Department of Pharmaceutical Sciences, School of Pharmacy (F.A., K.Z., H.W., T.P.R., R.B., X.Z., J.E.M.), and Department of Physiology and Neurobiology (R.P.), University of Connecticut, Storrs, Connecticut.
Department of Pharmaceutical Sciences, School of Pharmacy (F.A., K.Z., H.W., T.P.R., R.B., X.Z., J.E.M.), and Department of Physiology and Neurobiology (R.P.), University of Connecticut, Storrs, Connecticut
Drug Metab Dispos. 2022 Jun;50(6):879-887. doi: 10.1124/dmd.121.000418. Epub 2022 Feb 27.
The market for large molecule biologic drugs has grown rapidly, including antisense oligonucleotide (ASO) drugs. ASO drugs work as single-stranded synthetic oligonucleotides that reduce production or alter functions of disease-causing proteins through various mechanisms, such as mRNA degradation, exon skipping, and ASO-protein interactions. Since the first ASO drug, fomivirsen, was approved in 1998, the U.S. Food and Drug Administration (FDA) has approved 10 ASO drugs to date. Although ASO drugs are efficacious in treating some diseases that are untargetable by small-molecule chemical drugs, concerns on adverse drug reactions (ADRs) and toxicity cannot be ignored. Illustrative of this, mipomersen was recently taken off the market due to its hepatotoxicity risk. This paper reviews ADRs and toxicity from FDA drug labeling, preclinical studies, clinical trials, and postmarketing real-world studies on the 10 FDA-approved ASO drugs, including fomivirsen and pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, and casimersen. Unique and common ADRs and toxicity for each ASO drug are summarized here. The risk of developing hepatotoxicity, kidney toxicity, and hypersensitivity reactions co-exists for multiple ASO drugs. Special precautions need to be in place when certain ASO drugs are administrated. Further discussion is extended on studying the mechanisms of ADRs and toxicity of these drugs, evaluating the existing physiologic and pathologic states of patients, optimizing the dose and route of administration, and formulating personalized treatment plans to improve the clinical utility of FDA-approved ASO drugs and discovery and development of new ASO drugs with reduced ADRs. SIGNIFICANCE STATEMENT: The current review provides a comprehensive analysis of unique and common ADRs and the toxicity of FDA-approved ASO drugs. The information can help better manage the risk of severe hepatotoxicity, kidney toxicity, and hypersensitivity reactions in the usage of currently approved ASO drugs and the discovery and development of new and safer ASO drugs.
大分子生物制药市场发展迅速，其中包括反义寡核苷酸（ASO）药物。ASO 药物作为单链合成寡核苷酸，通过多种机制降低致病蛋白的产生或改变其功能，例如 mRNA 降解、外显子跳跃和 ASO-蛋白相互作用。自 1998 年首个 ASO 药物福米韦森获批以来，截至目前，美国食品和药物管理局（FDA）已批准了 10 种 ASO 药物。尽管 ASO 药物在治疗某些小分子化学药物无法靶向的疾病方面具有疗效，但不能忽视对药物不良反应（ADR）和毒性的关注。例如，米泊美生因肝毒性风险而最近被撤出市场。本文综述了 FDA 药物标签、临床前研究、临床试验和上市后真实世界研究中，10 种 FDA 批准的 ASO 药物（包括福米韦森和贝伐珠单抗、米泊美生、那西妥单抗、依替膦酸、地夫可特、依特司伦、戈洛多辛、维立西呱和卡司美生）的 ADR 和毒性。本文总结了每种 ASO 药物的独特和常见 ADR 和毒性。多种 ASO 药物存在肝毒性、肾毒性和过敏反应风险。在使用某些 ASO 药物时需要特别注意。本文还进一步讨论了研究这些药物 ADR 和毒性机制、评估患者现有生理和病理状态、优化剂量和给药途径以及制定个性化治疗方案的必要性，以提高 FDA 批准的 ASO 药物的临床应用价值，并开发减少 ADR 的新型 ASO 药物。
本综述提供了对 FDA 批准的 ASO 药物的独特和常见 ADR 及毒性的全面分析。这些信息有助于更好地管理目前批准的 ASO 药物使用中严重肝毒性、肾毒性和过敏反应的风险，以及新的和更安全的 ASO 药物的发现和开发。
