New Alnylam Pre-clinical Results on ALN-CC5, an RNAi Therapeutic Targeting Complement Component C5 for the Treatment of Complement-Mediated Diseases, Demonstrate up to 98% Serum C5 Knockdown and up to 94% Inhibition of Hemolytic Activity in Non-Human Primates – New Research Findings Presented at 55^th Annual Meeting of the American Society of Hematology (ASH) Confirm Potential of Subcutaneously Administered RNAi Therapeutic Strategy – – Alnylam Now Expects to Designate its ALN-CC5 Development Candidate in Early 2014 with an IND Filing Planned for Early 2015 – ASH 2013 Business Wire CAMBRIDGE, Mass. -- December 8, 2013 Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today that it has presented new pre-clinical data with ALN-CC5, a subcutaneously administered RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases. These data were presented at the 55^th Annual Meeting of the American Society of Hematology (ASH) held December 7 – 10, 2013 in New Orleans, and demonstrate that subcutaneous administration of ALN-CC5 in non-human primates (NHPs) led to an up to 98% knockdown of serum C5 and an up to 94% inhibition of hemolytic activity. Alnylam believes that ALN-CC5 – part of the company’s “Alnylam 5x15” product strategy – represents a novel approach for the treatment of complement-mediated diseases, with a potentially competitive profile compared with intravenously administered anti-C5 monoclonal antibody therapy. In addition, Alnylam presented two separate posters with new pre-clinical data on ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders. “C5 is both a genetically and clinically validated target that exemplifies the potential of Alnylam’s ‘5x15’ product strategy for innovative new medicines. First, C5 is predominantly expressed in liver, where we have established robust clinical activity and tolerability for RNAi therapeutics. In addition, our clinical development plan for ALN-CC5 will be facilitated by serum biomarkers in Phase I trials and what we believe will be a relatively streamlined and focused path for advanced development,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “These new non-human primate data demonstrate that ALN-CC5 can achieve up to 98% knockdown of serum C5 and up to 94% inhibition of hemolytic activity, at the lower limits of quantitation in these assays. We believe that this effect is likely to yield clinical benefit in the context of a disease like paroxysmal nocturnal hemoglobinuria (PNH), in which a greater than 80% inhibition of hemolytic activity is a clinically established target level based on published data with eculizumab, an intravenously administered monoclonal antibody that binds to serum C5. In sum, we believe that a subcutaneously administered RNAi therapeutic that blocks C5 synthesis could represent an important advance for the treatment of a broad range of complement-mediated diseases.” “The complement system plays a central role in immunity as part of host defense. However, dysregulation of this pathway can lead to life-threatening complications in a wide range of human diseases including PNH, atypical hemolytic uremic syndrome (aHUS), neuromyelitis optica, amongst others,” said Jeff Szer, M.D., Professor and Director of the Department of Clinical Haematology and Bone Marrow Transplant Service at Royal Melbourne Hospital and Director at the Western and Central Melbourne Integrated Cancer Service. “I am very encouraged by these pre-clinical data showing potent, dose-dependent, and durable knockdown of serum C5 with greater than 90% inhibition of hemolytic activity using a subcutaneously administered RNAi therapeutic. If these results can be extended to the clinical setting, I believe that they could represent a very promising therapeutic strategy and potential new treatment option for patients with complement-mediated diseases.” In a presentation titled “Development of RNAi Therapeutics Targeting the Complement Pathway” Alnylam scientists presented data showing robust, dose-dependent, and durable knockdown of serum C5 in NHPs. Multiple doses of ALN-CC5 at 2.5 or 5.0 mg/kg led to rapid and dose-dependent knockdown of serum C5 of up to 97.8%, with mean knockdown at nadir of 97.5% (p<0.001) at the top dose. Knockdown of C5 was durable, with greater than 90% knockdown sustained for up to three weeks after the final dose. Further, subcutaneous administration resulted in a consistent greater than 80% knockdown of C5 during the treatment period. The results are consistent with published literature that shows an hepatic origin for the vast majority of circulating C5, and confirms that the serum component of locally produced C5 is minimal at best. In addition, multi-dose administration of ALN-CC5 resulted in robust and durable inhibition of hemolytic activity. At the top dose of 5.0 mg/kg, an up to 94% inhibition of hemolytic activity was observed, with a mean nadir reduction of 92% (p<0.01). Inhibition of hemolytic activity was sustained for at least two weeks after the final dose. Further, inhibition of hemolytic activity was shown to be highly correlated with serum levels of C5 (r^2=0.93, p<10^-15). Importantly, a greater than 80% inhibition in hemolytic activity has been previously validated in studies of eculizumab, an intravenously administered monoclonal antibody targeting C5, in patients with PNH as being associated with