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

Citations Over TimeTop 10% of 2024 papers

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.

Related Papers

• → Telomerase: cellular immortalization and neoplastic transformation. Multiple functions of a multifaceted complex(2008)34 cited
• → Genetic changes associated with telomerase activity in breast cancer(1999)33 cited
• → Clonal Heterogeneity in Telomerase Activity and Telomere Length in Tumor‐Derived Cell Lines(2000)2 cited
• [Telomere lengths and telomerase activity in liposarcomas].(1998)
• → Therapeutic Targets and Drugs I: Telomerase and Telomerase Inhibitors(2009)