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Telomerase is an enzyme required for maintenance of telomeric DNA “capping” of the ends of eukaryotic chromosomes. Without telomerase, telomeres shorten to a critical length, resulting in chromosomal instability, and cell cycle arrest or death. Human telomerase is repressed in most normal somatic cells, transiently inducible in certain stem or progenitor cells, and constitutively activated in germline and tumor cells. There is a strong correlation between tumorigenesis and telomerase activation, therefore telomerase is considered a promising therapeutic target for the treatment of cancer. GRN163L is a lipid-conjugated thio-phosphoramidate (N3’-P5’) oligonucleotide being developed as the first specific telomerase inhibitor for the treatment of cancer. GRN163L binds tightly to the template region of the RNA component of telomerase, blocking the active site of the enzyme. GRN163L inhibition of telomerase activity results in the slowing of tumor cell growth and progression in vitro as well as inhibiting tumor growth in various in vivo tumor models, including myeloma, hepatocellular, ovarian, and lung cancer. Additionally, combination studies with various cytotoxics, including melphalan, Velcade and taxol in selected tumor models, including melanoma, myeloma and ovarian carcinoma models have demonstrated increased efficacy of GRN163L and chemotherapy co-treatment over either agent alone. Preclinical safety studies indicate that GRN163L generally has a toxicity profile that is similar to that typically observed for the oligonucleotide class of molecules, with a clear relationship between plasma concentration and acute toxicity effects, and are readily managed by dose and infusion time. ADME and pharmacodynamic studies support an intermittent treatment schedule at drug levels that should achieve efficacious concentrations of GRN163L in cancer patients. GRN163L has been manufactured under GLP and GMP conditions, yielding sufficient drug substance to support preclinical toxicity, safety pharmacology, and pharmacokinetic studies, as well as Phase I clinical studies. Selection of the clinical indication(s) and design for Phase I and subsequent clinical studies are in progress with guidance from ongoing preclinical safety, pharmacodynamic and efficacy studies.

[Proc Amer Assoc Cancer Res, Volume 46, 2005]