Safety assessment of drug impurities is a routine part of the drug development process. For oligonucleotide-based drugs, impurities can arise from impurities in starting materials, as by-products of the manufacturing process or from degradation, and are generally structurally similar to the parent oligonucleotide. To study the potential impact of impurities, a representative batch of a 2'-O-methoxyethyl (MOE) antisense oligonucleotide (ASO) was compared to batches of drug that were enriched with nine of the common impurities encountered with the chemical class. Mice were treated for 3 months with weekly subcutaneous injection of 10 or 30 mg/kg. The impurity content of the parent batch was 0.25%-2.5% of total drug substance. The enriched impurity mixtures contained from 3% to 10% of the various impurities. The expected common class effects were observed at the 30 mg/kg/week dose level in hematology, serum chemistry, and histopathology. However, there were no differences between the representative batch of material and those enriched with impurities. Based on these data, common oligonucleotide impurity studies do not appear to contribute to the overall toxicology profile.

中文翻译：

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2'-O-甲氧基乙基修饰的反义抑制剂在小鼠中的杂质鉴定毒理学研究。

药物杂质的安全性评估是药物开发过程的常规部分。对于基于寡核苷酸的药物，杂质可能来自原材料中的杂质（作为制造过程的副产品）或降解，并且通常在结构上类似于亲本寡核苷酸。为了研究杂质的潜在影响，将代表批次的2'-O-甲氧基乙基（MOE）反义寡核苷酸（ASO）与富含9种常见化学类别杂质的药物批次进行了比较。每周皮下注射10或30mg / kg的小鼠治疗3个月。母料中的杂质含量为原料药总量的0.25％-2.5％。富集的杂质混合物包含3％至10％的各种杂质。在血液学，血清化学和组织病理学方面，以30 mg / kg /周的剂量水平观察到了预期的普通分类作用。但是，代表性物料与富集杂质的物料之间没有差异。根据这些数据，常见的寡核苷酸杂质研究似乎对总体毒理学特征没有贡献。