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

Area of Science:

• Pharmacology and Toxicology
• Cardiovascular Safety
• Oncology Drug Development

Background:

• Imetelstat is a novel oligonucleotide telomerase inhibitor.
• Evaluation of proarrhythmic potential is crucial for drug safety.
• Myelodysplastic syndromes (MDS) are a group of cancers in which immature blood cells do not mature or become healthy blood cells.

Purpose of the Study:

• To assess the proarrhythmic potential of imetelstat.
• To evaluate the effect of imetelstat on cardiac repolarization (QTc interval).
• To integrate nonclinical and clinical data for a comprehensive risk assessment.

Main Methods:

• In vitro assessment of hERG channel current inhibition.
• In vivo cardiovascular parameter monitoring in cynomolgus monkeys.
• Ventricular repolarization substudy in the IMerge Phase III trial for lower-risk MDS patients, including intensive ECGs and pharmacokinetic analyses.

Main Results:

• Imetelstat did not inhibit the hERG channel in vitro.
• No treatment-related changes in cardiac parameters or QTc interval (QTcF) were observed in monkeys.
• In MDS patients, imetelstat showed no significant effect on QTcF at therapeutic doses, with a predicted change of 2.36 ms at Cmax.

Conclusions:

• Nonclinical studies indicated no proarrhythmic risk at exposures significantly higher than therapeutic levels.
• Clinical evaluations demonstrated no clinically significant effect of imetelstat on the QTc interval or other ECG parameters.
• The integrated risk assessment supports a low proarrhythmic potential for imetelstat.