Background: Oligonucleotides are relatively novel therapies; single strand nucleic acid polymers that can be used to alter gene expression via various mechanisms. New chemical or biological entities are required to undergo preclinical and clinical assessments to profile their QT liability. While monoclonal antibodies most often obtain thorough QT (TQT) study waivers due to their large size, a consensus on oligonucleotides has yet to be reached. This review seeks to identify nonclinical and clinical aspects of consideration regarding risk of QT prolongation with oligonucleotides. Methods: With regards to risk of QT prolongation, literature was reviewed in accordance with the E14 and S7B Guidances1,2; requirements of nonclinical evidence (hERG assay and animal studies), clinical evidence (phase 1 studies), and concentration-QT analyses were summarized. Drug approval packages were also reviewed to understand frequency of granted TQT waivers and evidence supporting such waivers. Results: Of seven drug approval packages reviewed, six obtained a TQT waiver based on integrated nonclinical and clinical risk assessments, including phase 1 studies, hERG assays, animal studies, and exposure-responses (ER) analyses. Review of ER analyses in ten oligonucleotides demonstrated no evidence for QT prolongation associated with increasing plasma concentrations. Conclusion: This review provided overwhelming collected evidence which suggests the lack of potential for QT prolongation by oligonucleotides. As such, consideration should be given as to the process for obtaining a TQT waiver for oligonucleotides, and whether adequately conducted nonclinical and clinical assessments may provide evidence to waive the need for TQT studies for oligonucleotides.
1. U. S. Food and Drug Administration/Center for Drug Evaluation and Research. (2012). E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. 2. U. S. Food and Drug Administration/Center for Drug Evaluation and Research. (2012). S7B Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals
