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 500 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).

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

Imetelstat is currently being tested in two clinical trials: IMbark, a Phase 2 trial in myelofibrosis (MF), and IMerge, a Phase 2/3 trial in myelodysplastic syndromes (MDS). 


IMerge is an ongoing two-part Phase 2/3 clinical trial of imetelstat in red blood cell (RBC) transfusion-dependent patients with lower risk MDS who are refractory or resistant to 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. Part 2 is designed as a Phase 3, randomized, placebo-controlled trial. The Phase 3 IMerge clinical trial was opened for enrollment in August 2019, and the first patient was dosed in October 2019. 

The primary efficacy endpoint of the IMerge Phase 2/3 clinical trial 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.

32 patients were initially enrolled in the Phase 2 portion of IMerge, of which 13 patients had not received prior treatment with either a hypomethylating agent (HMA) or lenalidomide and did not have a deletion 5q chromosomal abnormality (non-del(5q)). Preliminary data from the Phase 2 portion of IMerge were presented at the European Hematology Association (EHA) Annual Congress in June 2018.  The data showed that the 13-patient initial cohort exhibited an increased rate and durability of transfusion independence compared to the overall trial population (8-week RBC-TI rate: 54% vs. 34%). 

To increase the clinical experience and confirm the benefit-risk profile of imetelstat in the initial 13-patient cohort, enrollment was expanded to include 25 additional patients in an expansion cohort who were non-del(5q) and naive to HMA and lenalidomide treatment. In November 2017, the first patient was dosed in the expanded Phase 2 portion of IMerge and enrollment was completed in February 2018. The Phase 2 portion of IMerge is closed to new patients.

Detailed results from the combined initial cohort of 13 patients and the expanded cohort of 25 patients (n=38) were presented at the European Hematology Association Annual Congress in June 2020

Meaningful and durable transfusion indepedence (TI):

  • High rates of TI and hematologic improvement-erythroid (HI-E):  42% 8-week TI rate and 68% HI-E rate
  • Durable TI and HI-E: Median duration of TI of 20 months and median duration of TI of 21 months

Potential disease-modifying activity:

  • 29% (11/38) of patients were transfusion-free for more than one year
  • 75% of 8-week TI responders had a hemoglobin rise of greater than or equal to 3g/dL from pretreatment level

The safety profile in the Phase 2 portion of IMerge 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 most frequent adverse events. 


IMbark is an ongoing Phase 2 clinical trial 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. The first patient in IMbark was dosed in September 2015 and the last patient was enrolled in October 2016. The trial has been officially closed to new patient enrollment since March 2018 and has entered an extension phase to enable patients remaining in the treatment phase to continue to receive imetelstat treatment, per investigator discretion. During the extension phase, standard data collection will primarily consist of safety information.

A protocol-specified primary analysis of IMbark was initiated in the second quarter of 2018. The IMbark protocol-specified primary analysis, which included an assessment of overall survival, or OS, coincided with the protocol-specified final analysis for the trial, which resulted in a primary/final analysis and is referred to as the primary analysis. The results of the primary analysis and updated data on OS were presented at the American Society of Hematology Annual Meeting in December 2018.

For the assessment of OS, the clinical cut-off date for the ASH presentation was October 22, 2018. The median follow-up was 27.4 months (range 0.2 - 33.0). The median OS for the high dose arm (9.4 mg/kg) was 29.9 months.

The safety profile was consistent with prior clinical trials of imetelstat in hematologic malignancies, and no new safety signals were identified.

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