Preclinical Pharmacology And Clinical Efficacy Of Azd9150 (Isis-Stat3rx), A Potent Next-Generation Antisense Oligonucleotide Inhibitor Of Stat3

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Genomic technologies have greatly expanded our understanding of cancer biology, although they have not yet been effectively translated into improved cancer therapeutics, partly due to the inability of available therapeutic modalities to target the most promising cancer driver pathways. In contrast to other therapeutic approaches, antisense technology allows the rational design of potent, sequence-specific inhibitors based on genome sequencing information alone. Recent human clinical data have demonstrated the potent activity of antisense oligonucleotides (ASOs) targeted to genes expressed by the liver. Here we describe preclinical and clinical activity of a high affinity, new generation chemistry (constrained ethyl modified) ASO, AZD9150. AZD9150 targets the mRNA coding for the transcription factor STAT3, which is considered a difficult protein to target therapeutically. Systemic delivery of unformulated AZD9150 resulted in strong inhibition of STA3 RNA and protein levels in demonstrates in a broad range of preclinical cancer models in vivo including several patient-derived xenograft models. AZD9150 administration resulted in 2 partial responses highly treatment-refractory diffuse large B-cell lymphoma and in 2 mixed responses in Hodgkin's Lymphoma patients in the phase I dose escalation study. These findings suggest that this technology has the potential to help bridge the pharmacogenomic divide in cancer drug discovery. [D.H. and Y.K. contributed equally to this work.] Citation Format: David Hong, Youngsoo Kim, Anas Younes, John Nemunaitis, Nathan Fowler, Jeff Hsu, Tianyuan Zhou, Luis Fayad, Nancy Zhang, Sarina Piha-Paul, Richard Woessner, Murali VP Nadella, Deborah Lawson, Corinne Reimer, Minji Jo, Joanna Schmidt, Xiaokun Xiao, Sarah Greenlee, Gene Hung, Mason Yamashita, David C. Blakey, Brett P. Monia, A. Robert Macleod, Razelle Kurzrock. Preclinical pharmacology and clinical efficacy of AZD9150 (ISIS-STAT3Rx), a potent next-generation antisense oligonucleotide inhibitor of STAT3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-227. doi:10.1158/1538-7445.AM2014-LB-227