About Imetelstat

Originally known as GRN163L, imetelstat sodium (imetelstat) is a 13-mer N3’---P5’ thio-phosphoramidate (NPS) oligonucleotide that has a covalently bound 5’ palmitoyl (C16) lipid group. The proprietary nucleic acid backbone provides 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. The lipid group enhances cell permeability to increase potency and improve pharmacokinetic and pharmacodynamic properties. The compound has a long residence time in bone marrow, spleen and liver. Imetelstat binds with high affinity to the template region of the RNA component of telomerase, resulting in direct, competitive inhibition of telomerase enzymatic activity, rather than elicit its effect through an antisense inhibition of protein translation. Imetelstat is administered by intravenous infusion.


Imetelstat Bound to Telomerase

Preclinical Studies with Imetelstat

Prior to the start of clinical trials, a series of preclinical efficacy studies of imetelstat were conducted by Geron scientists and academic collaborators. These data showed that imetelstat:

  • Inhibits telomerase activity, and can shorten telomeres.
  • Inhibits the proliferation of a wide variety of tumor types, including solid and hematologic, in cell culture systems and rodent xenograft models of human cancers, impacting the growth of primary tumors and reducing metastases.
  • Inhibits the proliferation of malignant progenitor cells from hematologic cancers, such as multiple myeloma, myeloproliferative neoplasms and acute myelogenous leukemia.
  • Has additive or synergistic anti-tumor effect in a variety of cell culture systems and xenograft models when administered in combination with approved anti-cancer therapies, including radiation, conventional chemotherapies and targeted agents.

Clinical Experience with Imetelstat

Over 600 patients have been enrolled and treated in imetelstat clinical trials.

completed Phase 1 trials

Six clinical trials evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics both as a single agent and in combination with standard therapies in patients with solid tumors and hematologic malignancies:

  • Single agent studies of imetelstat were in patients with advanced solid tumors, multiple myeloma and chronic lymphoproliferative diseases. Combination studies with imetelstat were with bortezomib in patients with relapsed or refractory multiple myeloma, with paclitaxel and bevacizumab in patients with metastatic breast cancer, and with carboplatin and paclitaxel in patients with advanced non-small cell lung cancer (NSCLC).
  • Doses ranging from 0.5 mg/kg to 11.7 mg/kg were tested in a variety of dosing schedules ranging from weekly to once every 28 days.
  • The human pharmacokinetic profile was characterized in clinical trials of patients with solid tumors and chronic lymphoproliferative diseases. Single-dose kinetics showed dose-dependent increases in exposure with a plasma half-life (t1/2) ranging from 4-5 hours. Residence time in bone marrow is long (0.19-0.51 µM observed at 41-45 hours post 7.5 mg/kg dose).
  • Telomerase inhibition was observed in various tissues where the enzymes's activity was measurable.

completed Phase 2 trials

Imetelstat was studied in two randomized clinical trials, two single arm proof-of-concept studies and an investigator sponsored pilot study:

  • Randomized trials were conducted in combination with paclitaxel in patients with metastatic breast cancer and as maintenance treatment following a platinum-containing chemotherapy regimen in patients with NSCLC.
  • Single arm studies were conducted as a single agent or in combination with lenalidomide in patients with multiple myeloma and as a single agent in essential thrombocythemia (ET) or polycythemia vera (PV).
  • An investigator sponsored pilot study was conducted as a single agent in patients with myelofibrosis (MF) or myelodysplastic syndromes (MDS).
  • A Phase 2 clinical trial, IMbark, to evaluate two doses of imetelstat in Intermediate-2 or High-risk MF patients who are refractory to or have relapsed after treatment with a JAK inhibitor. 

Safety and Tolerability

The safety profile of imetelstat across the completed Phase 1 and 2 trials has been generally consistent. Reported adverse events (AEs) and laboratory investigations associated with imetelstat administration included cytopenias, transient prolonged activated partial thromboplastin time (aPTT; assessed only in Phase 1 trials), gastrointestinal symptoms, constitutional symptoms, hepatic biochemistry abnormalities, and infusion reactions. Dose limiting toxicities include thrombocytopenia and neutropenia.

A Focus on Hematologic Myeloid Malignancies

Early clinical data from the Phase 2 clinical trial in ET and the investigator sponsored pilot study in MF suggest imetelstat may have disease-modifying activity by suppressing the proliferation of malignant progenitor cell clones for the underlying diseases, and potentially allowing recovery of normal hematopoiesis in patients with hematologic myeloid malignancies.

