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 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. 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 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 manageable and reversible. The dose-limiting toxicities were thrombocytopenia and neutropenia. Clinically relevant and significant inhibition of telomerase activity was observed following administration of imetelstat 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, at tolerable dosing regimens.
From the results observed in our preclinical studies and Phase 1 clinical trials, we designed four Phase 2 clinical trials to study cancers for which we had supportive non-clinical data, evidence that the disease was driven by malignant progenitor cell proliferation, and in which imetelstat could be tested as a single agent treatment or in combination with cytotoxic chemotherapy. Based on these criteria, for our Phase 2 program, we selected two hematologic tumors: essential thrombocythemia (ET) and multiple myeloma, and two solid tumors: metastatic breast cancer and advanced non-small cell lung cancer (NSCLC). Data from this program, described below, has led us to pursue clinical development of imetelstat in hematologic myeloid malignancies.
Phase 2 Results: Essential Thrombocythemia
In June 2013 at the Congress of the European Hematology Association (EHA), we presented updated clinical results from the company’s Phase 2 trial of imetelstat in ET. The initial trial results from 14 patients with ET were presented at the American Society of Hematology (ASH) annual meeting in December 2012. The updated results, which showed robust hematologic and molecular responses in patients treated with imetelstat, included data for an additional six months of treatment and follow-up for the original 14 patients, as well as data from four additional patients enrolled in the trial after the data cut-off for the ASH presentation.
Clinical Trial Design and Rationale
The multi-center, single arm, open-label Phase 2 trial of imetelstat in patients with ET was designed to provide proof-of-concept for the potential use of the drug as a treatment for hematologic myeloid malignancies, including myelofibrosis (MF), myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). The trial leveraged clinical observations from Phase 1; i.e., 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. Published non-clinical data also suggest elevated telomerase activity in malignant progenitors and shorter telomeres in granulocytes from patients with MPNs compared to healthy controls.
The primary endpoint of the trial was hematologic response and the secondary endpoints included molecular response and safety. Hematologic responses were measured by reductions in platelet counts, which are elevated in patients with ET. Molecular mutations, such as JAK2 V617F, which occur in 50% of patients with ET and are believed to be acquired in malignant clonal progenitor cells, can be used as molecular markers of disease burden. Therefore, molecular responses were measured by reductions in JAK2 V617F allelic burden compared to the normal, or wild type, JAK2 gene in circulating granulocytes. A decrease in the proportion of JAK2 V617F relative to wild type JAK2 is consistent with selective inhibition of the neoplastic progenitor cells responsible for the disease. Hematologic and molecular responses were graded using adapted European LeukemiaNet criteria, as defined by Barosi, et al, in the journal Blood (2009).
Clinical Trial Status
The trial was closed to enrollment in December 2012, with a total of 20 patients enrolled: 18 with ET and two with polycythemia vera (PV). Results for efficacy were presented from all 18 ET patients enrolled in the trial, with a median time on imetelstat treatment of 14 months (range 3 months to 2.5 years), as of a May 2013 data cut-off date. At this data cut-off date, there was insufficient efficacy follow-up data available from the two patients with PV, but follow-up data for safety were included. The presentation at the ASH annual meeting in December 2012 reported data as of an October 2012 cut-off date from the first 14 ET patients, with a median time on imetelstat treatment of eight months. Under the protocol, the approved duration of treatment is up to three years.
All 18 ET patients were refractory to, intolerant of or had refused conventional therapies (hydroxyurea, anagrelide and/or interferon-alpha). Platelet counts were reduced in all patients (a 100% hematologic response rate) and normalized in 16 out of 18 patients (an 89% complete response (CR) rate). The JAK2 V617F gene mutation was detected in eight patients. Seven out of the eight (88%) patients achieved 72% to 96% reductions in JAK2 V617F allele burden that qualified as partial molecular responses (PRs) within three to 12 months of treatment with imetelstat. Molecular PRs 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. The median durations of hematologic and molecular response have not yet been reached.
