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

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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 rare bleeding disorders. The data were presented at the XXIV Congress of the International Society on Thrombosis and Haemostasis (ISTH) being held June 29 – July 4, 2013 in Amsterdam. The new pre-clinical data demonstrate that ALN-AT3, a subcutaneously administered RNAi therapeutic targeting antithrombin (AT), can normalize thrombin generation and improve hemostasis in hemophilia mice and fully correct thrombin generation in a non-human primate (NHP) hemophilia “inhibitor” model. 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. ALN-AT3 utilizes the company's proprietary GalNAc conjugate delivery platform which enables subcutaneous dose administration.

“Hemophilia and other rare bleeding disorders are characterized by deficiencies in clotting factors that ultimately lead to inadequate thrombin generation and a bleeding phenotype. ALN-AT3 is aimed at correcting these defects by knockdown of AT – an endogenous anticoagulant – thus, increasing thrombin generation and improving hemostasis. This innovative approach is strongly supported in human genetics by findings in hemophilia patients who have co-inherited prothrombotic traits, including AT deficiency, and are characterized with a mild bleeding phenotype,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “We are very excited by these new data with ALN-AT3 which demonstrate normalization of thrombin generation and improvement of hemostasis in hemophilia models. Most importantly, we have demonstrated that ALN-AT3 can fully correct thrombin generation in a non-human primate hemophilia ‘inhibitor' model, providing key proof of concept for our program. Finally, by administering highly exaggerated doses of ALN-AT3 to wild type and hemophilia animals, we've demonstrated that our RNAi therapeutic has a very wide therapeutic index in the hemophilia setting. We remain on track to file an investigational new drug application for ALN-AT3 in mid-2013 and to initiate our Phase I study in late 2013.”

“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 am very encouraged by Alnylam's pre-clinical progress to date with ALN-AT3, especially the results in a non-human primate hemophilia ‘inhibitor' model showing full correction of impaired thrombin generation. These results are particularly important since clinical studies have demonstrated that thrombin generation correlates strongly with bleeding phenotype; severe hemophilia patients have low thrombin generation as compared to moderate and mild patients who have significantly higher levels. I very much look forward to the advancement of this important program in the clinical setting in the months to come.”

In a presentation titled “An RNAi Therapeutic Targeting Antithrombin Increases Thrombin Generation and Improves Hemostasis,” Alnylam scientists and collaborators presented data demonstrating efficacy of ALN-AT3 in models of hemophilia. First, a series of studies were performed in murine models of hemophilia. A single subcutaneous dose of ALN-AT3 that resulted in plasma AT reduction of 90% led to normalization of thrombin generation in hemophilia B (HB) mice. In addition, in a microvessel laser injury model, both hemophilia A (HA) and HB mice treated with a single subcutaneous dose of ALN-AT3 demonstrated marked improvements in hemostatic plug formation compared to untreated HA or HB mice. Additional studies were performed in NHP models. In wild type NHPs, repeat dosing with ALN-AT3 resulted in potent, titratable, and reversible silencing of plasma AT3. Weekly subcutaneous doses of 0.50 mg/kg resulted in 90% AT knockdown, while an ED50 knockdown was achieved at a dose as low as 0.125 mg/kg. Dosing was continued for over five months with consistent pharmacologic effects, including no evidence of tachyphylaxis or any neutralizing immune response associated with prolonged exposure to ALN-AT3. Studies were then performed in an NHP hemophilia “inhibitor” model, in which a HA phenotype was induced via administration of a polyclonal anti-factor VIII antibody. The anti-factor VIII antibody treatment resulted in a sharp decrease in plasma factor VIII activity levels to less than 1% of normal, similar to a severe hemophilia state in the presence of anti-factor VIII inhibitors. Animals received six weekly doses of saline or ALN-AT3 at 0.25 or 0.50 mg/kg. ALN-AT3 treated animals showed the expected level of AT knockdown but also showed a statistically significant (p<0.01 by ANOVA) dose-dependent increase in thrombin generation, fully restoring this hemostatic parameter back to normal levels. These results demonstrate that ALN-AT3 can normalize thrombin generation in the absence of functional levels of factor VIII and/or in the presence of anti-factor VIII antibodies in a large animal model, providing key proof of concept for the program.

ALN-AT3 Pre-clinical Efficacy in NHP Hemophilia “Inhibitor” Model N AT Knockdown (Mean % ± SD) Peak Thrombin (nM) (Mean ± SD) Peak Thrombin (% of Normal, Pre-Dose) Normal Pre-dose 12+ - 97 ± 36 - HA Inhibitor Saline 4 - 37 ± 9 38% 0.25 mg/kg 4 60 ± 10 58 ± 6 60% 0.50 mg/kg 4 80 ± 6 97 ± 27** 100% ** p < 0.01, Dunnett's post hoc test vs. saline + 12 animals x 3 pre-dose measurements per animal

In addition, Alnylam presented results of tolerability studies that demonstrate a wide therapeutic index for ALN-AT3 in the hemophilia setting. Highly exaggerated doses of ALN-AT3 resulting in essentially complete ablation of AT were evaluated in wild-type and hemophilia mice. Specifically, weekly doses of ALN-AT3 at 10 or 30 mg/kg in wild-type mice were associated with mortality, consistent with the genetics of homozygous AT deficiency which is known to be embryonic lethal. In sharp contrast, seven weekly doses of greater than 100 mg/kg were very well tolerated in HA mice; 100% of animals survived, and there were no toxicologically significant findings in clinical or anatomic pathology exams. Furthermore, single doses as high as 500 mg/kg were very well tolerated in both HA and HB mice. Since ALN-AT3 efficacy toward improved hemostasis is achieved at weekly doses less than 1 mg/kg, these results support a greater than 100-fold therapeutic index for ALN-AT3 in the hemophilia setting.

Alnylam plans to file an investigational new drug (IND) application for ALN-AT3 in mid-2013. The company then plans to initiate a Phase I clinical trial in late 2013, with initial clinical data for ALN-AT3 in hemophilia patients expected to be reported in 2014.

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 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.

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