Geron Announces Publication Characterizing GRN163L, Its Telomerase Inhibitor Drug Currently In Clinical Development For Cancer

Geron Corporation (Nasdaq:GERN) announced today the publication of data on cell and animal testing of GRN163L, its telomerase inhibitor anti-cancer drug. The results describe (1) the synthesis and structure of GRN163L, (2) its potency for inhibiting telomerase in multiple types of human cancer cells in culture, (3) its ability to trigger telomere shortening and tumor cell death, and (4) its in vivo uptake by tumor tissue and the resulting telomerase inhibition within the cancer cell. The paper, authored by researchers at Geron, the Indiana University Cancer Center, and the University of Texas Southwestern Medical Center, currently appears in the advance online publication of the journal Oncogene.

Telomerase, an enzyme that maintains telomere length in immortal cells, is active in most tumors from all common forms of cancer, but is inactive or expressed only transiently in most normal tissues in humans. Since telomerase plays a critical role in the ability of cancer cells to divide and metastasize over long periods of time, it is an attractive target for anti-cancer drug development. Geron recently received FDA clearance to begin human clinical studies of GRN163L in patients with chronic lymphocytic leukemia (CLL).

GRN163L is a novel lipid-based conjugate of Geron's first-generation anti-cancer drug, GRN163. The newly published studies document the improved potency for telomerase inhibition and enhanced in vivo anti-tumor activity of GRN163L in multiple cancer types. The oligonucleotide backbone of both compounds utilizes the N3'-P5' thio-phosphoramidate linkage, which leads to improved stability against degradation and improved binding to target sequences compared to other oligonucleotide chemistry. Moreover, these oligonucleotide compounds do not exhibit antisense activity (binding to messenger RNA), but rather directly bind to the RNA component of telomerase at the active site of the enzyme, thereby acting like a conventional pharmaceutical drug.

Geron selected a specific lipid-modification of GRN163 to enable enhanced inhibition of telomerase in tumor cells. The Oncogene publication, titled "Lipid modification of GRN163, an N3'-P5' thio-phosphoramidate oligonucleotide, enhances the potency of telomerase inhibition," shows that GRN163L was 1.4 to 40-fold more active than GRN163 in inhibiting telomerase in 14 different tumor cell lines representing 9 different human cancer types (including lung, breast, prostate, liver, and early stage of human breast cancer). GRN163L caused a more rapid rate of telomere loss than GRN163, and GRN163L-treated cells exhibited growth inhibition and apoptosis (cell death) after only 20 cell divisions. In another experiment reported in this publication, a single tail vein injection of fluorescently labeled versions of GRN163L and GRN163 into mice harboring subcutaneous human prostate cancer resulted in greater tumor cell uptake and greater telomerase inhibition by GRN163L compared to the non-lipidated drug.

"These data formed part of our rationale for taking GRN163L through preclinical development leading to our first FDA-approved IND for the treatment of patients with CLL," stated Calvin Harley, Ph.D., Geron's chief scientific officer. "The most exciting aspect of our work to date is that GRN163L has demonstrated the potential to be effective in every tumor type we have investigated, suggesting that GRN163L could be an anti-cancer drug with broad clinical applications. We look forward to pursuing clinical trials with GRN163L in multiple cancer types."