May 17, 2015 Press Release for Alnylam

Alnylam Files Clinical Trial Application (CTA) for ALN-AAT, an Investigational RNAi Therapeutic for the Treatment of Alpha-1 Antitrypsin Deficiency-Associated Liver Disease (Alpha-1 Liver Disease)

May 17, 2015

- Company Guides that it Plans to Initiate Phase 1/2 Trial in Late 2015 and Report Initial Clinical Results in Early 2016 -

- New Pre-Clinical Data with ALN-AAT Presented at Digestive Disease Week (DDW) Meeting, Showing Robust Knockdown of Serum AAT of Up to 93% with Monthly Subcutaneous Dosing in Non-Human Primates and a Wide Therapeutic Index -

CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (NASDAQ:ALNY), a leading RNAi therapeutics company, announced today that it has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase 1/2 clinical trial with ALN-AAT, a subcutaneously administered investigational RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease (alpha-1 liver disease). As per the CTA filing, the intended clinical study of ALN-AAT will be performed in normal healthy volunteers, and, then, in subjects with alpha-1 liver disease. ALN-AAT now becomes the company's sixth clinical stage program in its Genetic Medicine Strategic Therapeutic Area (STAr), the seventh clinical pipeline program overall, and the fifth clinical program employing the company's Enhanced Stabilization Chemistry (ESC)-GalNAc delivery technology. Consistent with previous guidance, the company expects that following approval of the CTA, it will initiate the Phase 1/2 study in late 2015, with initial data expected to be reported in early 2016. In addition, Alnylam scientists presented new pre-clinical data in an oral presentation at the Digestive Disease Week (DDW) meeting, held May 16 - 19, 2015 in Washington, D.C. Amongst other reported research findings, new data showed a robust knockdown of serum AAT of up to 93% in non-human primates (NHPs) with monthly subcutaneous dosing and a wide therapeutic index.

"We believe ALN-AAT holds considerable promise as a novel therapeutic approach for the treatment of alpha-1 liver disease, an increasingly recognized clinical manifestation of alpha-1-antitrypsin deficiency where there is a significant unmet need and where liver transplantation is the only available treatment option. Our pre-clinical results, including new data presented at this year's DDW meeting, demonstrate that monthly subcutaneous doses of ALN-AAT achieves robust knockdown of serum AAT - the disease-causing protein - of up to 93% in NHPs, with highly durable effects and a wide therapeutic index. In earlier reported and recently updated studies, we've demonstrated that ALN-AAT can reduce liver levels of mutant AAT, improve histopathology associated with mutant AAT expression, and reduce liver fibrosis and the incidence of tumor formation in a mouse model of alpha-1 liver disease," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer of Alnylam. "The filing of this new CTA also highlights the reproducible and modular features of Alnylam's platform, as ALN-AAT now becomes our sixth clinical stage program in our Genetic Medicine STAr, our seventh clinical pipeline program overall, and the fifth clinical program employing our ESC-GalNAc delivery technology. We very much look forward to the continued advancement of this program toward the clinic, consistent with our guidance where we expect to start the Phase 1/2 trial in late 2015, with initial clinical results expected to be reported in early 2016."

"Alpha-1 liver disease is caused by expression of the mutant ‘Z allele' of the AAT gene and misfolding of the Z-AAT protein, which then accumulates in liver cells and causes cellular damage. Individuals who are homozygous for the mutant Z allele make up approximately 95% of all people with AAT deficiency liver disease. These individuals have a lifetime risk of liver disease of 10% to 50%, which can manifest as cholestatic disease, chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Severe liver disease can occur in both children and adults and is currently managed with supportive care, or in the case of liver failure, with liver transplantation. Clearly, there is a very high unmet need for novel therapies for alpha-1 liver disease," said Jeffrey Teckman, M.D., Professor in the Department of Pediatrics and Director of Pediatric Gastroenterology and Hepatology at Saint Louis University School of Medicine. "I am encouraged by the pre-clinical data with ALN-AAT, and if these results extend in clinical studies, I believe that this investigational RNAi therapeutic has the potential to become an important treatment option for the management of alpha-1 liver disease. I am also pleased with Alnylam's commitment to advance this candidate to clinical stages, bringing a new potential treatment option forward for patients."

