Imetelstat: a first-in-class telomerase inhibitor

Telomerase

A key target for anti-cancer therapeutics.
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Geron's anti-cancer strategy is to inhibit the activity of telomerase. Telomerase is a rational target for the treatment of cancer, because most cancers have a high level of telomerase activity and relatively short telomeres compared to normal cells.

Despite the clinical potential of telomerase as a target for developing new cancer treatments, small molecule telomerase inhibitors have not progressed to the clinic due to lack of potency or specificity.

About Imetelstat

We utilized our proprietary nucleic acid chemistry to develop imetelstat as a short, modified oligonucleotide that is a potent and specific inhibitor of telomerase.

Nucleic Acid Chemistry

Imetelstat uses proprietary nucleic acid chemistry.
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Imetelstat is a lipid-conjugated 13-mer oligonucleotide sequence that is complementary to and binds with high affinity to the RNA template of telomerase, thereby directly inhibiting telomerase activity. The compound has a proprietary thio-phosphoramidate backbone, which is designed to provide resistance to the effect of cellular nucleases, thus conferring improved stability in plasma and tissues, as well as significantly improved binding affinity to its target. To improve the ability of imetelstat to permeate through cellular membranes, we conjugated the oligonucleotide sequence to a lipid group. Imetelstat’s IC50, or half maximal inhibitory concentration, is 0.5-10nM in cell-free assays. The tissue half life of imetelstat, or the time it takes for the concentration or amount of imetelstat to be reduced by half, in bone marrow, spleen, liver and tumor has been estimated to be 41 hours in humans, based on data from animal studies and clinical trials. The tissue half life indicates how long a drug will remain present in the tissues, and a longer tissue half life may enable a drug to remain at effective doses for a longer period of time.

Imetelstat has been shown in preclinical studies to exhibit relatively preferential inhibition of clonal proliferation of malignant progenitor cells compared to normal progenitors. For this reason, imetelstat has been studied as a treatment for malignant diseases. Imetelstat is the first telomerase inhibitor to advance to clinical development. The Phase 1 trials that we completed evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of imetelstat. Doses and dosing schedules were established that were tolerable and achieved target exposures in patients that were consistent with those required for efficacy in animal models. Adverse events were generally manageable and reversible. The dose-limiting toxicities were thrombocytopenia and neutropenia. Following intravenous administration of imetelstat using tolerable dosing regimens, clinically relevant and significant inhibition of telomerase activity was observed in various types of tissue in which telomerase activity is measurable, including normal bone marrow hematopoietic cells, malignant plasma cells, hair follicle cells, and peripheral blood mononuclear cells.

Leading the Charge

Our groundbreaking science is the foundation of our innovative clinical program

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