Advances in medicinal chemistry have produced new chemical classes of antisense oligonucleotides (ASOs) with enhanced therapeutic properties. Conjugation of the triantennary N-acetylgalactosamine (GalNAc3) moiety to the extensively characterized phosphorothioate (PS)-modified 2'-O-methoxyethyl (2'MOE) ASO exemplifies such an advance. This structure-activity optimized moiety effects receptor-mediated uptake of the ASO prodrug through the asialoglycoprotein receptor 1 to support selective targeting of RNAs expressed by hepatocytes. In this study we report the integrated assessment of data available from randomized placebo-controlled dose-ranging studies of this chemical class of ASOs administered systemically to healthy human volunteers. First, we compare the pharmacokinetic and pharmacodynamic profiles of a subset of the GalNAc3-conjugated PS-modified 2'MOE ASOs to the parent PS-modified 2'MOE ASOs for which plasma analytes are available. We then evaluate the safety profile of the full set of GalNAc3-conjugated PS-modified 2'MOE ASO conjugates by the incidence of signals in standardized laboratory tests and by the mean laboratory test results as a function of dose level over time. With hepatocyte targeted delivery, the ED50 for the GalNAc3-conjugated PS-modified 2'MOE ASO subset ranges from 4 to 10 mg/week, up to 30-fold more potent than the parent PS-modified 2'MOE ASO. No GalNAc3-conjugated PS-modified 2'MOE ASO class effects were identified from the assessment of the integrated laboratory test data across all doses tested with either single or multidose regimens. The increase in potency supports an increase in the safety margin for this new chemical class of ASOs now under broad investigation in the clinic. Although the total exposure is limited in the initial phase 1 trials, ongoing and future investigations in patient populations will support evaluation of the effects of long-term exposure.

中文翻译：

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GalNAc3偶联的2'-O-甲氧基乙基嵌合反义寡核苷酸临床表现的综合评估：I.人类志愿者经验。

药物化学的进步产生了具有增强治疗特性的新化学类别的反义寡核苷酸（ASO）。三天线的N-乙酰半乳糖胺（GalNAc3）部分与广泛表征的硫代磷酸酯（PS）修饰的2'-O-甲氧基乙基（2'MOE）ASO的共轭体现了这种进步。这种结构活性最优化的部分通过脱唾液酸糖蛋白受体1影响受体介导的ASO前药摄取，以支持肝细胞表达的RNA的选择性靶向。在这项研究中，我们报告了对健康人志愿者全身性给药的这一化学类ASO的随机安慰剂对照剂量范围研究的可用数据综合评估。第一，我们比较了GalNAc3偶联的PS修饰的2'MOE ASO与可用于血浆分析物的母体PS修饰的2'MOE ASO的一部分的药代动力学和药效学特征。然后，我们通过标准化实验室测试中的信号发生率以及平均实验室测试结果随时间变化的剂量水平，评估全套GalNAc3偶联的PS修饰的2'MOE ASO偶联物的安全性。通过肝细胞靶向递送，GalNAc3偶联的PS修饰的2'MOE ASO亚组的ED50为4至10 mg /周，效力比亲代PS修饰的2'MOE ASO高30倍。没有GalNAc3偶联的PS修饰的2' 通过对单剂量或多剂量方案测试的所有剂量的综合实验室测试数据进行评估，确定了MOE ASO类效应。效力的提高支持了这种新的化学类别的ASO的安全边际的提高，目前正在临床上对此进行广泛研究。尽管在第一阶段的初始试验中总暴露量是有限的，但是正在进行的和将来的患者人群调查将支持评估长期暴露的影响。