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

In Press Release by Cameron


ESC-GalNAc-Conjugate Platform Enables Subcutaneous Delivery of RNAi Therapeutics with Increased Potency and Durability, and a Wide Therapeutic Index

May 11, 2014

Alnylam Pharmaceuticals, Inc., 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 company’s 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. Alnylam’s 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 Alnylam’s 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 Alnylam’s 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

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5×15™” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5×15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as NatureNature MedicineNature BiotechnologyCell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit