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

Sep 21, 2026

Uploaded by Quinn

Most cancers and neoplastic progenitor cells show elevated telomerase activity and preserved telomeres that enable cellular immortality, making telomerase a rational cancer target. Imetelstat is a first-in-class 13-mer oligonucleotide that binds the RNA template region of human telomerase with high affinity and competitively inhibits telomerase enzymatic activity. Pharmacokinetics, pharmacodynamics, exposure-response, efficacy, and safety were assessed across in vitro, in vivo, and clinical studies, including LR-MDS and myeloproliferative neoplasms. Approved in the US in June 2024 for adult LR-MDS with transfusion-dependent anemia, it showed red-blood-cell transfusion independence and a manageable safety profile mainly featuring short-lived neutropenia and thrombocytopenia.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages15

Reading Time38 min

AccessFree to download

Introduction

Imetelstat mechanism of action

Drug regulatory approval

Clinical development and evidence

DOI: 10. 1111/cts.70076 MINI REVIEW Imetelstat, a novel, first-in-class telomerase inhibitor: Mechanism of action, clinical, and translational science Ashley L. Lennox1 | Fei Huang1 | Melissa Kelly Behrs1 | Mario González-Sales2,3 | Neha Bhise3 | Ying Wan1 | Libo Sun1 | Tymara Berry1 | Faye Feller1 | Peter N. Morcos4 1Geron Corporation, Foster City, CA, USA 2Modeling Great Solutions Pharmaceutical Research & Studies, FZE, Dubai, UAE 3Allucent, Cary, North Carolina, USA 4Morcos Pharmaceutical Consulting, LLC, Marlboro, New Jersey, USA Correspondence Ashley L. Lennox, Geron Corporation, 919 E. Hillsdale Blvd, Suite 250, Foster City, CA 94404, USA. [Email:](Email: alennox@geron.com)[ alennox@geron.com](Email: alennox@geron.com) 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. INTRODUCTION Telomeres are repetitive DNA sequences located at the end of chromosomes that are reduced during cell division in somatic cells.1 After a set number of divisions, telomere length (TL) is shortened to a critical limit, and further cell division is prevented, leading to cell senescence or apoptosis.1 Cancer development is frequently accompanied by the preservation of TL.2 This often results from the reactivation of telomerase caused by the This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2024 Geron Corporation. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics. Clin Transl Sci. 2024;17:e70076 . [https://doi.org/10.1111/cts.70076](https://doi.org/10.1111/cts.70076) [www.cts-journal.com](www.cts-journal.com) 1 of 15 upregulation of human telomerase reverse transcriptase (hTERT) expression.3 Reactivation of telomerase and increased telomerase activity (TA) is believed to be critical for tumor progression as it enables cancer cells to maintain TL, acquire cellular immortality, and avoid apoptosis.4 The ribonucleoprotein enzyme, telomerase, functions by adding the telomeric repeats onto chromosomes at the 3 ′ ends.5 Telomerase comprises a functional RNA component (hTR), an 11 base pair sequence that acts as a template for telomeric DNA

FAQs

Why is telomerase considered a rational target in cancer treatment?

Telomerase helps cancer cells preserve telomere length and support cellular immortality, enabling tumor progression. Many cancers show increased telomerase activity correlated with disease stage.

How does imetelstat inhibit telomerase enzymatic activity?

Imetelstat is a 13-mer oligonucleotide that binds with high affinity to the template region of the RNA component of human telomerase, acting as a competitive inhibitor of telomerase activity.

What was the key regulatory approval indication and dosing in June 2024?

In the US, imetelstat was approved for adults with low- to intermediate-1 risk LR-MDS with transfusion-dependent anemia requiring four or more RBC units over 8 weeks who meet specified criteria regarding response or eligibility to erythropoiesis-stimulating agents. The recommended regimen is 7.1 mg/kg given as a 2-hour intravenous infusion every 4 weeks.

Sep 21, 2026

Uploaded by Quinn