Geron Looks to Break Through With Telomerase Inhibitor Imetelstat

Some researchers believe the uncontrolled cell division that defines cancer is a characteristic of damage that occurs at the telomeres, the protective caps at the end of the chromosomes that contain the cell’s genetic material. Telomerase is a naturally occurring enzyme that helps to maintain the telomeres during cell division. The enzyme consists of an RNA template, which binds to the telomere, and a catalytic subunit with reverse transcriptase activity, which adds a specific DNA sequence at the ends of the chromosome. Geron Corporation’s anticancer research strategy is to focus on telomerase activity through the continuing clinical development of the telomerase inhibitor imetelstat.

The company presented data at the 55th Annual Meeting of the American Society of Hematology (ASH) demonstrating imetelstat’s activity in myelofibrosis. In that trial, nine of 22 patients had objective responses, four of which were complete remissions. Two-thirds of the patients met criteria for an objective response or had a >50% reduction in white blood cell count. The findings were presented by Ayalew Tefferi, MD, a hematologist at the Mayo Clinic in Rochester, Minnesota.

These findings followed on the heels of updated clinical results from a phase II proof-of-concept trial of imetelstat in essential thrombocythemia. Those trial results were presented at the 18th Annual Congress of the European Hematology Association. The data showed a 100% response rate in patients, including 16 complete responses. Those results added to a favorable report at the 2012 ASH Annual Meeting involving fewer patients and a shorter duration of follow-up.

The rationale for Geron Corporation’s focus on inhibiting telomerase in cancer is the belief that inhibiting the enzyme may limit the proliferative capacity of malignant cells. Geron researchers have observed in various in vitro and rodent tumor models that inhibiting telomerase results in telomere shortening and arrests uncontrolled malignant cell proliferation and tumor growth. Many blood-based cancers are known to arise from malignant progenitor cells in the bone marrow, providing a strong rationale for potential treatment with a telomerase inhibitor.

The number of divisions that occur during cell division is regulated by telomere length. Each time a cell divides, the telomeres shorten. Eventually, they shrink to a critically short length, and as a result the cell either dies by apoptosis or stops dividing and senesces. In contrast to normal cells, most cancer cells have relatively short telomeres and exhibit high levels of the enzyme telomerase.

Imetelstat is a short, modified, lipid-conjugated 13-mer oligonucleotide that is complementary to and binds with a high affinity to the RNA template of telomerase. This high affinity characteristic directly inhibits 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.

In general, commercial development of telomerase inhibitors has been slow because small molecules undergoing development have lacked potency and specificity. However, imetelstat has made some significant clinical progress.