New Paper in Journal of the American Chemical Society Documents Pioneering Discovery of GalNAc-Conjugated siRNA by Alnylam Scientists


- GalNAc-siRNA Conjugates Enable Potent and Durable Knockdown of Hepatocyte-Expressed Disease Genes with Subcutaneous Dosing and Wide Therapeutic Index -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication of a peer-reviewed 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. The paper, titled "Multivalent N-Acetylgalactosamine-Conjugated siRNA Localizes in Hepatocytes and Elicits Robust RNAi-Mediated Gene Silencing," (Nair et al., J. Am. Chem. Soc., doi:10.1021/ja505986a) documents the pioneering discovery of GalNAc-siRNA conjugates as a novel delivery approach for potent and durable knockdown of hepatocyte-expressed disease targets in vivo. GalNAc-siRNA conjugates are a clinically validated, proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNA therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor (ASGPR). This targeted delivery platform enables specific, potent and durable knockdown of hepatocyte-expressed disease genes with subcutaneous dosing and a wide therapeutic index. GalNAc-conjugates have emerged as a promising strategy for the delivery of RNA therapeutics in advanced pre-clinical and initial clinical studies.

"This publication as a JACS ‘Communication' documents the landmark discovery by Alnylam scientists of GalNAc-conjugates as a potent and durable approach for subcutaneous administration of RNAi therapeutics with a wide therapeutic index. Indeed, our scientists championed the application of GalNAc-conjugates for delivery of RNA therapeutics, including siRNAs, and we believe that this approach has emerged as the optimal strategy across the entire industry for RNA therapeutics targeting hepatocyte-expressed disease genes," said Muthiah (Mano) Manoharan, Ph.D., Senior Vice President, Drug Discovery at Alnylam. "Over the last two years, we've now witnessed a steady flow of advanced pre-clinical and clinical data on GalNAc-conjugates for RNA therapeutics. This includes our Phase 1 and Phase 2 data on revusiran with an up to 98.2% knockdown of the disease-causing transthyretin protein; initial top-line clinical data for ALN-AT3 - our investigational RNAi therapeutic targeting antithrombin for the treatment of hemophilia - showing significant target gene knockdown at doses as low as 0.03 mg/kg; and non-human primate data for our PCSK9 and complement C5 programs showing potent and durable effects supportive of once-monthly, and possibly once-quarterly, low volume, subcutaneous dose administration regimens. In addition, our clinical and non-clinical safety data continue to support what we believe to be a wide therapeutic index for this delivery modality. Moreover, we're now pleased to see this approach being advanced by our licensees at Regulus Therapeutics, showing impressive clinical data with RG-101 in hepatitis C, and at Isis, with encouraging pre-clinical data on GalNAc-conjugated antisense oligonucleotides. In sum, we're proud to have pioneered this important innovation in the RNA therapeutics field, and we look forward to realizing the full impact of our science on the treatment of human disease."

Alnylam's GalNAc-siRNA conjugate platform is a clinically validated delivery technology that is being employed in essentially all of Alnylam's RNAi therapeutic pipeline programs. Recently, the company presented positive initial Phase 2 data with revusiran (ALN-TTRsc), a GalNAc-conjugated RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR cardiac amyloidosis; revusiran is a first generation GalNAc-conjugate that utilizes Standard Template Chemistry (STC). In the Phase 2 multi-dose study, revusiran demonstrated clinical activity with an up to 98.2% knockdown of serum TTR - the disease-causing protein - and was found to be generally well tolerated in patients with TTR cardiac amyloidosis and advanced disease burden. The Phase 2 results support advancement of revusiran in a Phase 3 randomized, double-blind, placebo-controlled study in TTR cardiac amyloidosis, and the company expects to start the study before year's end.

