PII-128 - NOVEL NONLINEAR POPULATION PHARMACOKINETIC MODEL OF IMETELSTAT, A FIRST-IN-CLASS OLIGONUCLEOTIDE TELOMERASE INHIBITOR

M. González Sales¹, A. Lennox², F. Huang³, C. Pamulapati³, Y. Wan³, L. Sun³, T. Berry³, M. Kelly Behrs³, F. Feller³, P. Morcos⁴; ¹Allucent, Modeling Great Solutions, ²Allucent, ³Geron Corporation, ⁴Morcos Pharmaceutical Consulting, LLC.

Background: Imetelstat is a novel, first-in-class, 13-mer N3'→P5' thio-phosphoramidate oligonucleotide telomerase inhibitor in development for the treatment of hematologic malignancies including myelodysplastic syndromes (MDS). A comprehensive population PK (popPK) model was developed to quantitatively describe imetelstat PK and identify and quantify covariates which contribute to its PK variability.

Methods: A popPK model was developed using pooled data from 424 patients with solid tumors or hematologic malignancies from 7 clinical studies, including the pivotal Phase 2/3 MDS3001 study in patients with MDS (NCT02598661). Patients received intravenous infusion of imetelstat at various dose levels (0.4 mg/kg to 11.7 mg/kg) and schedules (qw to q4w). Covariate analysis included demographic, disease, laboratory, organ function, and anti-drug antibody (ADA) related factors. Serial and sparse plasma PK data were analyzed using NONMEM v7.4. The model was qualified using predictive checks.

Results: Imetelstat PK was described by a 2-compartment nonlinear disposition model with saturable binding/distribution and dose- and time-dependent elimination from the central compartment (Figure). Imetelstat PK increased in a greater than dose proportional manner. Theory-based allometric scaling for body weight was included on disposition parameters. The final covariates included sex, time, malignancy type, and dose on clearance (CL); malignancy type and sex on central volume of distribution; and malignancy type and spleen volume on total concentration of target. CL in females was modestly lower, resulting in non-clinically relevant increases ( < 30% increase) in predicted exposure relative to males. No effects on imetelstat PK were identified for mild to moderate hepatic or renal impairment, age, race, and ADA status. All model parameters were estimated with adequate precision (RSE < 30%). Visual predictive checks confirmed the capacity of the model to describe the data.

Conclusion: A popPK model was established for the novel oligonucleotide, imetelstat. The analysis supports a body-weight based dosing approach and no starting dose adjustments in mild to moderate renal or hepatic impairment. Individual exposure metrics can be reliably derived for exposure-response analyses in the MDS population.