Originally known as GRN163L, imetelstat sodium (imetelstat) is a small oligonucleotide, composed of a nucleic acid and a lipid moiety. The proprietary nucleic acid backbone provides resistance to degradation, thus conferring improved stability in plasma and tissues, as well as significantly improved binding affinity to its target. The lipid group enhances cell permeability which results in increased potency and improved 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.
Clinical Experience with Imetelstat
Over 600 patients have been enrolled and treated in imetelstat clinical trials.
We recently completed two Phase 2 clinical trials of imetelstat in lower risk MDS and relapsed/refractory myelofibrosis:
- IMerge: Imetelstat Achieves Meaningful and Durable Transfusion Independence in High Transfusion–Burden Patients With Lower-Risk Myelodysplastic Syndromes in a Phase II Study. Steensma, et al., Journal of Clinical Oncology 2021
- IMbark: Randomized, Single-Blind, Multicenter Phase II Study of Two Doses of Imetelstat in Relapsed or Refractory Myelofibrosis. Mascarenhas, et al., Journal of Clinical Oncology 2021
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. We believe that these cytopenias are manageable and reversible with limited clinical consequences.
Current Clinical Trials
Geron is currently conducting two Phase 3 clinical trials of imetelstat with registrational intent: IMerge, a Phase 2/3 trial in lower risk myelodysplastic syndromes (MDS), and IMpactMF, a Phase 3 trial in refractory myelofibrosis (MF).