Low Proarrhythmic Risk of Imetelstat, a Novel Oligonucleotide Telomerase Inhibitor: A Translational Analysis

作者：Ashley L. Lennox, Libo Sun, Fei Huang, Melissa Kelly Behrs, Robert Kleiman, Hongqi Xue, Neha Bhise, Ying Wan, Tymara Berry, Faye Feller, Peter N. Morcos · 发表于：Clinical and Translational Science · 年份：2025 · DOI：10.1111/cts.70169 · 被引用次数：3 · 研究领域：Telomeres, Telomerase, and Senescence、Advanced biosensing and bioanalysis techniques、Acute Myeloid Leukemia Research

ABSTRACT 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 (IC 50 > 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 (C max ) 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...