Key Scientific Data on Enhanced Stabilization Chemistry (ESC)-GalNAc-Conjugate Technology

We are presenting key scientific data on our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform at the TIDES 2014 meeting held May 12 – 15, 2014 in Providence, Rhode Island. This technology enables subcutaneous dosing of RNAi therapeutics with increased potency and durability, and a wide therapeutic index.  Data show that chemical modifications of siRNA that enhance in vitro stability result in higher liver exposure in vivo and lead to a significantly increased potency and durability of effect in pre-clinical studies. As compared with the “standard template chemistry” (STC)-GalNAc-conjugate approach used in our ALN-TTRsc program for the treatment of transthyretin (TTR) cardiac amyloidosis, ESC-GalNAc-siRNA conjugates demonstrated a 10-fold increased potency in non-human primate (NHP) studies, and a durability of effect that supports once-monthly or possibly even less frequent subcutaneous dosing regimens.

With these data, we have demonstrated that increased siRNA stability is the key to realizing potency and durability improvements.  In addition, our data suggest that further improvements in potency and durability might be realized in human studies based on an attenuated nuclease environment.  Accordingly, we believe that once-monthly and possibly less frequent subcutaneous dose regimens could be achieved in our clinical pipeline programs with this technology.