Pre-Clinical Data on Pharmacology of GalNAc-siRNA Conjugates

Pre-Clinical Data on Pharmacology of GalNAc-siRNA Conjugates

We presented new pre-clinical data on the pharmacology of GalNAc-siRNA conjugates at the 12th US-Japan Symposium on Drug Delivery Systems held December 16 – 20, 2013 in Lahaina, Maui, Hawaii. These new research findings describe the effects of long-term chronic dosing of GalNAc-siRNA conjugates on tissue drug levels and sustained target knockdown.



Weekly subcutaneous dosing in mice resulted in mean steady state liver drug levels that compare favorably with other oligonucleotide platforms that require greater than 100 micrograms of drug per gram of tissue for similar biologic effects; this corresponds to 100- to 1000-fold lower levels of required tissue exposure for GalNAc-siRNA conjugates, which could underscore the potential for a more favorable tolerability profile. There was no evidence of drug accumulation in liver tissue during chronic dosing. In addition, weekly dosing of a GalNAc-siRNA led to steady, dose-dependent knockdown of the target gene, which was sustained for the entire 196-day time period analyzed. The knockdown effect was found to be highly consistent, with very low levels of inter-animal variation.  Finally, the steady level of knockdown was achieved with no evidence of tachyphylaxis or sensitization. Collectively, these findings are very encouraging, as they will likely have significant implications for RNAi-mediated silencing with chronic dosing in the clinical setting.



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