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

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 (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 (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), 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 C_max. 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.