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Drug Metabolism & Disposition

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Adverse Drug Reactions and Toxicity of the FDA-approved Antisense Oligonucleotide Drugs

Feryal Alhamadani, Kristy Zhang, Rajvi Parikh, Hangyu Wu, Theodore P Rasmussen, Raman Bahal, Xiao-bo Zhong and Jose E. Manautou PhD
Drug Metabolism and Disposition February 27, 2022, DMD-MR-2021-000418; DOI: https://doi.org/10.1124/dmd.121.000418
Feryal Alhamadani
1University of Connecticut, United States
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Kristy Zhang
1University of Connecticut, United States
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Rajvi Parikh
1University of Connecticut, United States
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Hangyu Wu
1University of Connecticut, United States
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Theodore P Rasmussen
1University of Connecticut, United States
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Raman Bahal
1University of Connecticut, United States
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Xiao-bo Zhong
2Pharmaceutical Sciences, University of Connecticut, United States
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  • For correspondence: jose.manautou@uconn.edu
Jose E. Manautou PhD
2Pharmaceutical Sciences, University of Connecticut, United States
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  • For correspondence: jose.manautou@uconn.edu
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Abstract

The market for large molecule biological 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. After the first ASO drug Fomivirsen was approved in 1998, the US Food and Drug Administration 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 post-marketing real-world studies on the ten 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 physiological and pathological 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.

  • antisense oligonucleotides
  • biologics
  • safety evaluation
  • toxicology
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 51 (2)
Drug Metabolism and Disposition
Vol. 51, Issue 2
1 Feb 2023
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Safety of Antisense Oligonucleotide Drugs

Feryal Alhamadani, Kristy Zhang, Rajvi Parikh, Hangyu Wu, Theodore P Rasmussen, Raman Bahal, Xiao-bo Zhong and Jose E. Manautou
Drug Metabolism and Disposition February 27, 2022, DMD-MR-2021-000418; DOI: https://doi.org/10.1124/dmd.121.000418

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Safety of Antisense Oligonucleotide Drugs

Feryal Alhamadani, Kristy Zhang, Rajvi Parikh, Hangyu Wu, Theodore P Rasmussen, Raman Bahal, Xiao-bo Zhong and Jose E. Manautou
Drug Metabolism and Disposition February 27, 2022, DMD-MR-2021-000418; DOI: https://doi.org/10.1124/dmd.121.000418
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