(ALNY) Positive Top-Line Results in TTR-Mediated Amyloidosis

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today positive top-line results from its ongoing Phase I trial of ALN-TTRsc, a subcutaneously administered RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The company is reporting that ALN-TTRsc achieved robust and statistically significant (p<0.01) knockdown of serum TTR protein levels of greater than 80% in healthy volunteer subjects, in line with results for ALN-TTRsc previously reported in non-human primates. In addition, to date ALN-TTRsc was found to be generally safe and well tolerated. Dose escalation in this trial continues and results will be presented at the Annual Scientific Meeting of the Heart Failure Society of America (HFSA), being held September 22 – 25, 2013 in Orlando, Fla. These human study results are the first to be reported for Alnylam’s proprietary GalNAc-siRNA conjugate delivery platform, enabling subcutaneous dosing of RNAi therapeutics with a wide therapeutic index.

“These clinical results with ALN-TTRsc establish human translation for RNAi therapeutics that utilize our GalNAc-siRNA conjugate delivery platform. This platform enables subcutaneous dose administration with a wide therapeutic index and has now become our primary approach for development of RNAi therapeutics. As a result, we believe these data are very meaningful not only for the continued advancement of ALN-TTRsc, but also for the continued execution on our entire ‘Alnylam 5×15’ product strategy,” said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. “Specifically, we are very excited to report top-line results from the study showing statistically significant knockdown of serum TTR to levels greater than 80% in treated subjects, results which are in line with our non-human primate experience. We look forward to continued advancement of our ALN-TTRsc program, including presentation of data from the Phase I trial at the HFSA meeting in September, start of a Phase II study in familial amyloidotic cardiomyopathy patients by the end of this year, and – assuming positive results – start of a pivotal Phase III trial for ALN-TTRsc in 2014.”

ATTR is caused by mutations in the TTR gene which cause abnormal amyloid protein deposits to accumulate in various tissues including peripheral nerves and heart, resulting in neuropathy and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people worldwide. ALN-TTRsc, which is being developed for the treatment of FAC, is a subcutaneously administered RNAi therapeutic that comprises an siRNA conjugated to a GalNAc ligand that enables receptor-mediated delivery to the liver. ALN-TTRsc is the first GalNAc-siRNA – and the first subcutaneously delivered – systemic RNAi therapeutic to enter clinical development stages. Alnylam is also developing ALN-TTR02, an intravenously administered RNAi therapeutic targeting TTR for the treatment of FAP patients with ATTR.

The ongoing Phase I trial of ALN-TTRsc is being conducted in the U.K. as a randomized, double-blind, placebo-controlled, single- and multi-dose, dose-escalation study, enrolling up to 40 healthy volunteer subjects. Subjects received single or multiple ascending subcutaneous doses of ALN-TTRsc ranging from 1.25 to 10 mg/kg. The primary objective of the study is to evaluate the safety and tolerability of single and multiple doses of subcutaneously administered ALN-TTRsc. Secondary objectives include assessment of clinical activity of the drug as measured by serum TTR levels. Upon completion of the Phase I trial, the company plans to start a Phase II clinical study of ALN-TTRsc in FAC patients in late 2013 and, assuming positive results, expects to start a pivotal Phase III trial for ALN-TTRsc in FAC patients in 2014.

Pre-clinical studies have shown that subcutaneous administration of ALN-TTRsc resulted in potent and sustained suppression of TTR. In non-human primates, ALN-TTRsc administration resulted in an approximately 80% reduction of TTR at doses as low as 2.5 mg/kg. In single- and multi-dose pre-clinical safety studies in rodents and non-human primates, ALN-TTRsc was found to be generally safe and well tolerated. Specifically, at doses as high as 300 mg/kg in non-human primates, ALN-TTRsc was well tolerated with no clinical signs, no adverse laboratory or histopathologic findings, no elevations in cytokines or complement, and no significant injection site reactions; these results demonstrate an approximately 100-fold therapeutic index for GalNAc-siRNA conjugates.

In 2012, Alnylam entered into an exclusive alliance with Genzyme, a Sanofi company, to develop and commercialize RNAi therapeutics, including ALN-TTR02 and ALN-TTRsc, for the treatment of ATTR in Japan and the broader Asian-Pacific region. Alnylam plans to develop and commercialize the ALN-TTR program in North and South America, Europe, and rest of the world.

Alnylam is hosting an R&D Day today from 8:30 a.m. – 12:00 p.m. ET at the Sofitel New York in New York City. Alnylam scientists and management will review progress with the company’s “Alnylam 5×15” product strategy for the development of RNAi therapeutics. The event will be webcast live on the News & Investors section of the company’s website, www.alnylam.com. An audio replay of the event will be available on the Alnylam website approximately 90 minutes after the event.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is an inherited, progressively debilitating, and fatal disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for retinol binding protein. Mutations in TTR cause abnormal amyloid proteins to accumulate and damage body organs and tissue, such as the peripheral nerves and heart, resulting in intractable peripheral sensory neuropathy, autonomic neuropathy, and/or cardiomyopathy. ATTR represents a major unmet medical need with significant morbidity and mortality; familial amyloidotic polyneuropathy (FAP) affects approximately 10,000 people worldwide and familial amyloidotic cardiomyopathy (FAC) affects at least 40,000 people worldwide. FAP patients have a life expectancy of five to 15 years from symptom onset, and the only treatment options for early stage disease are liver transplantation and tafamidis (approved in Europe). The mean survival for FAC patients is approximately 2.5 years, and there are no approved therapies. There is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

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 5×15” 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 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 toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: 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 acute intermittent porphyria (AIP); 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-CC5, an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases, amongst other programs. As part of its “Alnylam 5×15^TM” 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, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About “Alnylam 5×15™”

The “Alnylam 5×15” 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 5×15” programs include: 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 acute intermittent porphyria (AIP); 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-CC5, an RNAi therapeutic targeting the C5 component of the complement pathway for the treatment of complement-mediated diseases, 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; these include ALN-TTR, ALN-AT3, and ALN-AS1; the company will seek global development and commercial alliances for other programs.

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam’s future expectations, plans and prospects, including without limitation, Alnylam’s expectations regarding its “Alnylam 5×15” product strategy, Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-TTRsc, its expectations regarding the reporting of data from its ALN-TTRsc clinical trials, its expectations with respect to the timing and success of its clinical trials for ALN-TTRsc, and its expectations regarding the potential market opportunity for ALN-TTRsc, 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, including ALN-TTRsc, 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 current report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 7, 2013 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.