Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science

Abstract

Most cancers and neoplastic progenitor cells have elevated telomerase activity and preservation of telomeres that promote cellular immortality, making telomerase a rational target for the treatment of cancer. Imetelstat is a first-in-class, 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase and acts as a competitive inhibitor of human telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response analyses, efficacy, and safety of imetelstat have been evaluated in vitro, in vivo, and clinically in solid tumor and hematologic malignancies, including lower-risk myelodysplastic syndromes (LR-MDS) and myeloproliferative neoplasms. Imetelstat was approved in the United States in June 2024 for the treatment of adult patients with LR-MDS with transfusion-dependent anemia requiring four or more red blood cell units over 8 weeks who have not responded to or have lost response to or are ineligible for erythropoiesis-stimulating agents, with a recommended dosing regimen of 7.1 mg/kg administered via 2-h intravenous infusion every 4 weeks. In the pivotal trial, significantly more patients treated with imetelstat versus placebo achieved ≥8-week and ≥24-week red blood cell-transfusion independence, and imetelstat was associated with a manageable safety profile characterized primarily by short-lived and manageable neutropenia and thrombocytopenia. This mini-review summarizes the mechanism of action, pharmacokinetic and pharmacodynamic characteristics, clinical development, and clinical efficacy and safety data of imetelstat.

FIGURE 1

Imetelstat mechanism of action. MDS, myelodysplastic syndromes.

FIGURE 2

Imetelstat dose‐normalized C _max (a) and AUC_inf (b) across the 0.4–11.0 mg/kg dose range; PK profile after administration of 7.1 mg/kg in patients with LR‐MDS (c) and distribution of EOI values after repeated 7.1 mg/kg q4w administration in patients with LR‐MDS (d). Panels a and b are boxplots of observed dose‐normalized C _max and AUC_inf estimated with noncompartmental analysis using data after administration of a single dose of imetelstat 0.4–11.0 mg/kg over 2‐h i.v. infusion in patients with STs (study CP05‐101), ET/PV (study CP14B015), MF (study MYF2001), or LR‐MDS (study MDS3001). Panel c shows the imetelstat concentration–time profile in a typical patient with LR‐MDS receiving imetelstat 7.1 mg/kg in cycle 1 derived from the final imetelstat population PK model. Panel d is a boxplot of observed imetelstat EOI concentrations in patients with LR‐MDS receiving imetelstat 7.1 mg/kg q4w in study MDS3001. AUC_inf, area under the csoncentration–time curve from 0 days to infinity; C _max, maximum plasma concentration; EOI, end of infusion; ET/PV, essential thrombocythemia/polycythemia vera; i.v., intravenous; LLOQ, lower limit of quantification (0.588 μg/mL); LR‐MDS, lower‐risk myelodysplastic syndromes; MF, myelofibrosis; PK, pharmacokinetic; q4w, every 4 weeks; ST, solid tumor.

FIGURE 3

Exposure‐response relationships for imetelstat efficacy and safety after administration of imetelstat 7.1 mg/kg q4w in patients with LR‐MDS. Figure illustrates results from univariate logistic regression models evaluating the probability of each efficacy or safety event and imetelstat exposure in the study IMerge/MDS3001. Efficacy or safety events are reported in the header, y axis depicts the proportion of patients with (reported at 1) or without (reported at 0) the event, and x axis reports the imetelstat exposure metric. The results of the linear logistic regression model along with the 95% confidence interval are illustrated in the black line and gray shading. Line and whisker plots illustrate the observed proportion of patients reporting the event within each quartile of imetelstat exposure and 90% confidence intervals. Statistical significance was evaluated by chi‐square statistic and confirmed against the null model using the likelihood ratio test. C _avg, average concentration; C _max, maximum concentration; LR‐MDS, lower‐risk myelodysplastic syndromes; q4w, every 4 weeks.