Alnylam Presents New Pre-clinical Data with its RNAi Therapeutic Program in Hemophilia

CAMBRIDGE, Mass.--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with its RNAi therapeutic for the treatment of hemophilia at the World Federation of Hemophilia World Congress being held July 8-12, 2012 in Paris. Alnylam scientists presented data comparing robust RNAi-mediated silencing of protein C (PC) and antithrombin (AT), two natural anticoagulant proteins. Studies showed that AT, an endogenous inhibitor of thrombin generation, is the optimal anticoagulant target and Alnylam has now designated ALN-AT3, an RNAi therapeutic targeting AT, as the development candidate for its hemophilia program. ALN-AT3 utilizes Alnylam's proprietary GalNAc-siRNA conjugate delivery approach enabling subcutaneous administration with the potential for a once-weekly or twice-monthly dosing regimen. In pre-clinical animal models of hemophilia, administration of ALN-AT3 resulted in increased thrombin generation demonstrating proof of concept for this novel strategy. Alnylam expects to file an investigational new drug (IND) application for ALN-AT3 in 2013.

"Our 'Alnylam 5x15' product development strategy is the foundation of our transformation from a platform company to a product company as we advance novel RNAi therapeutics with a focus on genetically defined targets for diseases where there are limited treatment options for patients and their caregivers. ALN-AT3 for the treatment of hemophilia is a key program within this strategic initiative. This effort has now advanced to development candidate status from a systematic examination of molecular targets, including AT and PC, and delivery approaches, including lipid nanoparticles and conjugates," said Akshay K. Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "We are very excited by our pre-clinical data with ALN-AT3 showing potent and durable AT knockdown with subcutaneous dosing. Further, we believe our new results demonstrate key proof of concept with this strategy as administration of ALN-AT3 was shown to improve thrombin generation in animal models of hemophilia. We anticipate filing an IND with ALN-AT3 in 2013."

"New therapeutic options are needed in hemophilia to prevent bleeding and the associated pathology. Human genetic data on co-inheritance of thrombophilic traits in patients with hemophilia support the hypothesis that inhibition of endogenous anticoagulant proteins, such as AT, can improve hemostasis," said Claude Négrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. "I am very encouraged by these new pre-clinical data with ALN-AT3 which support a novel approach for the treatment of hemophilia. Availability of a subcutaneously administered therapeutic, with long duration of action, could represent an exciting opportunity for hemophilia patients, including those with inhibitors to their replacement factor."

These new results included studies performed to identify the optimal endogenous anticoagulant target and delivery modality for further RNAi therapeutic development in hemophilia. siRNA targeting both PC and AT were designed, synthesized, and evaluated in vivo, showing robust, dose-dependent silencing of the target mRNA. An RNAi therapeutic targeting AT was selected for further development. First, using a validated in silico model of human thrombin generation, knockdown of AT was found to generate significantly higher levels of thrombin in the absence of factor VIII as compared with knockdown of PC. In addition, exogenous supplementation of human plasma depleted of both factor IX and AT showed that an approximately 50% decrease in endogenous AT can significantly correct thrombin generation in a hemophilia setting. A GalNAc-siRNA conjugate was selected as the delivery modality for further development. Specifically, a large series of GalNAc-siRNA were designed and synthesized, leading to the selection of ALN-AT3 as the program's development candidate. As a GalNAc-siRNA conjugate, ALN-AT3 achieves target gene knockdown with subcutaneous dose administration, a highly preferred mode of administration in the setting of hemophilia. Based on these results, Alnylam will be advancing ALN-AT3 for its hemophilia program in its "Alnylam 5x15" product strategy. Further efforts on ALN-APC, an RNAi therapeutic targeting PC, will therefore be stopped.

Additional data presented demonstrate that subcutaneous administration of ALN-AT3 results in potent, dose-dependent, and durable silencing of AT in pre-clinical models and that AT reduction can normalize thrombin generation in the setting of hemophilia, establishing proof of concept for this program. ALN-AT3 demonstrated potent activity in both mice and non-human primates, with an ED50 for AT plasma protein knockdown of approximately 1 mg/kg after a single subcutaneous dose. Studies showed a very durable response, where a single subcutaneous dose of ALN-AT3 achieved nadir knockdown of AT at about day 10, with effects lasting over 25 days. These data support a once-a-week or twice-a-month subcutaneous dosing paradigm. In studies performed in mouse models of hemophilia, ALN-AT3 was found to achieve dose-dependent knockdown of endogenous AT and to significantly increase thrombin generation. Specifically, in a mouse model of hemophilia, animals treated with ALN-AT3 showed a complete normalization of thrombin generation to levels found in wild-type mice. These results confirm the findings from human genetics where co-inheritance of prothrombotic traits in hemophilia patients is associated with improved hemostasis. Further, we believe these new data with ALN-AT3 establish clear pre-clinical proof of concept for this novel therapeutic strategy.

About Hemophilia

Hemophilias are hereditary disorders caused by genetic deficiencies of various blood clotting factors, resulting in recurrent bleeds into joints, muscles, and other major internal organs. Hemophilia A is defined by loss-of-function mutations in factor VIII, and there are greater than 40,000 registered patients in the U.S. and E.U. Hemophilia B, defined by loss-of-function mutations in factor IX, affects greater than 9,500 registered patients in the U.S. and E.U. Standard treatment for hemophilia patients involves replacement of the missing clotting factor either as prophylaxis or on-demand therapy. However, as many as one third of hemophilia A patients will develop an antibody to their replacement factor - a very serious complication; these 'inhibitor' patients become refractory to standard replacement therapy. There exists a small subset of hemophilia patients who have co-inherited a prothrombotic mutation, such as factor V Leiden, protein C deficiency, and prothrombin G20210A. Hemophilia patients that have co-inherited these prothrombotic mutations are characterized as having a later onset of disease, lower risk of bleeding, and reduced requirements for factor VIII or factor IX treatment as part of their disease management. There exists a significant need for novel therapeutics to treat hemophilia patients.

About Antithrombin (AT)

Antithrombin (AT, also known as "antithrombin III" and "SERPINC1") is a liver-expressed plasma protein and member of the "serpin" family of proteins that acts as an important endogenous anticoagulant by inactivating factor Xa and thrombin. AT plays a key role in normal hemostasis, which has evolved to balance the need to control blood loss through clotting with the need to prevent pathologic thrombosis through anticoagulation. In hemophilia, the loss of certain procoagulant factors (factor VIII and factor IX, in the case of hemophilia A and B, respectively) results in an imbalance of the hemostatic system toward a bleeding phenotype. In contrast, in thrombophilia (e.g., factor V Leiden, protein C deficiency, antithrombin deficiency, amongst others), certain mutations result in an imbalance in the hemostatic system toward a thrombotic phenotype. Since co-inheritance of prothrombotic mutations may ameliorate the clinical phenotype in hemophilia, inhibition of AT defines a novel strategy for improving hemostasis in this inherited bleeding disorder.

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 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 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.

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 5x15™" 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 partner-based 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, and Cubist. 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

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, its expectations regarding ALN-AT3, including the timing of an IND filing for ALN-AT3, and 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, the pre-clinical and clinical results for these product candidates, including ALN-AT3, 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.