New ALN-PCSsc data presented at AHA are based on studies performed in NHPs. Updated results show that ALN-PCSsc led to an up to 95% knockdown of plasma PCSK9, with mean PCSK9 knockdown at nadir of 87% (p<0.0001 compared with pre-dose values according to ANOVA models) and an up to 67% lowering of LDL-C, with mean LDL-C lowering at nadir of 62% (p<0.0001 compared with pre-dose values). The level of LDL-C reduction was achieved in the absence of statin co-administration. Knockdown of PCSK9 and lowering of LDL-C was rapid and durable, with effects lasting greater than 50 days after the final dose, supportive of the potential for once-monthly dosing and a highly competitive target product profile. In February 2013, Alnylam formed an exclusive global alliance with The Medicines Company for the development and commercialization of the ALN-PCS program, including ALN-PCSsc. Alnylam and The Medicines Company have recently announced selection of their Development Candidate for ALN-PCSsc. Alnylam plans to file an Investigational New Drug (IND) application in 2014 and will lead the program through the completion of Phase I. The Medicines Company is responsible for leading and funding development from Phase II forward and commercializing the ALN-PCS program if successful.In addition to updating data on the company’s PCSK9 program, Alnylam scientists and collaborators presented new pre-clinical data from the company’s ALN-ANG discovery program. ANGPTL3 is an inhibitor of cellular lipases involved in the metabolism of lipoproteins. Human genetic as well as exome sequencing studies have identified a statistically significant relationship of loss-of-function mutations in ANGPTL3 with decreased levels of triglycerides and LDL-C ( N. Engl. J. Med (2010) 363:2220-2227). The new pre-clinical studies were performed in an “ob/ob” mouse model of obesity and mixed hyperlipidemia. A single dose of a GalNAc-siRNA targeting ANGPTL3 was found to lead to robust, dose-dependent knockdown of ANGPTL3 protein, with a single dose ED 50 of approximately 1 mg/kg. In a multi-dose experiment, subcutaneous doses of 3.0 mg/kg led to a greater than 95% knockdown of ANGPTL3 protein. This ANGPLT3 protein reduction resulted in a greater than 95% reduction in triglycerides, and a more than 85% reduction in LDL-C. In addition, total cholesterol was reduced by greater than 60%. These new data with ALN-ANG support further advancement of this program for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia, which are associated with increased risk of coronary artery disease and/or recurrent pancreatitis. “Cardiovascular disease remains the leading cause of mortality worldwide. Elevated LDL-C and triglycerides are two well validated and modifiable risk factors. A substantial number of patients, especially those at high risk for cardiovascular disease, are unable to achieve reduced levels of LDL and triglycerides with current drugs, such as statins or fibrates, and it is clear that new therapeutic options are needed,” said Daniel J. Rader, M.D., professor of Medicine and chief, Division of Translational Medicine and Human Genetics, at the Perelman School of Medicine at the University of Pennsylvania. Dr. Rader also serves on Alnylam’s Scientific Advisory Board. “As a key regulator of LDL receptor levels, liver-expressed PCSK9 is an important and well validated novel target in molecular medicine for the treatment of hypercholesterolemia. Likewise, loss-of-function ANGPTL3 mutations in humans are associated with reduced levels of LDL-C and triglyceride and it is encouraging that an RNAi-based therapeutic targeting ANGPTL3 expression in the liver reproduced these effects in a mouse model. I look forward to continued advancement of novel therapeutics, including RNAi, toward these important disease targets.”
About HypercholesterolemiaHypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Some forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving target LDL-C goals with statin therapy, including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe forms of hypercholesterolemia are estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with hypercholesterolemia whose disease is inadequately managed by existing therapies. About ALN-PCS ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene proprotein convertase subtilisin/kexin type 9 (PCSK9), a target validated by human genetics that is involved in the metabolism of low-density lipoprotein cholesterol (LDL-C, or “bad” cholesterol). ALN-PCS therapies are PCSK9 synthesis inhibitors that lower levels of both intracellular and extracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations ( N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523). PCSK9 synthesis inhibition through an RNAi mechanism has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDL-C levels in the blood stream. Lower LDL-C is associated with a decreased risk of cardiovascular disease, including myocardial infarction and stroke. About Mixed Hyperlipidemia and Severe Hypertriglyceridemia Mixed hyperlipidemia is a genetically inherited condition characterized by very high levels of cholesterol and triglycerides in the blood, both of which are known to increase the risk of coronary artery disease, the leading cause of death in the U.S. It is estimated that as many as 1 out of every 100 individuals have mixed hyperlipidemia and are at increased risk of developing cardiovascular disease. Some forms of mixed hyperlipidemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation), and medicines such as statins or fibrates; however, a large portion of mixed hyperlipidemia patients are unable to reach either their LDL-C and/or triglyceride goals with the current standard of care. Patients with severe, inherited forms of hypertriglyceridemia (e.g., familial chylomicronemia syndrome, or “FCS”) are at extremely high risk of developing recurrent pancreatitis. FCS is a rare orphan genetic disease that affects 1 to 2 individuals per million.
About ALN-ANGALN-ANG is an RNAi therapeutic targeting the gene angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. ANGPTL3 is a liver-expressed, genetically validated target that acts to inhibit lipoprotein lipase and endothelial lipase, and has been shown to increase plasma triglycerides, as well as low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol. Exome sequencing studies have identified a statistically significant relationship of loss-of-function mutations in ANGPTL3 with decreased levels of triglycerides and LDL-C ( N. Engl. J. Med (2010) 363:2220-2227). A subcutaneously administered RNAi therapeutic that inhibits ANGPTL3 synthesis and lowers both LDL-C and triglycerides represents a novel approach to the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia. ALN-ANG utilizes Alnylam’s proprietary GalNAc conjugate delivery platform enabling subcutaneous dose administration. 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 PharmaceuticalsAlnylam 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 targeting ANGPTL3 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) in development for the treatment of AAT deficiency liver disease; and ALN-ANG, an RNAi therapeutic targeting ANGPTL3 in development 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 StatementsVarious 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-PCSsc and ALN-ANG, its expectations with respect to further advancing ALN-ANG in development, the filing of an IND application for ALN-PCSsc, its expectations with respect to the timing and success of clinical trials with ALN-PCSsc, and its expectations regarding the potential market opportunity for ALN-PCSsc, 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.