clinical benefit (N. Engl. J. Med. (2004) 350:552-559; N. Engl. J. Med. (2006) 355:1233-1243). A summary of key data are provided below: Serum C5 Knockdown and Inhibition of Hemolytic Activity in NHPs % C5 % Dose Max C5 Knockdown Max % Hemolysis (mg/kg) Knockdown at Hemolysis Inhibition (%) Nadir, Inhibition at Nadir, Mean (SD) Mean (SD) 2.5 96.5 94.9 82.4 74.9 (1.7)*** (8.9)^+ 5.0 97.8 97.5 93.5 91.8 (0.3)*** (2.1)** ^+ p < 0.1, * p < 0.05, ** p < 0.01, *** p < 0.001 p values correspond to post hoc pairwise comparisons (under ANOVA models) of dose groups (n=3) vs. control (n=1) The essentially complete knockdown of C5 was well tolerated in NHPs, as evidenced by no changes in hematology, serum chemistry, or coagulation parameters at 24 hours after the last dose. Alnylam is continuing to optimize its C5-targeted siRNA lead candidate, and now expects to identify its final Development Candidate for ALN-CC5 in early 2014 and to file an Investigational New Drug (IND) application or IND equivalent in early 2015. In addition, in two posters titled “ALN-TMP: A subcutaneously administered RNAi therapeutic targeting Tmprss6 for the treatment of β-Thalassemia” and “An RNAi-Therapeutic Targeting Tmprss6, in Conjunction With Oral Chelator Therapy, Ameliorates Anemia and Additively Diminishes Secondary Iron Overload In a Mouse Model Of β-Thalassemia Intermedia,” Alnylam scientists presented new pre-clinical data from the company’s ALN-TMP program. The new study showed that weekly subcutaneous administration of ALN-TMP resulted in robust knockdown of TMPRSS6 mRNA in mice, with about 90% knockdown (p<0.0001) at a dose of 1.0 mg/kg. This level of knockdown was associated with a two-fold increase in hepcidin levels (p<0.05), and a greater than 50% decrease in transferrin saturation (p<0.001). The data also demonstrated a linear relationship between TMPRSS6 mRNA silencing and transferrin saturation, suggesting that ALN-TMP can modulate iron restriction in a predictable manner. In addition, studies in a mouse model of β-thalassemia intermedia (Hbb^th3/+ mice) were conducted to explore the effects of ALN-TMP in combination with the iron chelator deferiprone compared to either treatment alone. Administration of ALN-TMP, but not deferiprone, was shown to ameliorate anemia and extramedullary hematopoiesis, including increases in hemoglobin, decreases in serum erythropoietin, and reduction in splenomegaly. On the other hand, ALN-TMP and deferiprone were found to act in an additive manner toward reducing serum and liver iron levels. These new findings suggest that combined ALN-TMP and iron chelation therapy may provide improved management of secondary iron overload in β-thalassemia, including thalassemia major, and also support the potential for ALN-TMP as a therapeutic option in a broader range of iron overload disorders. About ALN-CC5 ALN-CC5 is an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases. The complement system plays a central role in immunity as a protective mechanism for host defense, but its dysregulation results in life-threatening complications in a broad range of human diseases including paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic-uremic syndrome (aHUS), myasthenia gravis, neuromyelitis optica, amongst others. Complement component C5, which is predominantly expressed in liver cells, is a genetically and clinically validated target; loss of function human mutations are associated with an attenuated immune response against certain infections and intravenous anti-C5 monoclonal antibody therapy has demonstrated clinical activity and tolerability in a number of complement-mediated diseases. A subcutaneously administered RNAi therapeutic that silences C5 represents a novel approach to the treatment of complement-mediated diseases. ALN-CC5 utilizes Alnylam’s proprietary GalNAc conjugate delivery platform enabling subcutaneous dose administration. About ALN-TMP ALN-TMP comprises a systemically delivered RNAi therapeutic targeting transmembrane protease, serine 6 (Tmprss6) for the treatment of β-thalassemia and iron overload disorders. These blood disorders are associated with chronic anemia, extra-medullary hematopoiesis, and ineffective erythropoiesis. Tmprss6, a genetically validated target expressed on hepatocytes, functions by cleaving hemojuvelin, resulting in reduced hepcidin levels and increased iron mobilization. Pre-clinical animal model studies with ALN-TMP have demonstrated corrective effects on iron overload in addition to broader disease modifying effects including improvements in hemoglobin levels, spleen histopathology, and globin gene expression. 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. 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-CC5 and ALN-TMP, and its expectations regarding selection of a Development Candidate and filing of an Investigational New Drug (IND) application for ALN-CC5, 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) 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. Contact: Alnylam Pharmaceuticals, Inc. Cynthia Clayton, 617-551-8207 Vice President, Investor Relations and Corporate Communications or Spectrum Amanda Sellers, 202-955-6222 x2597 Media
New Alnylam Pre-clinical Results on ALN-CC5, an RNAi Therapeutic Targeting Complement Component C5 for the Treatment of
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