Alnylam Presents New Data from its Conjugate Delivery Platform, Enabling Subcutaneous Administration of RNAi Therapeutics with Wide Therapeutic Index

Alnylam Presents New Data from its Conjugate Delivery Platform, Enabling Subcutaneous Administration of RNAi Therapeutics with Wide Therapeutic Index

– New Pre-clinical Data from 'Alnylam5x15' Programs Including ALN-TTRsc for the Treatment of Transthyretin-Mediated Amyloidosis (ATTR) and ALN-AT3 for the Treatment of Hemophilia –

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Aug. 6, 2012-- Alnylam Pharmaceuticals, Inc.(Nasdaq: ALNY), a leading RNAi therapeutics company, is presenting new data today from its GalNAc-conjugate siRNA programs for the systemic delivery of RNAi therapeutics at the XX International Roundtable on Nucleosides, Nucleotides and Nucleic Acids being held August 5-9 in Montreal, Canada. GalNAc-conjugate siRNA are designed to achieve targeted delivery of RNAi therapeutics to hepatocyte cells of the liver through uptake by the asialoglycoprotein receptor. The research findings demonstrate potent and durable target gene silencing with subcutaneously administered GalNAc-conjugate siRNA from Alnylam's ALN-TTRsc and ALN-AT3 pre-clinical programs. In addition, extensive safety evaluation studies demonstrate a wide therapeutic index for GalNAc-conjugate siRNA. ALN-TTRsc is an RNAi therapeutic targeting transthyretin (TTR) for the treatment of transthyretin-mediated amyloidosis (ATTR), and ALN-AT3 is an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia; both are key programs in the 'Alnylam 5x15' product development strategy.

"Our conjugate delivery platform is now ready for clinical translation, and enables subcutaneous dose administration of RNAi therapeutics with a very wide therapeutic index. We believe these advances clearly extend the potential of RNAi medicines, complementing the success we have already achieved in systemic delivery with lipid nanoparticles," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "We are very excited to now fully integrate this delivery approach in our 'Alnylam 5x15' efforts with ALN-TTRsc for the treatment of ATTR, ALN-AT3 for the treatment of hemophilia, and potentially future programs. We anticipate submitting investigational new drug applications for ALN-TTRsc by the end of 2012 and for ALN-AT3 in 2013."

Data presented today showed potent, dose-dependent, and durable knockdown of serum TTR with Alnylam's GalNAc-conjugate approach in its ALN-TTRsc pre-clinical program. Specifically, subcutaneous administration of ALN-TTRsc resulted in potent and sustained suppression of TTR, the disease-causing protein in ATTR. In non-human primates, ALN-TTRsc was administered in a loading regimen of once a day for five days, followed by a maintenance regimen of once a week for four weeks resulting in an approximately 80% reduction of TTR at doses as low as 2.5 mg/kg. TTR knockdown was achieved rapidly, with nadir TTR levels observed at about day 14. Suppression of TTR of approximately 80% was sustained with a weekly maintenance dose, and recovery to baseline levels was observed at day 40 after the last dose. At an ED80 dose of 2.5 mg/kg and based on solubility of the GalNAc-siRNA, subcutaneous administration of ALN-TTRsc is expected to be achieved in human studies at a dose volume of approximately 1 mL. In single dose and multi-dose pre-clinical safety studies in rodents and non-human primates, ALN-TTRsc was found to be generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection site reactions. Therefore, the "no adverse effect level," or "NOAEL," was determined to be greater than or equal to 300 mg/kg and the therapeutic index was determined to exceed 100-fold.

In addition, new data was presented from Alnylam's ALN-AT3 program, which targets AT for the treatment of hemophilia. Results from a pre-clinical rodent study demonstrated that weekly subcutaneous administration of ALN-AT3 resulted in potent and durable AT suppression. Specifically, repeat dosing with ALN-AT3 showed an ED50 for AT plasma protein knockdown of less than 0.75 mg/kg. Knockdown of AT was achieved rapidly, with nadir suppression observed at day 14. Weekly injections at doses as low as 0.75 mg/kg provided sustained AT knockdown of approximately 80%. In addition, subcutaneous administration of ALN-AT3 in non-human primates also resulted in potent, dose-dependent, and durable AT knockdown, with an ED50 for AT knockdown of approximately 1 mg/kg after a single dose. Studies in non-human primates showed a very durable response, where a single subcutaneous dose of ALN-AT3 achieved nadir knockdown of AT plasma levels at about day 15, with effects lasting over 22 days. Alnylam believes these data will support a once-a-week or twice-a-month subcutaneous dosing paradigm for ALN-AT3, at doses less than 1 mg/kg and injection volumes of less than 1 mL. ALN-AT3 was found to be generally safe and well tolerated in these pre-clinical studies.

About RNA Interference (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 RNAs (siRNAs), 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 for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. As part of its "Alnylam 5x15TM" strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in clinical development, including programs in advanced stages, on its own or with a partner by the end of 2015. Alnylam has additional partnered programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington's disease. The company's leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, and Ascletis. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for applications in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam's VaxiRNA™ platform applies RNAi technology to improve the manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

About "Alnylam 5x15™"

The "Alnylam 5x15" strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in Phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. By the end of 2015, the company expects to have five such RNAi therapeutic programs in clinical development, including programs in advanced stages, on its own or with a partner. The "Alnylam 5x15" programs include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in the United States and potentially certain other countries; the company will seek development and commercial alliances for other core programs both in the United States and in other global territories.

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, statements regarding Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-TTRsc and ALN-AT3, its expectations with respect to the timing of submitting regulatory filings for ALN-TTRsc and ALN-AT3, its advances in certain systemic delivery approaches, including novel GalNAc-conjugate siRNA, the potential of such novel approaches for RNAi therapeutic development, and Alnylam's expectations regarding its "Alnylam 5x15" product strategy, 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, successfully demonstrate the efficacy and safety of its drug candidates, including ALN-TTRsc and ALN-AT3, Alnylam's ability to discover and develop novel delivery approaches, such as GalNAc-conjugate siRNA, and successfully demonstrate the efficacy and safety of its delivery approaches, such as GalNAc-conjugate siRNA, the pre-clinical and clinical results for these product candidates, which may not support further development of such product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, obtaining, maintaining and protecting intellectual property, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, and Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, as well as those risks more fully discussed in the "Risk Factors" section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. 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 does not assume any obligation to update any forward-looking statements.