8:00AM Alnylam Pharma presents new pre-clinical data on pharmacology of GalNAc-siRNA Conjugates; new results demonstrate achievement of steady state liver drug levels during chronic dosing with no evidence for drug accumulation (ALNY) 63.00 :
Co announced today that it has 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. In a presentation titled "Advances in Systemic Delivery of RNAi Therapeutics,"
Alnylam scientists presented new data on tissue drug levels and sustained target knockdown achieved with long-term chronic dosing of GalNAc-siRNA conjugates.
GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform, and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. This targeted delivery platform enables subcutaneous dose administration with a wide therapeutic index, and has demonstrated potent and durable gene silencing, as well as a favorable tolerability profile, in clinical and pre-clinical studies from multiple programs in the company's "Alnylam 5x15" product pipeline.
The new data demonstrate the pharmacodynamic and pharmacokinetic properties of GalNAc-siRNA conjugates following repeat dosing. Specifically, in mouse studies, weekly subcutaneous dosing of ALN-AT3, an RNAi therapeutic targeting antithrombin (AT), resulted in mean steady state liver drug levels of approximately 0.4 and 1.1 micrograms per gram at doses of 0.2 and 0.5 mg/kg, respectively. These drug levels were shown to correspond to roughly 60% and 75% knockdown of serum AT, and compare very favorably with other oligonucleotide platforms requiring 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.
Further, no evidence of drug accumulation in liver tissue during chronic dosing was observed after the third weekly dose. In addition, data from a long-term pharmacology study were presented with a GalNAc-siRNA conjugate targeting the transthyretin (TTR) mRNA in mice. Weekly dosing at 1.0 and 2.5 mg/kg led to steady TTR knockdown of 50% and 80%, respectively, which was sustained for the entire 196-day time period analyzed. The TTR 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.
