Alnylam Presents New Pre-clinical Data On RNAi Therapeutics For The Treatment Of Hemoglobinopathies At 54th American Society Of Hematology (ASH) Annual Meeting

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 hemoglobinopathies at the 54 th American Society of Hematology Annual Meeting being held December 8-11, 2012 in Atlanta. Alnylam scientists presented data showing that ALN-TMP, an RNAi therapeutic targeting Tmprss6, leads to disease modifying effects, including a correction in globin gene expression, in a model of β-thalassemia. These studies were conducted in collaboration with Boston Children’s Hospital. Alnylam’s program in hemoglobinopathies 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 ‘Alnylam 5x15’ strategy 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. ALN-TMP exemplifies this strategy where we are advancing RNAi therapeutics for the treatment of hemoglobinopathies,” 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-TMP where we have demonstrated disease modifying effects in models of β-thalassemia, including amelioration of anemia, iron overload, extra-medullary hematopoiesis, and ineffective erythropoiesis, in addition to correction of globin gene expression.”

“Mouse genetic studies have shown that knockdown of Tmprss6 and up-regulation of the hepcidin pathway can result in disease modifying effects in models of β-thalassemia, a disease of enormous worldwide burden with limited treatment options for certain groups of patients. Our studies with ALN-TMP, an RNAi therapeutic targeting Tmprss6, recapitulate these genetic findings with an innovative pharmacologic strategy. This work is an example of how rare disease research that brings in RNA silencing technologies to ‘target the untargetable’ could rapidly lead to therapies for more common disorders,” said Mark Fleming, M.D., D.Phil., Pathologist-in-Chief at Boston Children’s Hospital and S. Burt Wolbach Professor of Pathology at Harvard Medical School, who collaborated on the work. “Specifically, we have demonstrated that ALN-TMP administration results in disease modifying effects in a model of β-thalassemia. Indeed, our studies show that ALN-TMP administration results in reduced iron overload, decreased extra-medullary hematopoiesis, increased hemoglobin levels, and a reduction in ineffective erythropoiesis. Further, we have found that these effects are accompanied by a decrease in membrane-associated hemoglobin, one of the primary causes of the decreased red blood cell survival in β-thalassemia. Clearly, these results could be of significance for the treatment of patients with β-thalassemia and possibly other hemoglobinopathies.”

In a poster titled RNAi-Mediated Inhibition of Tmprss6 Ameliorates Anemia and Secondary Iron Overload in a Mouse Model of β-Thalassemia Intermedia and Decreases Iron Overload in Hfe-/- Mice ,” (#1018) Alnylam scientists presented data showing that systemic administration of ALN-TMP, an RNAi therapeutic targeting Tmprss6, resulted in disease modifying effects in a model of β-thalassemia. In addition, ALN-TMP demonstrated pre-clinical efficacy in a model of hereditary hemochromatosis. In the pre-clinical studies, ALN-TMP administration resulted in a greater than 80% silencing of Tmprss6 mRNA levels and a greater than two-fold elevation of Hamp1, the gene that encodes for hepcidin, a liver hormone that negatively regulates iron transport and absorption. ALN-TMP administration resulted in an approximately 30% decrease in serum iron and non-heme liver iron, as well as a similar reduction in transferrin saturation. In a mouse model of β-thalassemia, ALN-TMP reduced the severity of anemia as evidenced by an approximately 1 g/dL increase in total hemoglobin. Moreover, treatment with ALN-TMP was found to significantly attenuate extra-medullary hematopoiesis, including a two-to-three fold reduction in spleen size. Treatment with ALN-TMP also decreased ineffective erythropoiesis, with a three-to-four fold decrease in reticulocyte count, an approximate 30% increase in red blood cell count (RBC), and a normalization of RBC morphology and lifespan. Finally, ALN-TMP administration was found to restore the ratio of alpha globin to beta globin, thereby correcting the genetic defect associated with β-thalassemia with possible implications for the treatment of other hemoglobinopathies such as sickle cell anemia.

In addition, Alnylam announced today that its research studies on ALN-TMP have been published in the journal Blood ( doi: 10.1182/blood-2012-09-453977) .

About ALN-TMP and Hemoglobinopathies

ALN-TMP comprises a systemically delivered RNAi therapeutic targeting transmembrane protease, serine 6 (Tmprss6) for the treatment of hemoglobinopathies, including β-thalassemia and sickle cell anemia. Hemoglobinopathies are associated with chronic anemia, extra-medullary hematopoiesis, and iron overload. 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 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 5x15 TM” 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.

About LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

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, including ALN-TMP, 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-TMP, 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.

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