Alnylam Presents Key Scientific Data On Enhanced Stabilization Chemistry (ESC)-GalNAc-Conjugate Technology

CAMBRIDGE, MASS.--(BUSINESS WIRE)--

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it is presenting key scientific data on its Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform. Specifically, the company will be presenting data showing 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 ALN-TTRsc a subcutaneously administered RNAi therapeutic targeting transthyretin (TTR) for the treatment of 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 potentially even less frequent subcutaneous dosing regimens. The ESC-GalNAc-conjugate technology is being used in a wide range of Alnylam development programs, including ALN-AT3 an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders which is currently in a Phase 1 clinical study.

Our ESC-GalNAc-conjugate delivery platform enables subcutaneous dosing of RNAi therapeutics with increased potency and durability, and a wide therapeutic index. Importantly, we have demonstrated that increased siRNA stability is the key to realizing these 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, said Muthiah (Mano) Manoharan, Ph.D., Senior Vice President, Drug Discovery of Alnylam. We look forward to sharing additional pre-clinical and clinical results in the weeks and months to come, where we expect to build on data sets that are defining what we believe will be a very attractive product profile for our RNAi therapeutics, including the ability to clamp down disease targets in a predictable, sustainable, and durable manner.

In a presentation at the TIDES 2014 meeting, being held May 12 15, 2014 in Providence, Rhode Island, Alnylam scientists presented new data on the companys ESC-GalNAc-conjugate delivery platform. Metabolic profiling studies were performed in vitro and showed that chemically modified siRNA using an STC-GalNAc-conjugate approach were prone to significant exonuclease and endonuclease degradation. More extensive, yet targeted, chemical modifications were introduced, including the use of chemistries that prevent exonuclease degradation at the 5-end of the siRNA sense and antisense strands and improved resistance towards endonuclease degradation at the inter-nucleotide linkages for both strands. These additional modifications resulted in a marked increase in in vitro metabolic stability. In in vivo studies where ESC-GalNAc siRNA were compared with STC-GalNAc siRNA, the enhanced stabilization resulted in markedly prolonged liver tissue exposure with a nearly 30-fold increase in area under the curve (AUC) values. In turn, the higher level of tissue exposure was associated with an over 10-fold increase in in vivo potency as measured toward target gene knockdown and a marked prolongation in durability of effect. Of interest, a comparative analysis in NHP and human studies of the efficacy and durability of ALN-TTRsc an STC-GalNAc siRNA revealed a significantly lower degradation rate in humans and a prolonged durability of target knockdown. These data suggest that ESC-GalNAc-siRNA conjugates could show even greater durability in human studies, providing further support for once-monthly and possibly even less frequent subcutaneous dosing regimens.

Finally, the preliminary safety of ESC-GalNAc-siRNA conjugates was evaluated in rodent and NHP toxicology studies. An ESC-GalNAc conjugate ALN-PCSsc was administered as five weekly subcutaneous doses of up to 300 mg/kg. At all doses tested, the siRNA was found to be well tolerated, with no adverse in-life findings, no significant changes in clinical pathology values (e.g., LFTs), and no adverse histopathology findings including at the injection sites. In these initial toxicology studies, the no adverse effect level (NOAEL) was determined to be greater than 300 mg/kg in both species. These data indicate that the improved potency and durability of ESC-GalNAc-siRNA conjugates do not appear to be associated with any negative safety consequences.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Alnylams Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in several of Alnylams genetic medicine programs, including programs in clinical development.

About RNAi

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as a major scientific breakthrough that happens once every decade or so, and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylams RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

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Alnylam Presents Key Scientific Data On Enhanced Stabilization Chemistry (ESC)-GalNAc-Conjugate Technology