Imetelstat: a first-in-class telomerase inhibitor


A key target for anti-cancer therapeutics.
Learn more

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

As an alternative strategy, 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.
Learn more

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.

Developing Imetelstat to Treat Hematologic Myeloid Malignancies

Proof-of-Concept in Essential Thrombocythemia

In January 2011, we initiated a Phase 2 clinical trial of imetelstat in patients with ET. The Phase 2 ET trial was a multi-center, single arm, and open-label trial that we designed to provide proof-of-concept for the potential use of imetelstat as a treatment for hematologic myeloid malignancies, including MF, MDS and AML. The trial leveraged clinical observations from Phase 1 trials suggesting that imetelstat reduces platelet counts, as well as non-clinical observations that imetelstat distributes well to bone marrow in rodent models and selectively inhibits the proliferation of malignant progenitors ex vivo from patients with ET. Hematologic responses were measured by reductions in platelet counts, and molecular responses were measured by reductions in the JAK2 V617F mutant allele burden in circulating granulocytes as assessed by reduction in the proportion of the abnormal Janus kinase 2, or JAK2, gene compared to the normal, or wild type JAK2 gene. We believe a decrease in the proportion of the JAK2 V617F mutant relative to the wild type JAK2 is consistent with selective inhibition of the malignant progenitor cells responsible for the disease.

We presented top-line data from the Phase 2 ET clinical trial at the American Society of Hematology (ASH) annual meeting in December 2012 and at the Congress of the European Hematology Association (EHA) in June 2013. A total of 18 ET patients were enrolled into the study. Imetelstat induced platelet count reductions in all patients (a 100% hematologic response rate) and normalizations in 16 out of 18 patients (an 89% complete response rate). The JAK2 V617F gene mutation was detected in eight patients at baseline. Seven out of the eight (88%) patients achieved 72% to 96% reductions in JAK2 V617F allele burden that qualified as partial molecular responses within three to 12 months of treatment with imetelstat. Partial molecular responses were maintained in six of the seven (86%) patients, with a median follow-up of 9.5 months (range 0 to 19 months) after first achieving a response. As of the EHA Meeting in June 2013, the median durations of hematologic and molecular response had not yet been reached, and 11 patients remained on study, with the longest duration being three years. These data suggest that imetelstat inhibits the progenitor cells of the malignant clone believed to be responsible for the underlying disease in a relatively selective manner.

Adverse events reported in the Phase 2 ET trial have been similar to the adverse events reported in other imetelstat clinical trials, with fatigue, gastrointestinal symptoms (specifically nausea, diarrhea, constipation, and vomiting) and cytopenias being the most frequently observed adverse events. At least one abnormal LFT was observed in laboratory findings in all patients in this trial, with some patients experiencing persistent low grade LFT abnormalities with longer dosing. With longer dosing, Grade 1 increases in alkaline phosphatase were observed, associated with mostly Grade 1 to some Grade 2 unconjugated hyperbilirubinemia. The clinical significance, long-term consequences and reversibility of such persistent low grade LFT abnormalities is currently undetermined.

In March 2014, we received written notice from the U.S. Food and Drug Administration (FDA), that our Investigational New Drug application (IND) for imetelstat has been placed on full clinical hold following their review of data related to hepatotoxicity in our then-ongoing clinical studies. A full clinical hold is an order that the FDA issues to a trial sponsor to suspend all ongoing clinical trials and delay all proposed trials. With this clinical hold, any patients in an ongoing Geron-sponsored clinical trial cannot receive any further treatment with imetelstat. Therefore, we have stopped imetelstat treatment in our Phase 2 clinical trial in ET. We have previously announced that our Phase 2 ET trial was a mechanistic proof-of-concept study, and that we did not plan to develop imetelstat for commercial use in ET.

Investigator-Sponsored Clinical Trial in Myelofibrosis

Based on the data from the Phase 2 ET trial, in November 2012, Dr. Ayalew Tefferi of Mayo Clinic initiated an investigator-sponsored trial at Mayo Clinic evaluating imetelstat in myelofibrosis, which we refer to as the Myelofibrosis IST. The Myelofibrosis IST is an open-label trial in patients with primary MF (PMF), post-ET MF, or post-PV MF who have two to three risk factors (intermediate-2) or four or more risk factors (high risk) as defined by DIPSS Plus. In the Myelofibrosis IST, imetelstat is administered as a single agent through a two-hour intravenous infusion to patients in multiple patient cohorts. In the first cohort, Cohort A, imetelstat is given once every three weeks. In the second cohort, Cohort B, imetelstat is given weekly for four weeks, followed by one dose every three weeks. Under the protocol, patients in Cohorts A and B may receive an intensified dosing regimen, up to once per week after the initial six cycles of treatment. The starting dose of imetelstat in Cohorts A and B is 9.4mg/kg, with dose reductions and dose holds allowed for toxicity. The primary endpoint is overall response rate, which is defined by the proportion of patients who are classified as responders having achieved either a clinical improvement (CI), partial remission (PR), or complete remission (CR) according to the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Secondary endpoints include reduction of spleen size by palpation, improvement in anemia or inducement of red blood cell transfusion independence, safety and tolerability. Please visit for a trial summary. As of January 2014, the Myelofibrosis IST is closed to new patient enrollment.

