Alnylam Introduces Pipeline Growth Strategy for RNAi Therapeutics in Three Strategic Therapeutic Areas, or "STArs"

– Expands Efforts on Pipeline Development and Commercialization in Genetic Medicine,

Cardio-Metabolic Disease, and Hepatic Infectious Disease STArs –

– Announces Updated Guidance to File Clinical Trial Application for ALN-AS1,

an Investigational RNAi Therapeutic for Hepatic Porphyrias, by End-2014 –

– Selects Potent Development Candidate for ALN-HBV, Showing Up to 3.9 Log10

Knockdown of Hepatitis Surface Antigen (HBsAg) after

Single Subcutaneous Dose in Rodent Model of HBV Infection –


– Company to Webcast its R&D Day Today –

CAMBRIDGE, Mass.--Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, announced today its pipeline growth strategy for development and commercialization of RNAi therapeutics across three Strategic Therapeutic Areas (STArs): Genetic Medicines, Cardio-metabolic Disease, and Hepatic Infectious Disease. The new strategy builds on the company's progress in the advancement of RNAi therapeutics, including its "Enhanced Stabilization Chemistry" (ESC)-GalNAc conjugate technology, as a modular and reproducible platform for discovery of innovative medicines. Alnylam's STArs will remain focused on liver-expressed and genetically validated or pathogen-derived disease targets, with biomarkers for assessment of clinical activity early in Phase 1 trials. The company will be discussing its STAr pipelines, recent progress, and plans for the future at a webcast R&D Day it is hosting in New York City today. In January 2015, the company expects to provide additional specific guidance on pipeline programs in its three STArs.

"Based on a wealth of growing pre-clinical and clinical data, we now believe that the breadth of Alnylam's opportunities for RNAi therapeutics extends beyond the original framework of our 'Alnylam 5x15' strategy. Accordingly, we are excited to announce an evolution in our growth strategy with a focus on development and commercialization of RNAi therapeutics in three Strategic Therapeutic Areas (STArs): Genetic Medicines, Cardio-metabolic Disease, and Hepatic Infectious Disease," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "Across our three STArs, we believe that we can address major unmet needs in a wide range of diseases with high-impact, differentiated medicines, and continue to build what we believe to be one of the most robust pipelines in biotech. By executing on this strategy, we believe we have the potential to make a meaningful difference in the lives of patients, and maximize value for shareholders."

In its Genetic Medicine STAr, Alnylam is advancing a broad pipeline of RNAi therapeutics for rare diseases. This pipeline includes patisiran and revusiran, investigational RNAi therapeutics for the treatment of transthyretin-mediated amyloidosis (ATTR), that are now in Phase 3 clinical trials with the company's APOLLO and ENDEAVOUR studies, respectively. In addition, the company is advancing ALN-AT3, an investigational RNAi therapeutic in development for hemophilia and rare bleeding disorders, where positive initial Phase 1 data were recently reported. Further, Alnylam's Genetic Medicine STAr includes ALN-CC5 in development for complement-mediated diseases, where the company recently announced filing of a CTA to initiate a Phase 1/2 clinical trial in healthy volunteers and patients with paroxysmal nocturnal hemoglobinuria (PNH). Amongst other disclosed and undisclosed programs, the company is also advancing ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of hepatic porphyrias. The company is announcing today that it plans on filing its Clinical Trial Application (CTA) for ALN-AS1 by the end of 2014, to enable the start of a Phase 1 trial in early 2015 in patients with asymptomatic acute intermittent porphyria (AIP) followed by AIP patients with recurrent attacks. Across its Genetic Medicine STAr, Alnylam plans on commercializing its products through direct marketing and sales in the U.S. and EU, while leveraging its landmark partnership with Genzyme, a Sanofi company, for commercialization in the rest-of-world.

