New Pre-Clinical Data on “Enhanced Stabilization Chemistry Plus” (ESC+) GalNAc-siRNA Conjugate Platform

New Pre-Clinical Data on “Enhanced Stabilization Chemistry Plus” (ESC+) GalNAc-siRNA Conjugate Platform

We and our collaborators presented new pre-clinical data highlighting our next generation “Enhanced Stabilization Chemistry Plus” (ESC+) GalNAc-siRNA conjugate platform, and additional data demonstrating our leadership in RNAi technologies, at the 13th Annual Meeting of the Oligonucleotide Therapeutics Society (OTS), held September 24 – 27, 2017 in Bordeaux, France.

Brown et al. – “Mechanistic Insights and Progress on the GalNAc-siRNA Platform for Targeted Delivery of RNAi Therapeutics to the Liver”

Jadhav et al. – “REVERSIRTM Platform for Rapid and Potent Reversal of RNAi-Mediated Silencing Activity”

Knight et al. – “Investigational RNAi Mediated Oxalate Reduction Therapy”

Maier et al. – “Impact of Enhanced Metabolic Stability on In Vivo Performance of GalNAc-siRNA Conjugates”

Milstein et al. – “Preclinical Development of an RNAi Therapeutic Drug Candidate Targeting Hepatitis B Virus”

Schlegel et al. – “Improved Specificity and Therapeutic Index with ESC+ siRNA Conjugates Utilizing Seed-Pairing Destabilization via Novel Chemical Modifications”

Schlegel et al. – “Impact of Glycol Nucleic Acid (GNA) on siRNA Structure and Function”

ESC+ GalNAc conjugates utilize advanced design features to further improve specificity, including a glycol nucleic acid (GNA) modification in the antisense seed region of the siRNA, while maintaining potency and durability. Incorporation of GNA destabilizes seed-driven pairing with partially complementary transcripts, thus greatly reducing off-target effects while maintaining on-target pairing and activity. Furthermore, GNA modifications confer enhanced specificity and a greater-than 6-fold improvement in therapeutic index as observed in pre-clinical studies in rodents.

The ESC+ design is now being applied to all of Alnylam’s pre-clinical programs and has shown successful translation of potency from rodents to non-human primates. Alnylam intends to employ its ESC+ siRNA conjugate platform in all future development programs.


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