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Low Proarrhythmic Risk of Imetelstat, a Novel Oligonucleotide Telomerase Inhibitor: A Translational Analysis
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Low Proarrhythmic Risk of Imetelstat, a Novel Oligonucleotide Telomerase Inhibitor: A Translational Analysis
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Journal Article
Low Proarrhythmic Risk of Imetelstat, a Novel Oligonucleotide Telomerase Inhibitor: A Translational Analysis
2025
Overview
Evaluation of the proarrhythmic potential of imetelstat, a novel oligonucleotide telomerase inhibitor, in nonclinical and clinical studies is presented. In vitro, imetelstat sodium ≤ 750 μg/mL and negative (vehicle) and positive (cisapride) controls were evaluated for hERG channel current inhibition. In vivo, cynomolgus monkeys received a single vehicle control or imetelstat sodium (5 mg/kg [2‐h infusion], 10 mg/kg [6‐h infusion], or 15 mg/kg [6‐ or 24‐h infusion]); cardiovascular parameters were collected before and after drug administration. A ventricular repolarization substudy of the IMerge phase III study evaluated patients with lower‐risk myelodysplastic syndromes administered imetelstat 7.1 mg/kg active dose every 4 weeks; intensive electrocardiograms and pharmacokinetic samples were collected for concentration‐QTc and by‐time point analyses after a single dose. In vitro, imetelstat did not inhibit the hERG channel (IC50 > 750 μg/mL). In monkeys, imetelstat demonstrated no treatment‐related changes in cardiac parameters, including QTc using Fridericia correction (QTcF). In the IMerge QTc substudy, 45 patients received imetelstat (n = 29) or placebo (n = 16). The concentration‐QTc relationship was described by a linear mixed‐effects model; at the geometric mean maximum plasma concentration (Cmax) for imetelstat 7.1 mg/kg of 89.5 μg/mL, the predicted effect on placebo‐corrected change from baseline QTcF was 2.36 ms (90% confidence interval, −3.04 to 7.76), supporting no evidence of QTcF prolongation. By‐time point analysis demonstrated no clinically significant effect of imetelstat on QTc. Nonclinical studies demonstrated no proarrhythmic risk at > 140× (in vitro) and > 2.6× (in vivo) imetelstat 7.1 mg/kg Cmax. Clinical evaluations showed no significant effects on QTcF or other electrocardiogram parameters at 7.1 mg/kg. Collectively, this integrated risk assessment supports the low proarrhythmic potential of imetelstat.
Publisher
John Wiley & Sons, Inc,Wiley
Subject
/ Aged
/ Anemia
/ Animals
/ Arrhythmias, Cardiac - chemically induced
/ Arrhythmias, Cardiac - diagnosis
/ Blood
/ Dose-Response Relationship, Drug
/ ECG
/ EKG
/ Enzymes
/ ERG1 Potassium Channel - antagonists & inhibitors
/ ERG1 Potassium Channel - metabolism
/ Female
/ Humans
/ in vitro
/ in vivo
/ Male
/ Oligonucleotides - administration & dosage
/ Oligonucleotides - adverse effects
/ Oligonucleotides - pharmacokinetics
/ Patients
/ phase 3
/ Placebos
/ Potassium channels (voltage-gated)
/ Sodium
/ Telomerase - antagonists & inhibitors
/ Translational Research, Biomedical
/ Tumors
