Upregulation of telomerase is necessary for most cancer cells to replicate indefinitely and thereby enable tumor growth and metastasis. One of our strategies for the development of anti-cancer therapies is to inhibit telomerase activity in cancer cells. Inhibiting telomerase activity should result in telomere shortening which can cause aging and death of cancer cells. Recent data show that telomerase can protect tumor cells from genomic instability and other forms of cellular stress, suggesting that inhibiting telomerase can cause a more rapid suppression of tumor growth than predicted by telomere loss alone. Because telomerase is expressed at very low levels, if at all, in most normal cells, the telomerase inhibition therapies described below are being developed with the goal of being less toxic to normal cells than conventional chemotherapy.
We have designed and synthesized a special class of short-chain nucleic acid molecules, known as oligonucleotides, which target the template region, or active site, of telomerase. Our recent work has focused on one of these oligonucleotides, called imetelstat sodium (originally known as GRN163L). We have demonstrated that it has highly potent telomerase inhibitory activity at very low concentrations in biochemical assays, various cellular systems and animal studies. Imetelstat is a direct enzyme inhibitor, not an antisense compound. It is smaller (lower molecular weight) than typical antisense compounds or other oligonucleotide drug candidates and uses a special thiophosphoramidate chemical backbone, for which we acquired key patents in March 2002 from Lynx Therapeutics.
Imetelstat sodium (imetelstat) is a 13-mer oligonucleotide N3'-- P5' thiophosphoramidate (NPS oligonucleotide) that is covalently attached to a C16 (palmitoyl) lipid moiety, which increases potency and improves its pharmacokinetic and pharmacodynamic properties. Imetelstat binds directly with high affinity to the template region of the RNA component of human telomerase (hTR), which lies in the active or catalytic site of hTERT, the telomerase reverse transcriptase. Imetelstat binding to hTR results in direct, competitive inhibition of telomerase enzymatic activity.
After completing a series of animal toxicology and preclinical efficacy studies of imetelstat in 2005 and filing an Investigational New Drug (IND) application, we received clearance from the U.S. Food and Drug Administration (FDA) to begin human clinical trials of imetelstat. We sponsored six Phase I or I/II clinical trials at 22 U.S. medical centers to examine the safety, tolerability, pharmacokinetics and pharmacodynamics of imetelstat, alone or in combination with other standard therapies in patients with chronic lymphoproliferative diseases, solid tumors, multiple myeloma, non-small cell lung and breast cancer. Four of those trials fulfilled their patient quotas and completed patient enrollment during the fourth quarter of 2009. Click here for clinical trial information.
Telomerase inhibition by imetelstat was first demonstrated in humans in the Phase I single agent trial in patients with relapsed or refractory multiple myeloma. The early results from this trial were presented at the 2008 American Society of Hematology annual meeting. Importantly, clinical data from the ongoing trial showed that imetelstat inhibits telomerase both in the bulk myeloma fraction as well as the stem cell-containing fraction in patients' bone marrow.
Preclinical studies have also demonstrated that imetelstat can inhibit growth of cancer stem cells from multiple tumor types. These data were presented during the April 2009 Annual Meeting of the American Association for Cancer Research. Cancer stem cells capable of clonogenic growth may play an important role in the regrowth of tumors after initial reduction by standard treatments. Preclinical study results showed that imetelstat inhibits in vitro cell colony growth of both primary patient samples and subpopulations from cell lines containing or enriched for cancer stem cells from myeloma, melanoma, breast, pancreatic, pediatric glioma, neuroblastoma, prostate, lung and glioblastoma tumor types. These subpopulations typically show resistance to several conventional chemotherapeutic agents.
At the November 2009 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, we presented interim data on the ongoing trial of imetelstat in patients with relapsed or refractory solid cancers. These data showed that with a modified dosing schedule we are achieving exposures to imetelstat that exceed the levels that have been associated with inhibiting tumor growth in several models of human cancers.
We have met our main objectives for Phase I of assessing the safety, tolerability, pharmacokinetics and pharmacodynamics of imetelstat. We have established our single agent Phase II dose and dosing schedule and are planning to advance the program to Phase II trials in 2010 in four different malignancies.
Upregulation of telomerase is necessary for most cancer cells to replicate indefinitely and thereby enable tumor growth and metastasis. One of our strategies for the development of anti-cancer therapies is to inhibit telomerase activity in cancer cells. Inhibiting telomerase activity should result in telomere shortening which can cause aging and death of cancer cells. Recent data show that telomerase can protect tumor cells from genomic instability and other forms of cellular stress, suggesting that inhibiting telomerase can cause a more rapid suppression of tumor growth than predicted by telomere loss alone. Because telomerase is expressed at very low levels, if at all, in most normal cells, the telomerase inhibition therapies described below are being developed with the goal of being less toxic to normal cells than conventional chemotherapy. 
