Imetelstat - First in Class, First in Clinic Telomerase Inhibitor: Current Status
S. Gryaznov, 12th Annual Meeting of the Oligonucleotide Therapeutics Society on September 28, 2016
Human telomerase is a unique reverse transcriptase, which is present in est. 85% of all primary tumor samples, while its activity is not detected in majority of normal tissues. This enzyme is responsible, among some other emerging functions, for maintaining telomere length and overall telomere and thus chromosomal stability of cancer cells. Hence, it is hypothesized, that inhibition of telomerase may provide an almost universal approach to specific cancer treatment.
Imetelstat , (a.k.a. GRN163L) , is a recently developed uniformly sugar - phosphate back bone modified oligonucleotide N3’ - P5’ thio - phosphoramidate 13 - mer, containing 5’ - conjugated lipid ( palmitic ) group. The molecule is not an antisense compound, but a direct telomerase enzyme inhibitor . It is a telomerase template antagonist that is fully complementary to the functionally important template region of telomerase RNA component (hTR). Imetelstat is a highly potent and sequence - specific inhibitor of telomerase, as demonstrated with various in vitro and in vivo animal models. This compound has advanced to several Phase 1 / 2 clinical trials to treat hemat o logic malignances and solid tumors. Currently, the main clinical focuses are myelofibros i s (MF), Phase 2 IMbark TM trial and myelodysplastic syndrome (MDS), Phase 2/3 IMerge TM trial .
Key activity - defining bio - chemical properties, as well as initial clinical data for Imetelstat will be presented.
Dr. Gryaznov is a Senior Director of Oligonucleotide Chemistry with Nucleic Acid Center of Excellence at Alios BioPharma, which is a part of the Janssen Pharmaceutical Companies. Prior to this appointment, he worked as a Director of Chemistry and Senior Research Fellow with Geron Corporation, where he defined major scientific and drug-discovery directions for the companies. While at Geron, Dr. Gryaznov developed new and broad-spectrum nucleic acid mimetic-based therapeutic discovery platform - oligo-N3’-P5’-(thio)-phosphoramidates, resulting in the discovery of first-in-class, first-in-clinic telomerase inhibitor Imetelstat (GRN163L), which is currently in multiple Phase II trials to treat hematological cancers.