Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Hemophilia and Other Bleeding Disorders at 54th American Society of Hematology (ASH) Annual Meeting


Alnylam Presents New Pre-clinical Data on RNAi Therapeutics for the Treatment of Hemophilia and Other Bleeding Disorders at 54th American Society of Hematology (ASH) Annual Meeting
– Efficacy for ALN-AT3, an RNAi Therapeutic Targeting Antithrombin for the Treatment of Hemophilia, Demonstrated in Non-Human Primate Models –
– Progress from the Therapeutic Program to be Included in an Upcoming RNAi Roundtable on Conjugate Delivery –
CAMBRIDGE, Mass.--Dec. 10, 2012-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data from its RNAi therapeutic program for the treatment of hemophilia and other bleeding disorders at the 54th American Society of Hematology Annual Meeting being held December 8-11, 2012 in Atlanta. Alnylam scientists presented data showing that ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT), yields potent, dose-dependent, and durable knockdown of AT in non-human primates (NHPs) with an up to four-fold increase in thrombin generation. Alnylam's program in hemophilia comprises part of its 'Alnylam 5x15' product strategy, by which the company aims to advance five programs in clinical development, including programs in advanced stages, by the end of 2015.
"Our ALN-AT3 program is central to our 'Alnylam 5x15' strategy, which is aimed at bringing innovative medicines to patients, with a focus on RNAi therapeutics toward genetically defined targets for diseases with very high unmet medical need. Hemophilia and other bleeding disorders exemplify these types of diseases, as there remains significant need for new treatment options," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "The new data with ALN-AT3 demonstrate potent and sustained knockdown of serum antithrombin and marked increases in thrombin generation in non-human primates. ALN-AT3 utilizes our GalNAc-siRNA conjugate delivery approach enabling subcutaneous dose administration, and is on track for an investigational new drug filing in mid-2013."
"New therapeutic options are needed for patients with hemophilia, including those with inhibitors to their replacement factors, to prevent bleeding and the associated pathology. In addition, there is growing recognition of unmet need in patients with other rare bleeding disorders where congenital deficiencies of blood coagulation factors result in impaired thrombin generation and bleeding diatheses," said Claude Negrier, M.D., head of the Hematology Department and director of the Haemophilia Comprehensive Care Centre at Edouard Herriot University Hospital in Lyon. "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. In aggregate, I am very encouraged by the emerging pre-clinical data on ALN-AT3. Indeed, availability of a subcutaneously administered therapeutic with a long duration of action could represent an exciting opportunity for hemophilia patients including those with inhibitors to their replacement factor, and patients with other rare bleeding disorders."
In a poster titled "An RNAi Therapeutic Targeting Antithrombin Increases Thrombin Generation in Nonhuman Primates," (#3370) Alnylam scientists showed that subcutaneous administration of ALN-AT3 in NHPs results in potent, dose-dependent, and durable knockdown in serum AT, resulting in significant increases in thrombin generation. Specifically, a single subcutaneous dose of ALN-AT3 led to potent knockdown of serum AT, with an ED50 of 1 mg/kg. AT suppression was durable, with effects lasting greater than six weeks after a single dose. In addition, weekly subcutaneous doses of ALN-AT3 in NHPs led to sustained AT knockdown of approximately 80% and greater than 90% at 0.5 mg/kg and 1.5 mg/kg, respectively. These data enable an estimation of an ED50 dose for weekly subcutaneous administration at 0.15-0.3 mg/kg at a volume of injection for human administration expected to be less than 0.5 mL/injection. Moreover, increased thrombin generation was closely correlated with AT reduction, with an up to four-fold increase in peak thrombin at 90% AT reduction. ALN-AT3 utilizes Alnylam's proprietary GalNAc-siRNA conjugate delivery approach enabling subcutaneous dose administration with potential for a once-weekly or twice-monthly dosing regimen. Alnylam expects to file an investigational new drug (IND) application for ALN-AT3 in mid-2013.
In addition, results from Alnylam's ALN-AT3 program will be discussed at an upcoming RNAi Roundtable on conjugate delivery that the company will host on Friday, December 14 at 11:00 a.m. ET. The discussion will focus on progress with the company's proprietary GalNAc-conjugate platform to deliver RNAi therapeutics with subcutaneous dose administration. The roundtable will also include a review of the company's two leading conjugate programs: ALN-TTRsc for the treatment of transthyretin-mediated amyloidosis (ATTR) and ALN-AT3 for the treatment of hemophilia and other bleeding disorders. The webinar will be available live on the Capella section of the company's website,, and will also be available for replay on the Alnylam website within 48 hours after the event.
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. Other Rare Bleeding Disorders (RBDs) are defined by congenital deficiencies of other blood coagulation factors. 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.
About GalNAc Conjugates
GalNAc-siRNAs are designed to achieve targeted delivery of RNAi therapeutics to hepatocyte cells of the liver through uptake by the asialoglycoprotein receptor. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple 'Alnylam 5x15' programs. Notably, GalNAc-siRNAs are being employed in Alnylam's ALN-TTRsc and ALN-AT3 RNAi therapeutic programs for the treatment of transthyretin-mediated amyloidosis (ATTR) and hemophilia and other bleeding disorders, respectively, both of which the company expects to have in clinical trials in 2013. GalNAc-siRNAs are a proprietary Alnylam delivery platform.
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 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, Ascletis, Monsanto and Genzyme. 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, Sanofi, AstraZeneca and Biogen Idec. 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 and its proprietary GalNAc-siRNA delivery platform, its expectations regarding the development of ALN-AT3, including the timing of an IND filing for ALN-AT3, its expectations regarding the initiation of clinical trials for ALN-TTRsc, 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, including drug candidates utilizing GalNAc-siRNA delivery, the pre-clinical and clinical results for these product candidates, including ALN-AT3 and ALN-TTRsc, 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.
Source: Alnylam Pharmaceuticals, Inc.
Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
Amanda Sellers, 202-955-6222 x2597

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