On April 20, 2016 Geron Corporation (Nasdaq:GERN) reported two poster presentations of data from non-clinical studies of the telomerase inhibitor, imetelstat, at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting held in New Orleans, Louisiana (Press release, Geron, APR 20, 2016, View Source;p=RssLanding&cat=news&id=2158608 [SID:1234511145]). The first poster presentation described results that treating acute myeloid leukemia (AML) cell lines with imetelstat enhanced the effects of agents currently used for the treatment of AML. These data extend the rationale from prior non-clinical studies for the potential use of imetelstat in hematologic myeloid malignancies, such as AML, including in combination with standard therapies. The second poster presentation described results from non-clinical studies that provide further evidence of potential on-target mechanisms of telomerase inhibition by imetelstat underlying the reduction in platelets observed in previously conducted imetelstat clinical trials.
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The non-clinical studies were conducted by scientists at Janssen Research & Development, LLC and academic collaborators under the terms of the exclusive worldwide imetelstat license and collaboration agreement between Geron and Janssen Biotech, Inc. The poster presentations are available on Geron’s website at www.geron.com/presentations.
Impact of hypomethylating agents on hTERT expression and synergistic effect in combination with imetelstat, a telomerase inhibitor, in AML cell lines
AML cells express high levels of the telomerase catalytic subunit (hTERT). The expression of hTERT may be regulated through chemical changes to DNA, known as epigenetic modifications, such as the addition of a methyl group (methylation). Non-clinical studies by various cancer biologists have suggested a correlation between hTERT overexpression and hypermethylation in some cancers. Two compounds that are currently used for the treatment of AML, decitabine and 5-azacitidine, act as hypomethylating agents by inhibiting DNA methylating enzymes. Furthermore, these compounds have been reported to also reduce hTERT expression in AML cells in addition to inhibiting cell growth.
The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to determine whether combining hypomethylating agents and imetelstat can further inhibit AML cell viability in vitro compared with either agent alone. Combination treatment of the AML cell lines with either decitabine or 5-azacitidine followed by imetelstat, resulted in a greater reduction in cell viability or slower recovery of growth, respectively, than when a hypomethylating agent was administered alone. Similarly, when AML cell lines were treated with decitabine or 5-azacitidine followed by imetelstat, apoptosis, or cell death, increased in a dose-dependent manner.
Rusbuldt J, et al. 2016 AACR (Free AACR Whitepaper)
Myelosuppression in patients treated with the telomerase inhibitor imetelstat is not mediated through activation of toll-like receptors
Toll-like receptors (TLRs) recognize pathogen-associated molecular patterns to trigger innate immune responses. For example, synthetic, single-stranded oligonucleotides with certain properties characteristic of bacteria and virus genomes activate the innate immune response through TLR9 signaling. In addition, TLR activation has been associated with lipopolysaccharide-induced thrombocytopenia in animal models.
The aim of the non-clinical study in the AACR (Free AACR Whitepaper) poster was to test a recent hypothesis that the thrombocytopenia observed in patients with myeloproliferative neoplasms (MPN) treated with imetelstat might occur through off-target effects by binding to and activating TLRs, such as TLR9. Results from the study suggest that the thrombocytopenia associated with imetelstat is not likely to be driven via interactions with TLRs. First, the oligonucleotide imetelstat is shorter and lacks certain features in its sequence required to activate TLR9. Second, in an assay for TLR activity, treatment with imetelstat at clinically relevant concentrations had no stimulatory effect on the majority of TLRs tested, including TLR9. Although a small induction of TLR8 was observed in the assay, such activity was not believed to be relevant because the induction was substantially lower than the positive control used in the experiment, and TLR8 has not been reported to be associated with thrombocytopenia.
The poster also cites results from previous non-clinical studies which suggest potential on-target mechanisms of telomerase inhibition for the observed thrombocytopenia in patients treated with imetelstat. Since telomerase activity is required for the differentiation of megakaryocyte progenitors into mature platelet-producing cells, previous ex vivo studies used cells taken from MPN patients and healthy individuals to show that treatment with imetelstat decreases hTERT expression and inhibits telomerase activity, which is concurrent with blocking the terminal maturation of normal megakaryocyte precursors, reducing the number of mature megakaryocytes available to produce platelets. Other prior ex vivo studies also included in the poster showed that imetelstat selectively inhibits the proliferation of malignant megakaryocyte progenitors from patients with essential thrombocythemia compared to normal progenitors from healthy individuals, suggesting that imetelstat may regulate telomerase differently in malignant versus normal cells.
Baerlocher GM, et al. 2016 AACR (Free AACR Whitepaper)
About Imetelstat
Imetelstat (GRN163L; JNJ-63935937) is a potent and specific inhibitor of telomerase that is administered by intravenous infusion. This first-in-class compound, discovered by Geron, is a specially designed and modified short oligonucleotide, which targets and binds directly with high affinity to the active site of telomerase. Preliminary clinical data suggest imetelstat has disease-modifying activity by inhibiting the progenitor cells of the malignant clones associated with hematologic myeloid malignancies in a relatively select manner. Most commonly reported adverse events in imetelstat clinical studies conducted previously by Geron included fatigue, gastrointestinal symptoms and cytopenias. Patients in those studies also experienced elevated liver enzymes, which resolved to normal or baseline in the majority of patients after imetelstat treatment was withdrawn. Imetelstat has not been approved for marketing by any regulatory authority.
About the Collaboration with Janssen
On November 13, 2014, Geron entered into an exclusive worldwide license and collaboration agreement with Janssen to develop and commercialize imetelstat for oncology, including hematologic myeloid malignancies, and all other human therapeutics uses. Under the terms of the agreement, Geron received an upfront payment of $35 million and is eligible to receive additional payments up to a potential total of $900 million for the achievement of development, regulatory and commercial milestones, as well as royalties on worldwide net sales. Certain regulatory, development, manufacturing and promotional activities are being managed through a joint governance structure, with Janssen responsible for these activities.
Janssen is conducting two imetelstat clinical trials: a Phase 2 clinical trial in patients with intermediate-2 and high risk myelofibrosis (MF) and a Phase 2/3 clinical trial in patients with low and intermediate-1 risk myelodysplastic syndromes (MDS). For more information about these clinical trials, please visit www.clinicaltrials.gov.