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TMCNet:  Alnylam Presents New Pre-clinical Data on ALN-AT3, an RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders (RBD)

[December 09, 2013]

Alnylam Presents New Pre-clinical Data on ALN-AT3, an RNAi Therapeutic Targeting Antithrombin (AT) for the Treatment of Hemophilia and Rare Bleeding Disorders (RBD)

CAMBRIDGE, Mass. --(Business Wire)--

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD), at the 55th Annual Meeting of the American Society of Hematology (ASH) held December 7 - 10, 2013 in New Orleans. In these new studies, repeat administration of ALN-AT3 was found to be well tolerated in Hemophilia A (HA) mice, with no adverse findings up to dose levels 200 times greater than levels required to achieve 50% AT knockdown. Further, the new studies demonstrate that ALN-AT3 administration achieves complete correction of the activated Partial Thromboplastin Time (aPTT) - an ex vivo measure of blood coagulation that is significantly prolonged in hemophilia - in HA mice. ALN-AT3 is a key program in the company's "Alnylam 5x15" product strategy, which is aimed at advancing five RNAi therapeutic programs directed toward genetically validated disease targets into clinical development, including programs in advanced stages, by the end of 2015.

"Hemophilia and other rare bleeding disorders are characterized by deficiencies in specific clotting factors that ultimately lead to inadequate thrombin generation and a bleeding diathesis. ALN-AT3 is aimed at correcting these bleeding disorders by knockdown of AT - an endogenous anticoagulant - thus, increasing thrombin generation and improving hemostasis," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. "These new data presented at ASH demonstrate that repeat administration of ALN-AT3 is well tolerated in animal models of hemophilia, and suggest that our RNAi therapeutic has the potential for a wide therapeutic index in subjects with hemophilia. With MHRA approval of our recently filed CTA, we look forward to the advancement of ALN-AT3 in our Phase I clinical trial that we expect to start in early 2014, with data from hemophilia subjects expected by the end of next year."

"The unmet need for new therapeutic options to treat hemophilia patients remains very high, particularly in those patients that develop inhibitory antibodies to their replacement factor. Indeed, availability of a safe and effective subcutaneously administered therapeutic with a long duration of action would represent a marked improvement over currently available approaches for prophylaxis," 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. "I continue to be encouraged by Alnylam's pre-clinical progress to date with ALN-AT3, including these new data demonstrating a wide therapeutic index and correction of aPTT for ALN-AT3 in animals with hemophilia. I look forward to the advancement of this innovative therapeutic candidate in clinical studies in the months to come."

In a presentation titled "Expanded Therapeutic Index of Antithrombin Silencing and Correction of APTT in a Hemophilia A Mouse Model," Alnylam scientists presented data demonstrating that, in contrast to wild type (WT) mice, repeat administration of ALN-AT3 was very well tolerated in HA mice. Specifically, HA mice treated with ALN-AT3 exhibited no adverse events up to 100 mg/kg - a dose that is 200-fold greater than the mouse ED50 and that essentially ablates AT protein levels in blood. In fact, 100% of the treated HA mice survived, with no adverse clinical signs or changes to body weight parameters. In WT mice (with intact coagulation systems), repeat administration of over 10 mg/kg ALN-AT3 led to greater than 90% knockdown of plasma AT, and resulted in the expected procoagulant phenotype and poor tolerability. This result was expected since AT knockout in mice and homozygous AT deficiency in humans are known to be embryonic lethal (J. Clin. Invest. (2000) 106:873-878; Blood (2008) 112:19-27). To evaluate the potential reversal of ALN-AT3 efficacy, WT mice treated with 100 mg/kg ALN-AT3 were also treated with exogenous human AT protein. Co-administration of human AT conferred complete protection from prothrombotic adverse events observed in WT mice receiving ALN-AT3 alone, demonstrating that human AT protein could serve as a potential reversal agent for ALN-AT3, if needed. In addition, HA mice treated with ALN-AT3 exhibited significant reductions in aPTT relative to control HA mice. Specifically, the aPTT in HA mice, which is significantly prolonged, was corrected back to aPTT values observed in WT mice. Collectively, these data suggest a substantially expanded therapeutic index of AT knockdown in the hemophilia disease condition, and confirm the active effects for ALN-AT3 that are expected to reset insufficient thrombin generation in people with hemophilia.

Alnylam remains on track to begin a Phase I trial with ALN-AT3 early in 2014. Alnylam announced today that it has received CTA approval from the MHRA for the initiation of the Phase I clinical study. The study will be conducted in the U.K. as a single- and multi-dose, dose-escalation study consisting of two parts. The first part will be a randomized, single-blind, placebo-controlled, single-dose, dose-escalation study, enrolling up to 24 healthy volunteer subjects. Only low doses of ALN-AT3 will be administered in this part of the study with stopping rules at greater than 40% AT knockdown, which is believed to be a well tolerated level of AT knockdown based on pre-clinical studies, in addition to data from people with heterozygous AT deficiency. The primary objective of the first part of the study is to evaluate the safety and tolerability of a single dose of subcutaneously administered ALN-AT3. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels. The second part of the study will be an open-label, multi-dose, dose-escalation study enrolling up to 18 people with moderate to severe hemophilia A or B. The primary objective of this part of the study is to ealuate the safety and tolerability of multiple doses of subcutaneously administered ALN-AT3 in hemophilia subjects. Secondary objectives include assessment of clinical activity as determined by knockdown of circulating AT levels and increase in ex vivo thrombin generation.


About Hemophilia and Rare Bleeding Disorders (RBD)
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 (RBD) are defined by congenital deficiencies of other blood coagulation factors, including Factors II, V, VII, X, and XI, and there are about 1,000 patients worldwide with a severe bleeding phenotype. 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, antithrombin deficiency, 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-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. 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.

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 (News - Alert) 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 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 familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-ANG, an RNAi therapeutic for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, amongst other programs. 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 partnered programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection and ALN-VSP for the treatment of liver cancers. 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, Genzyme, and The Medicines Company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. 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, Cell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About "Alnylam 5x15™"
The "Alnylam 5x15" strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics toward genetically defined targets for the treatment of 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: patisiran (ALN-TTR02), an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) in development for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR in development for the treatment of ATTR in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) in development for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-ANG, an RNAi therapeutic for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, amongst other programs. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in North and South America, Europe, and other parts of the world.

Alnylam Forward-Looking Statements
Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's expectations regarding its "Alnylam 5x15" product strategy, Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-AT3, its expectations regarding the potential for ALN-AT3 to have a wide therapeutic index in the hemophilia disease condition, its expectations with respect to the timing, execution, and success of its clinical trials for ALN-AT3, its expectations regarding the potential use of human AT as a reversal agent for ALN-AT3, and its expectations regarding the potential market opportunity for ALN-AT3, 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 manage operating expenses, 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 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 (News - Alert)) 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.


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