In its Cardio-metabolic Disease STAr, Alnylam is advancing its pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in dyslipidemias, hypertension, non-alcoholic steatohepatitis (NASH), and type 2 diabetes. The company believes that new discoveries in the human genetics of cardio-metabolic disease, together with development strategies in morbid sub-populations, create opportunities for new, potentially transformative medicines. Further, the emerging profile of ESC-GalNAc conjugates with once-monthly and possibly once-quarterly, low-volume, subcutaneous dose administration and a wide therapeutic index supports advancement of new medicines in this disease area. In its Cardio-metabolic Disease STAr, Alnylam is advancing ALN-PCSsc, an investigational RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia, in collaboration with The Medicines Company. Alnylam has recently initiated a Phase 1 clinical study of ALN-PCSsc, with initial data expected to be reported in mid-2015. Alnylam is also advancing additional investigational programs for the treatment of dyslipidemias, including ALN-AC3 targeting apoC3 for the treatment of hypertriglyceridemia and ALN-ANG targeting ANGPTL3 for the treatment of hypertriglyceridemia and mixed hyperlipidemia. In addition, the company is developing ALN-AGT, an RNAi therapeutic targeting angiotensinogen in development for the treatment of hypertensive disorders of pregnancy including preeclampsia. Finally, the company is advancing a number of undisclosed pre-clinical programs for the treatment of NASH and type 2 diabetes. The company intends to seek strategic partnership opportunities for programs in its Cardio-metabolic Disease STAr, while retaining significant product commercialization rights in the U.S. and EU.

Finally, in its Hepatic Infectious Disease STAr, Alnylam is advancing a pipeline of RNAi therapeutics that address major global health challenges, including hepatitis B virus (HBV) and hepatitis D virus (HDV) infections, amongst other hepatic infectious disease opportunities. Alnylam is advancing ALN-HBV as a lead program in this STAr, and is announcing today that it has selected a Development Candidate (DC) for the program. The ALN-HBV DC is an ESC-GalNAc-siRNA targeting the HBV genome. In a rodent model of HBV, a single subcutaneous dose at 3 mg/kg resulted in an up to 3.9 log10 reduction in hepatitis B surface antigen (HBsAg) levels (mean 1.8 log10 reduction). The company expects to file an investigational new drug (IND) application, or IND equivalent, for this program in late 2015. In addition, Alnylam is advancing ALN-HDV, in development for the treatment of HDV infection, and ALN-PDL, an approach for liver-specific knockdown of programmed death-ligand 1 (PD-L1) – an immune checkpoint inhibitor – and the treatment of chronic liver infections. The company intends to seek strategic partnership opportunities for programs in its Hepatic Infectious Disease STAr, while retaining significant product commercialization rights in the U.S. and EU.

Alnylam will webcast its R&D Day live on the Investors section of the company's website, The event will be held today from 8:00 a.m. to 12:00 p.m. ET at the Sofitel New York in New York City. An audio replay of the event will be available on the Alnylam website approximately 90 minutes after the event.

About GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC)-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. Alnylam's Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology enables subcutaneous dosing with increased potency and durability, and a wide therapeutic index. This delivery platform is being employed in several of Alnylam's genetic medicine programs, including programs in clinical development.

About 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. In late 2014, Alnylam launched its pipeline growth strategy for RNAi therapeutics in three strategic therapeutic areas (STArs): Genetic Medicines, Cardio-metabolic Disease, and Hepatic Infectious Disease. Alnylam's Genetic Medicine STAr investigational pipeline includes: patisiran (ALN-TTR02) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC); ALN-AT3 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); and other programs yet to be disclosed. Alnylam's Cardio-metabolic Disease STAr investigational pipeline includes: ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of mixed hyperlipidemia and hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; and other programs yet to be disclosed. Alnylam's Hepatic Infectious Disease STAr investigational pipeline includes: ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; and other programs yet to be disclosed. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's views with respect to the potential for RNAi therapeutics, including the timing of clinical studies for ALN-AS1 and ALN-HBV, amongst other programs, the reporting of data from clinical studies, its expectations regarding the potency and therapeutic index of GalNAc-siRNA conjugates, including Enhanced Stabilization Chemistry (ESC)-GalNAc conjugates, its expectations regarding its STAr pipeline growth strategy, and its plans regarding commercialization of RNAi therapeutics, 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 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 manage operating expenses, 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.



Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
Liz Bryan, 202-955-6222 x2526