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Alnylam Expands Hepatic Infectious Disease Pipeline; Adds ALN-HDV for the Treatment of Chronic Hepatitis Delta Virus (HDV) Infection and ALN-PDL for the Treatment of Chronic Liver Infections

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has expanded its hepatic infectious disease pipeline. Specifically, in a presentation at the American Association for the Study of Liver Diseases (AASLD) meeting, the company announced it has added ALN-HDV, an RNAi therapeutic targeting the hepatitis delta viral (HDV) genome in development for the treatment of HDV infection. Further, it has added ALN-PDL, an RNAi therapeutic targeting hepatocyte-expressed programmed death ligand 1 (PD-L1) in development for the treatment of chronic liver infections. In addition, Alnylam continues to advance its ALN-HBV program, in development for the treatment of hepatitis B viral (HBV) infection; the company remains on track to select a Development Candidate (DC) by the end of the year and expects to file an investigational new drug (IND) application or IND equivalent around the end of 2015.

“Hepatic infectious diseases, such as HBV and HDV infection, are major global health problems, affecting approximately 400 million and 15 million people worldwide, respectively. Significant unmet need exists for novel therapies to treat these infections, as they are the leading causes of fibrotic liver disease and liver cancer worldwide,” said Laura Sepp-Lorenzino, Ph.D., Vice President, Entrepreneur-in-Residence. “We believe that multiple opportunities exist for RNAi therapeutics for hepatic infectious diseases, and our initial focus on HBV will now be expanded to include programs for HDV and liver-specific immune checkpoint blockade by targeting hepatocyte-expressed PD-L1. In both cases, our approach will employ our Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate technology, enabling subcutaneous dose administration with high potency and long durability, and a wide therapeutic index. Finally, we remain on track to select our DC for ALN-HBV by end of this year, with the goal of filing an IND or IND equivalent for this program around the end of 2015.”

ALN-HDV, an investigational RNAi therapeutic targeting the HDV genome, is in development for the treatment of HDV infection. HDV is an RNA virus that infects hepatocytes and depends on a co-existing HBV infection to produce the envelope particle which holds its genome. HDV can be acquired at the same time or subsequent to infection with HBV, and is believed to infect between 15 and 20 million people worldwide. Chronic HDV infection results in more severe liver disease as compared to HBV infection alone, with higher risks of cirrhosis and hepatocellular carcinoma. Many chronic HDV patients progress to end-stage liver disease, where liver transplant is the only available treatment1. Alnylam plans to advance ALN-HDV as an ESC-GalNAc-siRNA conjugate combination with ALN-HBV targeting both the HBV and HDV genomes.

In addition, Alnylam is expanding its hepatic infectious disease efforts with ALN-PDL, an investigational RNAi therapeutic targeting PD-L1 in development for the treatment of chronic liver infections. PD-L1 is a cell surface protein that is believed to play a major role in suppressing the immune system in cancer and infection. HBV and HCV infection of hepatocytes is known to lead to increased PD-L1 expression2 which could subdue the immune response against the virus. Further, monoclonal antibodies targeting PD-L1 and its T-cell ligand PD-1 have shown anti-viral effects in pre-clinical and early clinical studies3, but are also associated with systemic toxicities. ALN-PDL is aimed at knocking down liver-expressed PD-L1 to reactivate an immune response against liver viral infection without the systemic toxicities observed with monoclonal antibody therapy. In pre-clinical studies published previously4 by Alnylam and collaborators, an siRNA targeting PD-L1 was shown to increase the endogenous immune response and viral clearance in a mouse model of liver adenovirus infection. Alnylam plans to advance ALN-PDL as an ESC-GalNAc-siRNA conjugate.

Finally, Alnylam is also continuing to advance ALN-HBV, an RNAi therapeutic targeting the HBV genome in development for the treatment of HBV infection. HBV infection afflicts 400 million people worldwide, with one to two million people in the U.S., and is a leading cause of liver disease and hepatocellular carcinoma (HCC) worldwide. An RNAi therapeutic targeting the HBV genome could have the potential to achieve a “functional cure” by effectively decreasing expression of tolerogenic hepatitis surface antigen (HBsAg), in addition to inhibiting all steps of the HBV life cycle. In pre-clinical study results presented at the TIDES 2014 meeting, Alnylam reported significant, multi-log reductions in HBsAg and HBV viral titers in chronically infected chimpanzees. Alnylam plans to advance ALN-HBV as an ESC-GalNAc-siRNA conjugate which should enable once monthly subcutaneous dose administration with potent and durable effects, and a wide therapeutic index. The company remains on track to select a DC in late 2014 and plans to file an IND or IND equivalent around year-end 2015.

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 with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company’s “Alnylam 5x15TM” product strategy. Alnylam’s genetic medicine programs are RNAi therapeutics directed 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) 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) and senile systemic amyloidosis (SSA); 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-PCS targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the HDV genome for the treatment of HDV infection; ALN-PDL targeting PD-L1 for the treatment of chronic liver infections; and other programs yet to be disclosed. As part of its “Alnylam 5×15″ strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. 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 www.alnylam.com.

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 ALN-HBV for the treatment of HBV infection, ALN-HDV for the treatment of HDV infection, and ALN-PDL for the treatment of chronic liver infections, its expectations with respect to timing of regulatory filings, and its expectations regarding its “Alnylam 5×15″ 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 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.

1 Noureddin and Gish, Current Gastroenterology Report (2014) 16(1), 365).

2 M”uhlbauer et al. J. Hepatol., 2006 vol. 45(4) pp. 520-8; Kassel et al. Hepatology 50(5), 1625-1637; Chen et al. Inflamm. Res., 2011 vol. 60(1) pp. 47-53

3 Gardiner et al., PLoS ONE 8(5): e63818. doi:10.1371/journal.pone.0063818 (2013)

4 Dolina et al., Molecular Therapy-Nucleic Acids (2013) 2, e72; doi:10.1038/mtna.2012.63

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