In hematologic malignancies
Imetelstat: a first-in-class telomerase inhibitor
TelomeraseA key target for anti-cancer therapeutics.
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.
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 ChemistryImetelstat uses proprietary nucleic acid chemistry.
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.
In the Phase 2 ET trial, long-term administration of imetelstat was generally well tolerated. One patient discontinued the trial due to drug-related Grade 1 and 2 constitutional adverse events and Grade 1 gastrointestinal adverse events. The majority of the non-hematologic adverse events were mild to moderate in severity, with the most frequently assessed imetelstat-related adverse events reported by investigators being gastrointestinal events and fatigue. No drug-related Grade 4 non-hematologic adverse events were reported. Three patients had Grade 4 neutropenia, but no cases of febrile neutropenia have been reported. No thromboembolic events or bleeding events associated with thrombocytopenia have been reported. At least one abnormal liver function test, or LFT, was observed in laboratory findings in all patients. The majority were Grade 1 elevations in alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST; two Grade 3 increases in ALT/AST were reversible on dose reduction. With longer dosing, Grade 1 increases in alkaline phosphatase were observed, associated with mostly Grade 1 to some Grade 2 unconjugated hyperbilirubinemia. LFT abnormalities do not appear to progressively worsen over time.
Although the Phase 2 ET trial is no longer enrolling patients, we are continuing to treat and follow the remaining patients on study. The high hematologic and molecular response rates led us to explore the feasibility of further development of imetelstat in ET. However, based on our own analysis and after consulting with medical experts, we plan to pursue other hematologic myeloid malignancies, such as MF, where there is an unmet medical need for a product that could potentially be disease-modifying.
Clinical Development of Imetelstat in Myelofibrosis
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 ClinicalTrials.gov 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.
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.
Geron-Sponsored Phase 2 Clinical Trial in Myelofibrosis
The next step we plan to undertake in this development process is to initiate a Geron-sponsored multi-center, Phase 2 clinical trial of imetelstat in patients with MF. The planned Geron-sponsored Phase 2 clinical trial will be conducted across multiple treating centers and across multiple geographic regions, and is being designed to evaluate whether the results observed in the Myelofibrosis IST are reproducible and not limited to a single treating center. A primary goal for the planned Geron-sponsored Phase 2 clinical trial is to characterize the parameters appropriate for one or more potential randomized Phase 3 clinical trials that could be designed to potentially support full regulatory approval. These parameters include defining the appropriate dosing regimen of imetelstat for MF patients, and defining and validating key components of a composite remission efficacy endpoint based on modifications of the IWG-MRT criteria. We expect to initiate the planned Geron-sponsored Phase 2 clinical trial in MF in the first half of 2014, with preliminary data expected to be available in mid-2015.
Potential Clinical Development in Other Hematologic Myeloid Malignancies
The Myelofibrosis IST has also enrolled additional patients to evaluate imetelstat in other hematologic myeloid malignancies, including MF patients that have transformed to AML (blast-phase MF) and patients with refractory anemia with ringed sideroblasts (RARS), a subpopulation of MDS. Data we receive from these additional patients will inform, in part, our decision to initiate one or more potential pilot studies in AML or MDS.
- ASH 2013: Myelofibrosis (MF) IST (Investor Event)
- EHA 2013: Essential Thrombocythemia (ET) Phase 2
- AACR 2013: NSCLC overall analysis
- AACR 2013: NSCLC short telomere tumor subgroup analyses
- ASH 2012: Essential Thrombocythemia
- AACR 2012
- ASH 2011
- AACR-NCI-EORTC 2011
- ASCO 2010
- AACR-NCI-EORTC 2010
- AACR-NCI-EORTC 2009
- Roeth A, Harley CB, Baerlocher GM. Imetelstat (GRN163L) – Telomerase-based cancer therapy. Recent Results in Cancer Research 2010; 184:221-34.
- 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.
- 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).
- 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.
- 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.
- Harley CB. Telomerase and cancer therapeutics. Nature Reviews Cancer 2008; 8:167-179.
- 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.
In hematologic malignancies