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

A series of preclinical efficacy studies of imetelstat have been 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.

Phase 1

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.

Phase 2

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

Safety and Tolerability

The safety profile of imetelstat across the 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.

Hematologic Myeloid Malignancies

Early clinical data, including molecular responses in ET and remissions, including reversal of bone marrow fibrosis in MF, suggest imetelstat may have disease-modifying activity by inhibiting the proliferation of malignant progenitor cell clones for the underlying diseases.

Proof-of-Concept in Essential Thrombocythemia

A Phase 2 multi-center, single agent and open label trial was conducted in 18 patients with ET to provide proof-of-concept for the potential use of imetelstat as a treatment for hematologic myeloid malignancies, such as MF, MDS or AML. Published results (Baerlocher GM, et al. Telomerase Inhibitor Imetelstat in Patients with Essential Thrombocythemia. N Engl J Med. 2015 Sep 3; 373(10):920-8) are summarized as follows:

  • 18 of 18 patients (100%) achieved a hematologic response with a reduction in platelets, including 16 of 18 patients (89%) achieving a complete response with a normalization of platelet counts.
  • The median time on therapy was 17.1 months (range: 6.9 months to 2.7 years).
  • Seven out of the eight (88%) patients with a JAK2 V617F gene mutation achieved 72% to 96% reductions in allele burden and qualified as partial molecular responses.
  • MPL and CALR mutant allele burdens were also reduced by 15% to 66%.
  • The nature of adverse events reported were similar to those reported in other imetelstat clinical trials, with fatigue, gastrointestinal symptoms, hepatic biochemistry abnormalities and cytopenias being the most frequently observed.

Pilot Study in Myelofibrosis

An open label, single agent, investigator sponsored, pilot study of 33 patients with intermediate-2-risk or high-risk MF, including 16 who had received prior therapy with a JAK inhibitor, was conducted at a single center. Published results (Tefferi A, et al. A Pilot Study of the Telomerase Inhibitor Imetelstat for Myelofibrosis. N Engl J Med. 2015 Sep 3; 373(10):908-19) are summarized as follows:

  • Seven of 33 (21%) patients achieved a complete or partial remission, bone marrow fibrosis was reversed in all four patients who had a complete remission, and a molecular response also occurred in three of the four patients. Median duration of complete remission was 18 months (range: seven months to 20+ months).
  • Spleen responses (by palpation lasting greater than 12 weeks) were observed in eight of 23 (35%) patients. Spleen responses were observed in three of 11 (27%) patients from the JAK inhibitor experienced subgroup.
  • The most clinically significant adverse events were hematologic. Myelosuppression was the primary reason for the protocol-mandated dose reduction that occurred in 22 out of 33 patients (67%).

Pilot Study in Myelodysplastic Syndromes

An open label, single agent, investigator sponsored, pilot study of nine anemic patients with intermediate-1 or intermediate-2 risk MDS-RARS (refractory anemia with ring sideroblasts), including eight who were dependent on red blood cell transfusions and six who had received prior therapy with an ESA, was conducted at a single center. Published results (Tefferi A, et al. Imetelstat Therapy in Refractory Anemia with Ring Sideroblasts with or without Thrombocytosis. Blood Cancer Journal 2016 Mar online) are summarized as follows:

  • Three of eight (38%) transfusion dependent patients became transfusion independent, defined as not requiring transfusions for at least eight weeks. Median duration was 28 weeks (9, 28 and 37 weeks respectively).
  • Safety data were consistent with the pilot study in MF.

Current Clinical Trials

Imetelstat is currently being tested in two clinical trials: IMbark, a Phase 2 trial in MF, and IMerge, a Phase 2/3 trial in MDS. These clinical trials are being conducted by Janssen Biotech, Inc. under the terms of an exclusive worldwide collaboration and license agreement. Information about the status of these clinical trials can be found on our Investors pages.