶联的反义寡核苷酸，靶向于肝脏，选择性地抑制apoC-III蛋白的合成。方法和结果在甘油三酯水平为90或200 mg/dL的健康志愿者中，AKCEA-APOCIII-LRx的安全性、耐受性和有效性通过双盲、安慰剂对照、剂量递增1/2a研究进行评估。单剂量组皮下注射10、30、60、90、120 mg，多剂量组皮下注射15、30 mg每周皮下注射6周，或每4周皮下注射60 mg皮下注射，疗程3个月。在服用10、30、60、90或120毫克AKCEA-APOCIII-LRx的单剂量队列中，服用14天后，载脂蛋白C-III的中位数下降了0、-42%、-73%、-81%和-92%，甘油三酯下降了-12%、-7%、-42%、-73%和-77%。在每周15和30毫克以及每4周60毫克的多剂量队列中，观察到在最后一次服药后1周，载脂蛋白C-III的中位数下降了-66%、-84%和-89%，甘油三酯下降了-59%、-73%和-66%。总胆固醇、载脂蛋白B、非高密度脂蛋白胆固醇、极低密度脂蛋白胆固醇显著降低，高密度脂蛋白胆固醇显著升高。AKCEA-APOCIII-LRx具有良好的耐受性，只有一个注射部位出现轻度红斑反应，没有流感样反应、血小板计数减少、肝脏或肾脏安全信号。结论AKCEA-APOCIII-LRx治疗高甘油三酯血症患者可广泛改善致动脉粥样硬化性血脂，具有良好的安全性和耐受性。
Aims Elevated apolipoprotein C-III (apoC-III) levels are associated with hypertriglyceridaemia and coronary heart disease. AKCEA-APOCIII-LRx is an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver that selectively inhibits apoC-III protein synthesis.Methods and results The safety, tolerability, and efficacy of AKCEA-APOCIII-LRx was assessed in a double-blind, placebo-controlled, dose-escalation Phase 1/2a study in healthy volunteers (ages 18-65) with triglyceride levels >= 90 or >= 200 mg/dL. Single-dose cohorts were treated with 10, 30, 60, 90, and 120 mg subcutaneously (sc) and multiple-dose cohorts were treated with 15 and 30 mg weekly sc for 6 weeks or 60 mg every 4 weeks sc for 3 months. In the single-dose cohorts treated with 10, 30, 60, 90, or 120 mg of AKCEA-APOCIII-LRx, median reductions of 0, -42%, -73%, -81%, and -92% in apoC-III, and -12%, -7%, -42%, -73%, and -77% in triglycerides were observed 14 days after dosing. In multiple-dose cohorts of 15 and 30 mg weekly and 60 mg every 4 weeks, median reductions of -66%, -84%, and -89% in apoC-III, and -59%, -73%, and -66% in triglycerides were observed 1 week after the last dose. Significant reductions in total cholesterol, apolipoprotein B, non-high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein cholesterol, and increases in HDL-C were also observed. AKCEA-APOCIII-LRx was well tolerated with one injection site reaction of mild erythema, and no flu-like reactions, platelet count reductions, liver, or renal safety signals.Conclusion Treatment of hypertriglyceridaemic subjects with AKCEA-APOCIII-LRx results in a broad improvement in the atherogenic lipid profile with a favourable safety and tolerability profile.