Results from these trials were published in the New England Journal of Medicine:

Current Clinical Trials

Geron is currently conducting two Phase 3 clinical trials of imetelstat with registrational intent: IMerge, a Phase 2/3 trial in myelodysplastic syndromes (MDS), and IMpactMF, a Phase 3 trial in refractory myelofibrosis (MF). 


IMerge is an ongoing two-part Phase 2/3 clinical trial evaluating imetelstat in red blood cell (RBC) transfusion-dependent patients with lower risk MDS who are relapsed after or refractory to prior treatment with an erythropoiesis stimulating agent (ESA). Part 1 is a Phase 2, open-label, single-arm trial of imetelstat administered as a single agent by intravenous infusion, and is ongoing. The Phase 2 portion of IMerge is closed to new patients.

The Phase 3 portion of IMerge, or IMerge Phase 3, is a double-blind, randomized, placebo-controlled clinical trial that, based on discussions with U.S. and European regulatory authorities, we expect will support, if successful, the registration of imetelstat in lower risk MDS. The trial is designed to enroll approximately 170 patients with lower risk transfusion dependent MDS who are relapsed or refractory to an ESA, have not received prior treatment with either an HMA or lenalidomide and are non-del(5q). IMerge Phase 3 is open for patient screening and enrollment and is being conducted at over 100 medical centers globally, including North America, Europe, Middle East and Asia. Further information on IMerge Phase 3, including the trial design, patient eligibility criteria and locations of clinical sites, is posted on clinicaltrials.gov.

The primary efficacy endpoint of IMerge is the rate of red blood cell transfusion independence (RBC-TI) lasting at least eight weeks (8-week RBC-TI rate), which is defined as the proportion of patients who are transfusion free for at least eight consecutive weeks since entry into the trial. Key secondary endpoints include the rate of RBC-TI lasting at least 24 weeks and the rate of hematologic improvement-erythroid, or HI-E, defined as a rise in hemoglobin of at least 1.5 g/dL above the pretreatment level for at least eight weeks or a reduction of at least four units of RBC transfusions over eight weeks compared with the prior RBC transfusion burden.

Clinical Data from IMerge Phase 2 Differentiate Imetelstat in Lower Risk MDS

IMerge Phase 2 is an open label, single arm trial to assess the safety and efficacy of imetelstat in transfusion dependent lower risk MDS patients relapsed or refractory to ESAs. The primary and secondary endpoints in IMerge Phase 2 are identical to IMerge Phase 3. Recently, more mature data from 38 patients in IMerge Phase 2 were presented at the European Hematology Association Annual Congress in June 2020, American Society of Hematology Annual Meeting in December 2020 and were published in the Journal of Clinical Oncology in October 2020.

We believe these data indicate potential disease-modifying activity of imetelstat treatment, which we believe differentiates imetelstat from other currently approved and investigational treatments in lower risk MDS.

The safety profile in the IMerge Phase 2 was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified. Reversible cytopenias, without significant clinical consequences, were the most frequent adverse events. 


IMpactMF is an ongoing open label, 2:1 randomized, controlled Phase 3 clinical trial to evaluate imetelstat compared to best available therapy (BAT) in approximately 320 patients with Intermediate-2 or High-risk MF. Patients eligible for the trial will be required to be non-responsive, or refractory, to treatment with a JAK inhibitor. The primary efficacy endpoint for the Phase 3 trial is overall survival (OS). Secondary endpoints include symptom response, spleen response, progression free survival, duration of response, safety, pharmacokinetics and patient reported outcomes. We expect to engage over 180 sites to participate in IMpactMF across North America, South America, Europe, Australia and Asia. Further information on IMpactMF, including the trial design, patient eligibility criteria and locations of clinical sites, is posted on clinicaltrials.gov.

The final analysis for OS is planned to be conducted after more than 50% of the patients planned to be enrolled in the trial have died (each death called an “event”). An interim analysis of OS is planned to be conducted after approximately 70% of the total projected number of events for the final analysis have occurred. Both the planned interim and final analyses are event driven and could occur on different timelines than we currently expect.

IMpactMF opened for patient screening and enrollment in December 2020, and the first patient was dosed in April 2021.

Additional information about the status of these clinical trials can be found on our Investors pages.