Alnylam Pharmaceuticals this week announced the presentation of preclinical data on tissue drug levels and sustained target knockdown achieved with long-term chronic dosing of GalNAc-siRNA conjugates.
The GalNAc technology facilitates liver delivery of siRNAs via uptake through the asialoglycoprotein receptors expressed on the surface of hepatocytes. Alnylam has been pushing the proprietary subcutaneous delivery approach forward in many of its pipeline programs as part of an effort to move past the lipid nanoparticles licensed from former partner Tekmira Pharmaceuticals.
According to Alnylam, the data show that weekly subcutaneous dosing of ALN-AT3, its RNAi therapeutic targeting antithrombin (AT), to mice 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 percent and 75 percent 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," it added.
No evidence of drug accumulation in the liver was observed after the third weekly dose.
Meanwhile, other mouse data showed that weekly dosing of siRNA-GalNAc conjugated designed to silence transthyretin at 1.0 and 2.5 mg/kg led to steady target mRNA knockdown of 50 percent and 80 percent, respectively, 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," Alnylam said, and "the steady level of knockdown was achieved with no evidence of tachyphylaxis or sensitization."
The data were presented at the US-Japan Symposium on Drug Delivery Systems in Hawaii.