Imetelstat was initially administered weekly by intravenous infusion during an induction phase. After achieving a hematologic CR, which occurred in a median time of six weeks, a maintenance treatment phase was begun in which dosing frequency was modified based on a patient’s individual response profile. As of the May 2013 data cut-off date, follow-up data for the maintenance phase were available for 15 out of 16 patients who attained a hematologic CR. In all 15 patients the frequency with which imetelstat was administered to maintain the response was reduced to every two weeks or less (up to every seven weeks), generally decreasing over time. 13 of the 16 patients (81%) who attained a hematologic CR remain on study as of May 2013, with the median duration of treatment of 14.5 months. As of May 2013, a total of four ET patients have discontinued study treatment. The reasons cited for discontinuation include frequency of imetelstat treatment that was required to maintain a response (n=1), co-morbid conditions/social issues (n=2) and convenience issues (n=1).
In the trial, long-term administration of imetelstat was generally well tolerated. There were no new safety signals observed in the six-month update, and no patients discontinued the trial due to drug-related adverse events. The majority of the non-hematologic adverse events were mild-to-moderate in severity, the most frequent assessed as imetelstat-related 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 were reported. No thromboembolic events or bleeding events associated with thrombocytopenia were reported.
At least one abnormal liver function test (LFT) was observed in laboratory findings in all patients. The majority were Grade 1 elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (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. No liver injury symptoms were reported and no patients discontinued study treatment due to enzyme elevations.
We believe that these results suggest that imetelstat had a selective inhibition of the malignant progenitor cells, which are believed to be responsible for the underlying disease, and may provide evidence indicating that imetelstat has a disease-modifying effect in ET. As a consequence, we also believe that imetelstat may have applicability for the treatment of other progenitor cell-driven hematologic malignancies, including myelofibrosis (MF).
Further Development of Imetelstat in Hematologic Malignancies
Our rationale for studying imetelstat in ET was to provide proof-of-concept for further development in a broader range of hematologic myeloid malignancies. Although high hematologic and molecular response rates led us to explore the feasibility of further development of imetelstat in ET, medical experts advised us that ET patients are adequately served by existing therapies and recommended that we pursue other hematologic myeloid malignancies, such as myelofibrosis (MF), a myeloproliferative neoplasm in the same spectrum of diseases as ET, where there is a clear unmet medical need for a product that could be disease-modifying.
Based on data from the trial of imetelstat in patients with ET, in November 2012, Dr. Ayalew Tefferi at Mayo Clinic initiated an investigator-sponsored trial (IST) to evaluate the safety and efficacy of imetelstat in patients with MF and to determine an appropriate dose and schedule for further evaluation. The study is an open-label trial in intermediate or high-risk patients with primary or secondary MF. 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, transfusion independence, safety and tolerability. Please visit ClinicalTrials.gov for a trial summary.
The investigator has informed us that more than fifty patients have been enrolled in the IST. Enrollment of the first 11 patients in the first cohort of MF patients (Cohort A) in which the dose of imetelstat is given once every three weeks was completed at the end of March 2013 and the pre-specified criteria in the clinical protocol of at least two responders in the first 11 patients were met to enable expanded enrollment. Enrollment of the first 11 patients of the second cohort of MF patients (Cohort B) in which imetelstat was given weekly for four weeks, followed by one dose every three weeks, was completed in May 2013 and the pre-specified criteria in the clinical protocol of at least two responders in the first 11 patients were met to enable expanded enrollment. In addition, the investigator has informed us that enrollment has commenced in additional cohorts to evaluate the safety and efficacy of imetelstat using different dosing algorithms, as well as to evaluate imetelstat in different patient populations, including patients with MF that has transformed into acute myelogenous leukemia (AML), or blast-phase MF, and certain subpopulations of myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN), or MDS.
Certain preliminary data from patients enrolled in Cohort A and Cohort B of the ongoing IST have been selected for presentation in an oral session at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition to be held in New Orleans, Louisiana from December 7-10, 2013.
Pending additional input from regulators, investigators and other experts, as well as further potential insights from the ongoing IST, we expect to initiate a Geron-sponsored, multi-center trial of imetelstat in MF in the first half of 2014.
- 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
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- 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).
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- 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