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Delivery of RNAi Therapeutics

In the early years of developing RNAi therapeutics, a challenge to the promise of RNAi as a therapeutic modality was delivery – i.e., getting the siRNA into the right body organs and cells so that it could trigger the RNAi mechanism.  Many people gave up hope, believing that RNAi therapeutics could never be delivered in a safe and effective manner. In more recent years, though, a tremendous amount of progress has been made, and Alnylam has been at the forefront of this advancement.

This delivery success is enabling execution on our product strategy.

Early efforts focused on delivery of RNAi therapeutics utilizing lipid nanoparticles (LNP) that encapsulate the siRNA molecule.  This technology enables systemic delivery with intravenous drug administration.  Studies with LNP-based RNAi therapeutics demonstrate potent, rapid, and durable target gene silencing in pre-clinical as well as clinical studies.  Further, LNP-based RNAi therapeutics were found to be generally well tolerated in the clinical studies conducted to date.

More recently, we began advancing proprietary technology that conjugates a sugar molecule called “GalNAc” to the siRNA molecule.  This much simpler delivery approach enables more convenient, subcutaneous administration of our drug candidates.  Recent findings from our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform demonstrated a 10-fold increase in potency over our earlier “standard template chemistry” (STC)-GalNAc-conjugate approach in pre-clinical and clinical studies, and a durability of effect that we believe supports once-monthly or possibly even less frequent subcutaneous dosing regimens.  Due to this increased potency and durability, as well as a wide therapeutic index, this conjugate platform has become our primary approach for development of RNAi therapeutics, and continued execution on our entire product pipeline.

In early 2014, Alnylam continued and extended its commitment to RNAi therapeutics innovation and delivery through the acquisition of Merck’s wholly owned subsidiary Sirna Therapeutics, Inc.  This acquisition extends and complements Alnylam’s progress and continued focus on RNAi therapeutics.  It also accelerates Alnylam’s overall efforts to develop and commercialize siRNA delivery technologies, including GalNAc-siRNA conjugate technology.

New Paper Documenting Alnylam’s Pioneering Discovery of GalNAc-Conjugated siRNA

New Paper Documenting Alnylam’s Pioneering Discovery of GalNAc-Conjugated siRNA

We have published an article in the Journal of the American Chemical Society describing the discovery of GalNAc-conjugated siRNA as a novel strategy for delivery of RNAi therapeutics. This publication as a JACS “Communication” documents the landmark discovery by our scientists of GalNAc-conjugates as a potent and durable approach for subcutaneous administration of RNAi therapeutics with a wide therapeutic index.



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

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.



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