ALN-AAT is a subcutaneously administered investigational RNAi therapeutic that utilizes Alnylam's proprietary ESC-GalNAc-siRNA conjugate delivery technology. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. As per the filed CTA, the Phase 1/2 trial of ALN-AAT will be a randomized, single-blind, placebo-controlled study conducted in three parts. Parts A and B will be single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 48 healthy adult volunteers. Part C will be a multi-dose study in adults with the PiZZ mutation in their AAT gene and with mild-to-moderate liver fibrosis. The primary objective of the study is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AAT. Secondary objectives include evaluation of pharmacokinetics of ALN-AAT and clinical activity for ALN-AAT as measured by knockdown of serum AAT. In addition, biopsies will be obtained from subjects with alpha-1 liver disease to quantify the effects of treatment on levels of periodic acid-Schiff (PAS)-stained globules, a measure of AAT misfolding observed in the livers of alpha-1 liver disease patients.

In an oral presentation at DDW, Alnylam scientists presented new data demonstrating an up to 93% knockdown of serum AAT (mean 90 ± 2%) following monthly subcutaneous dosing with ALN-AAT in NHPs at a dose of 3 mg/kg. This level of knockdown was highly durable, lasting for greater than 30 days following the final dose. Further, ALN-AAT was found to have a wide therapeutic index based on results from GLP toxicology studies. Specifically, 13-week studies were performed in the rat and NHP with q2W doses and showed No Adverse Effect Levels (NOAELs) of greater than or equal to 50 mg/kg and 150 mg/kg, respectively; these dose levels were the top doses in both studies. In addition, study results were reported from a transgenic mouse model of alpha-1 liver disease, where mice overexpress the human Z-AAT protein. A single subcutaneous dose of ALN-AAT led to dose-dependent, durable and reversible knockdown of Z-AAT, with an ED₅₀ of ~0.5 mg/kg, with mean Z-AAT knockdown of greater than 90% achieved following a single subcutaneous dose of 3mg/kg. As previously presented, sustained reduction of Z-AAT in aged transgenic mice with established liver disease led to improvement in tissue pathology, decrease in fibrosis, decrease in number of proliferating hepatocytes, and reduction in tumor burden as measured by both number and size of tumors.

"We applaud Alnylam for its efforts to develop a therapeutic for Alphas with liver disease, as there are few options available for them today. The Alpha-1 community is in clear need of a treatment option to improve the disease course and quality of life for both children and adults with Alpha-1 liver disease," said John Walsh, CEO and co-founder of the Alpha-1 Foundation. "We are all pleased with Alnylam's progress to date with ALN-AAT, including the filing of this CTA, and we look forward to following the progress of this program through the course of its clinical development."

About Alpha-1 Antitrypsin (AAT), AAT Deficiency, and Alpha-1 Liver Disease

Alpha-1 antitrypsin deficiency is an autosomal disorder that results in disease of the lungs and liver. AAT is a liver-produced serine proteinase inhibitor with the primary function of protecting the lungs from neutrophil elastase and other irritants that cause inflammation. About 95% of people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ) which expresses the Z-AAT protein. In the liver, misfolding of the mutant Z-AAT protein hinders its normal release into the blood thereby causing it to aggregate in hepatocytes, leading to liver injury, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). There are estimated to be approximately 120,000 individuals with the PiZZ mutation in the U.S. and major European countries, and of these, about 10% have an associated liver pathology (alpha-1 liver disease) caused by the misfolded Z-AAT protein. The only treatment options presently available for alpha-1 liver disease patients are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in people with alpha-1 liver disease may represent a promising new way to treat this rare disease.

About The Alpha-1 Project

Mission statement: The Alpha-1 Project will work with patients, academia, pharmaceutical and biotech companies, and public health organizations in the relentless pursuit of cures and therapies for COPD and liver disease caused by Alpha-1 Antitrypsin Deficiency. For more information, visit www.thealpha-1project.com. The Alpha-1 Project is a wholly-owned for-profit subsidiary of the Alpha-1 Foundation. For more information on the Foundation, visit www.alpha-1foundation.org.

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. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. 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 about Alnylam's pipeline of investigational RNAi therapeutics, 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-AAT for the treatment of AAT deficiency-associated liver disease, its expectations regarding the reporting of initial data from its ALN-AAT Phase 1 clinical study, its expectations regarding the potential market opportunity for ALN-AAT, 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 be replicated or continue to occur in other subjects or in additional studies or otherwise 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.

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