PII-050 - CLINICAL PHARMACOLOGY OF IMETELSTAT, A FIRST-IN-CLASS OLIGONUCLEOTIDE TELOMERASE INHIBITOR

A. Lennox¹, F. Huang², M. Kelly Behrs², C. Pamulapati², M. González Sales³, Y. Wan², L. Sun², T. Berry², F. Feller², P. Morcos⁴; ¹Allucent, ²Geron Corporation, ³Allucent, Modeling Great Solutions, ⁴Morcos Pharmaceutical Consulting, LLC.

Background: Imetelstat is a first-in-class, 13-mer N3'→P5' thio-phosphoramidate oligonucleotide telomerase inhibitor in development for hematologic malignancies. The clinical pharmacology (CP) program was evaluated in support of its optimal use to treat patients with lower risk myelodysplastic syndromes (MDS) at the proposed dose of 7.5 mg/kg IV q4w.

Methods: The CP program consists of nonclinical studies and clinical trials in patients with malignancies and is complemented by a population PK analysis (González Sales ASCPT 2024). Evaluations included characterization of single and multiple-dose PK, ADME properties, effects of intrinsic factors, drug-drug interaction (DDI) liability, QT prolongation potential, immunogenicity, and pharmacodynamics (PD).

Results: Following IV infusion, maximum plasma concentrations are reached by the end of infusion. Imetelstat AUC increases more than dose proportionally across doses of 0.4 to 11.7 mg/kg and does not accumulate following repeat dosing. PD changes were dose-dependent. Nonclinical studies demonstrate high protein binding (>94%) independent of concentration and rapid distribution from plasma to tissue. Similar to other oligonucleotides, imetelstat is not expected to be a substrate of CYP enzymes or transporters and is likely metabolized into fragments by tissue nucleases with components excreted in urine. Urine is the primary route of elimination followed by feces; unchanged imetelstat is not detected in urine. Imetelstat has an apparent plasma half life of 4.9 h. Imetelstat PK was described by a 2 compartment nonlinear disposition model. Body weight was included as a covariate, supporting the body weight-based dosing approach. The population PK analysis revealed no relevant effect of age, sex, race, or mild to moderate renal or hepatic impairment.

Based on in vitro studies and integrated clinical analyses, imetelstat has low potential for clinically meaningful DDIs. Nonclinical studies demonstrate low likelihood of QT prolongation; a dedicated clinical QT study is ongoing. Anti-drug antibodies developed at a low frequency in patients with MDS and had no impact on PK, efficacy, or safety.

Conclusion: The CP properties of imetelstat have been comprehensively characterized and are largely consistent with current knowledge of oligonucleotides