New Pre-Clinical Data on ALN-AS1 for the Treatment of Porphyria and PK/PD Properties of GalNAc-siRNA Conjugates

We presented new pre-clinical data supporting the selection of the ALN-AS1 Development Candidate for the treatment of hepatic porphyrias, including acute intermittent porphyria (AIP). The new research, presented at the 9th Annual Meeting of the Oligonucleotide Therapeutics Society, held October 6 – 8, 2013 in Naples, Italy, showed that multi-dose administration of a GalNAc-siRNA targeting ALAS-1 led to rapid, dose-dependent, and long-lasting knockdown of the ALAS-1 mRNA in non-human primates, with an ED50 of approximately 1.25 mg/kg.  Further, in a rat model of AIP, ALN-AS1 administration at doses as low as 2.5 mg/kg resulted in a complete blunting of phenobarbital-induced over-production of PBG and ALA, the toxic heme intermediates in AIP.

We are very pleased to advance ALN-AS1 as a new Development Candidate in our “Alnylam 5×15” pipeline. With the recent clinical experience of our GalNAc-siRNA conjugate delivery platform, we are encouraged by the potential ALN-AS1 could have for patients with AIP, an ultra-rare genetic disease with significant unmet medical need.

In addition, we presented new pre-clinical data on the pharmacokinetic and pharmacodynamic properties of GalNAc-siRNA conjugates.  Results showed that target gene silencing is achieved at very low levels of liver tissue exposure.  The ability of GalNAc-siRNA to achieve target gene knockdown at low tissue exposure underscores the potential for a wide therapeutic index for these RNAi therapeutics.