At the ASH annual meeting in December 2013, the investigator presented preliminary efficacy data from the Myelofibrosis IST for the first 22 patients enrolled sequentially in Cohorts A and B, and preliminary safety data from the first 33 patients treated in the same two cohorts in the trial.

Click here to download a presentation summarizing our preliminary efficacy analysis of the first 22 MF patients enrolled in the study as of October 2013 and the investigator’s findings related to safety of the first 33 MF patients enrolled as presented at ASH.

In January 2014, the Myelofibrosis IST was closed to new patient enrollment. The remaining patients in the Myelofibrosis IST continue to receive imetelstat treatment and are being followed under the Myelofibrosis IST protocol.

Future Clinical Development in Myelofibrosis or Other Hematologic Myeloid Malignancies

We believe that the preliminary efficacy data from the first two cohorts in the Myelofibrosis IST suggest that imetelstat treatment may produce clinical improvement in certain MF patients, and also possibly partial or even complete remissions, which may include bone marrow normalization, peripheral blood morphologic remission and resolution of splenomegaly and constitutional symptoms for some period of time, and that imetelstat may have potential disease modifying activity by possibly affecting the underlying malignant progenitor cells in the bone marrow driving the disease. However, we will be required to demonstrate through multiple Geron-sponsored clinical trials, including larger scale randomized Phase 3 clinical trials, that imetelstat is safe and effective for use in a diverse population before we can seek to obtain regulatory approval for its commercial sale.

In January 2014, we announced that we were planning to initiate a Geron-sponsored multi-center, Phase 2 clinical trial of imetelstat in MF in mid-2014. However, until the FDA lifts the full clinical hold on our IND, described above, or partially lifts the clinical hold, for example by permitting us to study imetelstat in indications other than ET, we are unable to submit any new clinical trial protocols to the FDA under our IND for imetelstat and are unable to initiate any new clinical trials for imetelstat in the United States. Therefore, the initiation of this potential Geron-sponsored Phase 2 clinical trial will be delayed. We plan to work diligently with the FDA to seek the release of the full clinical hold.



  • Roeth A, Harley CB, Baerlocher GM. Imetelstat (GRN163L) – Telomerase-based cancer therapy. Recent Results in Cancer Research 2010; 184:221-34.
    Read publication
  • Marian CO, Cho SK, McEllin BM, Maher EA, Hatanpaa KJ, Madden CJ, Mickey BE, Wright WE, Shay JW, Bachoo RM. The telomerase antagonist, imetelstat, efficiently targets glioblastoma tumor-initiating cells leading to decreased proliferation and tumor growth. Clin Cancer Res. 2010 Jan 1;16(1):154-63.
    Read publication
  • Sarah K. Brennan, Qiuju Wang, Robert Tressler, Calvin Harley, Ning Go, Ekaterina Bassett, Carol Ann Huff, Richard J. Jones, William Matsui. Telomerase Inhibition Targets Clonogenic Multiple Myeloma Cells through Telomere Length-Dependent and Independent Mechanisms. PLoS One. 2010 Sep 1;5(9).
    Read publication
  • Immanual Joseph, Robert Tressler, Ekaterina Bassett, Calvin Harley, Christen M. Buseman, Preeti Pattamatta, Woodring E. Wright, Jerry W. Shay, and Ning F. Go. The Telomerase Inhibitor Imetelstat Depletes Cancer Stem Cells in Breast and Pancreatic Cancer Cell Lines. Cancer Res. 2010 Nov 15;70(22):9494-504.
    Read publication
  • Goldblatt EM, Gentry ER, Fox MJ, Gryaznov SM, Shen C, Herbert BS. The telomerase template antagonist GRN163L alters MDA-MB-231 breast cancer cell morphology, inhibits growth, and augments the effects of paclitaxel. Mol Cancer Ther. 2009 Jul;8(7):2027-35.
    Read publication
  • Harley CB. Telomerase and cancer therapeutics. Nature Reviews Cancer 2008; 8:167-179.
    Read publication
  • Hochreiter AE, Xiao H, Goldblatt EM, Gryaznov SM, Miller KD, Badve S, Sledge GW, Herbert BS. Telomerase template antagonist GRN163L disrupts telomere maintenance, tumor growth, and metastasis of breast cancer. Clin Cancer Res. 2006 May 15;12(10):3184-92.
    Read publication

Clinical Trials

In hematologic malignancies

Learn more


Form content here please :)