Alnylam and The Alpha-1 Project (TAP) Form Collaboration for Advancement of ALN-AAT, an RNAi Therapeutic in Development for the Treatment of Alpha-1 Antitrypsin (AAT) Deficiency-Associated Liver Disease

CAMBRIDGE, Mass. & MIAMI--(BUSINESS WIRE)--

Alnylam Pharmaceuticals, Inc. ALNY, a leading RNAi therapeutics company, and The Alpha-1 Project (TAP), the venture philanthropy subsidiary of the Alpha-1 Foundation, announced today that they have entered into a collaboration agreement for the continued advancement of ALN-AAT, a subcutaneously administrated RNAi therapeutic in development for the treatment of alpha-1 antitrypsin (AAT) deficiency-associated liver disease. TAP's mission is to work with patients, academia, pharmaceutical and biotech companies, and public health organizations in the pursuit of cures and therapies for chronic obstructive pulmonary disease (COPD) and liver disease caused by AAT deficiency. TAP is partially funding research activities for ALN-AAT. Detailed financial terms of the research agreement were not disclosed. Alnylam remains on track to file an investigational new drug (IND) application for this program in mid-2015.

“We have assembled what we believe to be the industry's most robust pre-clinical data package supporting advancement of ALN-AAT – an ‘Enhanced Stabilization Chemistry' or ‘ESC'-GalNAc-siRNA conjugate targeting AAT – including results in rodent models that demonstrate knockdown of the disease-causing Z-allele and significant lowering of the mutant protein (Z-AAT) burden in the liver, with associated improvements in liver function, as seen by normalization of the proliferative index, improved liver pathology, attenuated tissue fibrosis, and decreased incidence of liver tumor formation. In addition, we believe we have confirmed the activity of ALN-AAT in non-human primate models and expect our Development Candidate to achieve human target gene knockdown at doses less than 1 mg/kg with a once-monthly dose regimen or better. Since our GalNAc-siRNA platform is clinically validated based on results from other Alnylam RNAi therapeutic programs, we have a high level of confidence that ALN-AAT can achieve potent knockdown of the disease-causing Z-allele protein with subcutaneous dose administration and a favorable safety profile,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “Accordingly, we are fully committed to the continued advancement of our RNAi therapeutic to patients with AAT deficiency with associated liver disease. This new recognition from TAP, part of the leading patient advocacy group for people afflicted with AAT deficiency, brings our efforts closer to patients in need and to their caregivers. We continue to expect that we will file our IND or IND equivalent for ALN-AAT in mid-2015.”

ALN-AAT is one of Alnylam's genetic medicine programs, which are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. Alnylam pioneered the application of RNAi therapeutics toward genetically defined targets expressed in the liver as part of the company's “Alnylam 5x15” product strategy. AAT deficiency-associated liver disease is caused by accumulation of mutant AAT protein (“Z-allele” or “Z-AAT”) in liver tissue with subsequent liver injury, fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. It is estimated that approximately 10,000 to 20,000 people with AAT deficiency in the U.S. and E.U. have associated liver pathology.

“I 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 desperate need of a treatment to improve the quality of life for both pediatric and adult liver patients,” said John Walsh, CEO and co-founder of the Alpha-1 Foundation.

Pre-clinical data from Alnylam's ALN-AAT program were first presented at the Annual Meeting of the American Association for the Study of Liver Diseases (AASLD, “The Liver Meeting”) in November 2013 and were most recently updated at Digestive Disease Week (DDW) in May 2014. Amongst other results presented, these data in rodent studies showed that administration of ALN-AAT was associated with a potent and dose-dependent knockdown of serum AAT (a surrogate for AAT knockdown in the liver) with a single-dose ED₅₀ of 0.5 mg/kg. In multi-dose rodent experiments, subcutaneous administration at 0.5 mg/kg resulted in approximately 90% knockdown of serum AAT. In addition, initial single-dose NHP results were performed showing dose-dependent knockdown of serum AAT with an ED₅₀ of less than 3 mg/kg; these results are expected to support a multi-dose ED₅₀ of less than 0.3 mg/kg. ALN-AAT employs Alnylam's ESC-GalNAc-conjugate technology, enabling subcutaneous administration with a wide therapeutic index. Alnylam's GalNAc-siRNA conjugate platform has been clinically validated for both activity and tolerability through the company's ALN-TTRsc (an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR cardiac amyloidosis; currently in Phase 2) and ALN-AT3 (an RNAi therapeutic targeting antithrombin for the treatment of hemophilia and rare bleeding disorders; currently in Phase 1) programs.

“TAP is very pleased to collaborate with Alnylam Pharmaceuticals. Their cutting-edge work on a therapy for liver disease brings us closer to finding a cure for Alpha-1 Antitrypsin Deficiency, thus fulfilling our mission,” said Jean-Marc Quach, Executive Director for The Alpha-1 Project.

About Alpha-1 Antitrypsin (AAT) and AAT Deficiency

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. 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). A deficient serum level of the protein can render the lungs susceptible to emphysema. About 95% of people with alpha-1 antitrypsin deficiency are homozygous and carry two copies of the abnormal Z allele (PiZZ). There are estimated to be approximately 200,000 people who are PiZZ in the U.S. and major European countries, and of these, at least 10% have an associated liver pathology caused by the misfolded protein encoded by the pathogenic Z-allele. Treatment for lung disease associated with AAT deficiency consists of routine emphysema care and, in some instances, augmentation therapy, which utilizes purified AAT from the plasma of healthy donors to increase circulating and airway levels of AAT to help restore its function in the lungs. The only treatment options presently available for patients with cirrhosis caused by mutant AAT accumulation in the liver are supportive care and, in the case of advanced cirrhosis, liver transplantation. RNAi-mediated inhibition of AAT in AAT-deficient PiZZ patients 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 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, durability, and a wide therapeutic index, and 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 with a core focus on RNAi therapeutics as genetic medicines, including programs as part of the company's “Alnylam 5x15^TM” 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), 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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. As part of its “Alnylam 5x15” 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. Alnylam is also developing ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection. 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, The Medicines Company, and Genzyme, a Sanofi company. 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, 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™” and Genetic Medicines

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics as genetic medicines. Alnylam's genetic medicine programs are RNAi therapeutics directed toward genetically defined targets for the treatment of diseases with high unmet medical need. These programs share several key characteristics including: a genetically defined target and disease expressed in the liver; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi platform with clinically proven delivery to the liver; the opportunity to monitor an early biomarker in Phase 1 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. 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 “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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) in development for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 in development for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) in development for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 in development for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 in development for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, a subcutaneously administered RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; and other programs yet to be disclosed. In 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs. 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 ALN-TTRsc in North America and Europe.

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 with respect to timing of regulatory filings for ALN-AAT, the potential therapeutic opportunities for ALN-AAT, its expectations regarding its “Alnylam 5x15” product strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-AAT, 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.

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