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Alnylam Presents Animal Data on siRNA Delivery via Inhalation, Adds PH1 to Pipeline

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NEW YORK (GenomeWeb) – Alnylam Pharmaceuticals this week released new preclinical data showing that a next-generation version of its GalNAc conjugates has the potential to deliver siRNAs against liver targets when administered via inhalation.

The company also announced that it has added primary hyperoxaluria type 1 (PH1), a rare kidney disease, to its pipeline and released rodent data demonstrating an RNAi approach to treating the disease.

The GalNAc approach is based on a sugar modification called N-acetyl galactosamine, which is a high-affinity ligand for the asialoglycoprotein receptors that are expressed on the surface of hepatocytes in all mammals. Alnylam has been using conjugates to enable subcutaneous delivery of its new drug candidates, while also developing a newer version with enhanced stability.

According to the company, siRNAs formulated with the improved GalNAc conjugates and targeting either Factor VII or transthyretin — the gene that is mutated in TTR-mediated amyloidosis — were able to knock down their liver-based targets in mice when administered via inhalation.

Notably, the level and duration of knockdown achieved was comparable to that seen when the molecules were delivered subcutaneously.

"These data provide proof of concept for inhalation as a needle-less, non-invasive approach for administration of RNAi therapeutics targeting liver disease genes," Alnylam said.

PH1 is rare, inherited autosomal-recessive condition characterized by the liver's inability to metabolize a precursor of oxalate due to disruption of an enzyme called alanine-glyoxylate aminotransferase 1 (AGT1). As a result, calcium oxalate builds up in renal tubules causing kidney stones and fibrosis.

According to Alnylam, its PH1 program will focus on silencing glycolate oxidase, and in rodent studies it was able to achieve robust knockdown of the target with substantial reductions in urinary oxalate levels.

The company aims to select a drug candidate for the program by mid-2015, with an investigational new drug application filed in 2016.

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