Abstract：
Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 μM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides.
摘要：
寡核苷酸疗法（ONT）代表了一种具有独特药理和化学性质的新方法，该方法通过互补的Watson-Crick碱基对杂交介导的高度靶标特异性来调节基因表达。迄今为止,ONT的致心律失常评估受到国际协调会议(ICH)E14和S7B指南的影响.要记录当前的hERG/QTc评估实践，我们回顾了美国食品和药物管理局(FDA)和欧洲药品管理局(EMA)批准包(来源:PharmaPendium.com),并整理了17项上市ONT的临床前和临床研究.此外,来自12例研究性ONT的临床QTc数据来自文献.在销售的ONT中，在hERG测定中测试了8个,在测试的最高浓度(范围:34-3,000μM)下没有鉴定出抑制作用。在非人灵长类动物心血管研究中评估了14种ONT，其中11种在专门的遥测研究中进行了评估。在所有研究中均未观察到对QTc间隔的影响（高暴露倍数）。临床上,在TQT研究中评估了四个ONT；通过浓度-QTc间隔分析评估了另外六个ONT，六是常规安全心电图监测。没有一项临床研究确定了QTc延长的风险；12个研究性ONT也是如此。对FDA不良事件数据库的搜索表明批准的ONT与心律失常之间没有关联。总的来说,根据ICHS7B/E14研究获得的数据,来自29例ONT的总体证据表明没有临床心律失常风险.因此，新的ONT可能受益于减少的测试策略，因为它们没有心律失常风险，与单克隆抗体相似的心脏安全性，蛋白质，和肽。