Earlier this year, Alnylam reported positive top-line clinical results with ALN-AT3, an investigational RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders; ALN-AT3 employs a second generation GalNAc-conjugate chemistry termed "Enhanced Stabilization Chemistry," or "ESC." In the first part of a Phase 1 clinical study, where ALN-AT3 was administered at low doses to healthy human volunteers, a single 0.03 mg/kg subcutaneous dose resulted in an up to 32% knockdown of serum AT and increases in thrombin generation. These clinical results suggest that ESC-GalNAc conjugates have a greater than 50-fold enhanced potency in humans as compared with STC-GalNAc conjugates due to enhanced stability in humans. Alnylam expects to present initial data from the ALN-AT3 Phase 1 study, including results in human volunteers and the first, lowest dose cohort of hemophilia subjects, at the American Society of Hematology meeting being held from December 6 - 9, 2014.

In addition, Alnylam has presented extensive non-human primate data with other ESC-GalNAc-siRNA conjugates, including ALN-PCSsc - an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia - and ALN-CC5 - an investigational RNAi therapeutic targeting complement C5 for the treatment of complement-mediated diseases. Recently, the company has filed and received approval for a Clinical Trial Application (CTA) to initiate a Phase 1 study of ALN-PCSsc in normal human volunteers with elevated LDL-C; the company expects to start the Phase 1 study by the end of 2014 and plans to report initial clinical data in mid-2015. In the case of ALN-CC5, Alnylam remains on track to file a CTA by the end of 2014, and expects to report initial clinical data in mid-2015.

In addition to data on siRNA conjugates, additional proof-of-concept for GalNAc-conjugates as a potent delivery platform for RNA therapeutics was recently reported by Regulus Therapeutics with positive interim clinical data with RG-101, a GalNAc-conjugated anti-miR targeting microRNA-122 for the treatment of hepatitis C virus (HCV) infection. As reported by Regulus, interim results from an ongoing clinical study demonstrated that treatment with a single subcutaneous dose of 2 mg/kg of RG-101 as monotherapy resulted in significant and sustained reductions in HCV RNA, as well as a mean viral load reduction of 4.1 log10 at day 29; RG-101 was reported to be well tolerated in the study. Regulus has a license to Alnylam's GalNAc-conjugate technology in the field of microRNA therapeutics through the companies' 2007 license agreement. Further, Isis Pharmaceuticals has reported successful adoption of GalNAc-conjugated antisense oligonucleotides (ASOs) in pre-clinical studies. Isis has obtained a license to Alnylam's GalNAc-conjugate technology in the field of single-stranded oligonucleotide therapeutics, including ASOs, through the companies' 2004 license agreement.

Alnylam has obtained broad intellectual property protection for its GalNAc-conjugate delivery platform for RNA therapeutics. Amongst other issued and granted patents, the Manoharan et al. patent (US 8,828,956) includes claims directed to compositions including those comprising a modified RNA agent linked to a biantennary or triantennary ligand. Specifically, the patent includes claims that broadly cover single-stranded or double-stranded chemically modified RNA therapeutics conjugated with an N-acetylgalactosamine (GalNAc) ligand, independent of length, sequence, or disease target.

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 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, durability, and a wide therapeutic index, and is being employed in several of Alnylam's genetic medicine programs, including programs in clinical development.

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 5x15™" 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) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) 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 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; and other programs yet to be disclosed. As part of its "Alnylam 5x15" 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, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. 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 Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's views with respect to the potential for RNAi therapeutics, including revusiran (ALN-TTRsc) for the treatment of TTR cardiac amyloidosis, ALN-AT3 for the treatment of hemophilia and rare bleeding disorders, ALN-PCSsc for the treatment of hypercholesterolemia, and ALN-CC5 for the treatment of complement-mediated diseases, the timing of submitting regulatory filings, beginning clinical studies, and reporting data, its expectations regarding the potency and therapeutic index of GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc conjugates, its expectations regarding its "Alnylam 5x15" product strategy, and its plans regarding commercialization of RNAi therapeutics, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, the pre-clinical and clinical results for its product candidates, which may not support further development of product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials, obtaining, maintaining and protecting intellectual property, Alnylam's ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to manage operating expenses, Alnylam's ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam's dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the "Risk Factors" filed with Alnylam's most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) and in other filings that Alnylam makes with the SEC. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation to update any forward-looking statements.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
Liz Bryan (Media), 202-955-6222 x2526

Source: Alnylam Pharmaceuticals, Inc.

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