The development process of antisense oligonucleotides (ASOs) as therapeutic agents in humans has advanced through the implementation of chemical compound modifications as well as increasingly sophisticated toxicological preclinical screening techniques. The Ionis Integrated Safety Database was utilized to determine if advances in ASO screening and clinical lead identification methods have improved the tolerability profiles of 2′-O-methoxyethyl (2′MOE)-modified ASOs as a class, relative to the first 2′MOE ASO approved for use in humans, mipomersen. Tolerability was assessed by the incidence and percentage of subcutaneous doses leading to adverse events at the injection site or flu-like reactions (FLRs), as well as by the incidence of dose discontinuations due to these events. In randomized placebo-controlled phase 1 and phase 2 trials, the incidence of each measure of tolerability was lower in the test group of 12 ASOs (713 ASO-treated subjects) compared with the reference, mipomersen (266 ASO-treated subjects); with the most marked reduction in the incidence of FLRs (0.6% vs. 9.4%). A similar reduction in the incidence of dose discontinuation due to FLRs was also observed (0.2% vs. 0.9%). When compared with mipomersen, 8 of 12 ASOs showed significant improvements in their respective mean percentage of doses leading to adverse events at the injection site, whereas 7 ASOs showed a significant improvement in mean percentage of doses leading to FLRs. These results support an overall improvement in the tolerability profile in 2′MOE ASOs that entered development after mipomersen, in parallel with advances in the drug discovery screening process as well as the gains in clinical experience during development of each ASO.

中文翻译：

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2'-O-甲氧基乙基嵌合反义寡核苷酸耐受性的改善与设计、筛选和其他方法的进步并行

通过实施化合物修饰以及日益复杂的毒理学临床前筛选技术，反义寡核苷酸 (ASO) 作为人类治疗剂的开发过程取得了进展。Ionis 综合安全数据库用于确定 ASO 筛查和临床先导识别方法的进展是否提高了 2'- O的耐受性- 甲氧基乙基 (2'MOE) 修饰的 ASO 作为一类，相对于第一个批准用于人类的 2'MOE ASO，mipomersen。耐受性通过皮下剂量导致注射部位不良事件或流感样反应 (FLR) 的发生率和百分比，以及由于这些事件导致的剂量中断发生率来评估。在随机安慰剂对照的 1 期和 2 期试验中，与参考 mipomersen（266 名 ASO 治疗的受试者）相比，12 名 ASO（713 名接受 ASO 治疗的受试者）的测试组中每种耐受性测量的发生率较低；FLR 的发生率下降最为显着（0.6% 对 9.4%）。还观察到由于 FLR 导致的剂量中断发生率也有类似的降低（0.2% 对 0.9%）。与米泊默森相比，12 个 ASO 中有 8 个在导致注射部位不良事件的各自平均剂量百分比上有显着改善，而 7 个 ASO 在导致 FLR 的平均剂量百分比上有显着改善。这些结果支持在 mipomersen 之后进入开发阶段的 2'MOE ASO 的耐受性总体改善，同时药物发现筛选过程的进展以及每个 ASO 开发过程中临床经验的增加。