Alnylam Initiates Phase I Clinical Study of ALN-TTR02, an RNAi Therapeutic Targeting Transthyretin

Alnylam Initiates Phase I Clinical Study of ALN-TTR02, an RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of TTR-Mediated Amyloidosis (ATTR)

– Data Demonstrating TTR Knockdown Expected in Third Quarter of 2012 –

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today that it has initiated dosing in its Phase I clinical trial with ALN-TTR02, an RNAi therapeutic targeting the transthyretin (TTR) gene for the treatment of TTR-mediated amyloidosis (ATTR). The study is aimed at evaluating the safety and tolerability of ALN-TTR02 in healthy volunteers. In addition, the study will evaluate the clinical activity of ALN-TTR02 based on measurements of serum levels of TTR, the disease-causing protein in patients with ATTR. ALN-TTR02 utilizes the company's proprietary second-generation lipid nanoparticle (LNP) technology using the "MC3" lipid. Alnylam expects to present data from this study in the third quarter of 2012.

    "a major scientific breakthrough that happens once every decade or so"

"Advancement of ALN-TTR02 into the clinic is an important milestone in our 'Alnylam 5x15' product strategy. Indeed, ALN-TTR02 is our lead program in this effort and we expect to initiate a Phase II trial later this year, followed by a pivotal trial starting in 2013," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "ALN-TTR02 utilizes our proprietary second-generation LNP technology which has shown significant potency improvements in both pre-clinical and clinical studies. We very much look forward to our expected reporting of TTR knockdown data from the Phase I study in the third quarter of this year."

"RNAi therapeutics represent a novel and exciting approach for the treatment of ATTR, as this new drug modality has the potential to make a meaningful impact in the treatment of this devastating disease. I am very encouraged by the recent results from Alnylam's Phase I study with ALN-TTR01 which showed knockdown in serum levels of TTR, the pathogenic protein in this disease. These results are important because we believe TTR suppression has the potential of halting or even reversing disease pathology in ATTR patients," said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose. "I support the continued advancement of this innovative medicine, and look forward to results from this new study, as well as additional clinical studies."

The Phase I trial of ALN-TTR02 is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single-ascending dose study, enrolling approximately 32 healthy volunteer subjects. The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-TTR02, with subjects being enrolled into five sequential cohorts of increasing doses ranging from 0.01 to 0.50 mg/kg. Secondary objectives include serial measurement of circulating TTR serum levels through at least day 56 following a single dose. Additional secondary objectives include plasma and urine pharmacokinetics of ALN-TTR02.

About Transthyretin-Mediated Amyloidosis

Transthyretin (TTR)-mediated amyloidosis (ATTR) is a hereditary, systemic disease caused by mutations in the TTR gene. TTR protein is produced primarily in the liver and is normally a carrier for thyroid hormones and retinol binding proteins. 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. In its severest form, ATTR represents a major unmet medical need with significant morbidity and mortality as an orphan disease; FAP (familial amyloidotic polyneuropathy) affects approximately 10,000 people worldwide and FAC (familial amyloidotic cardiomyopathy) affects at least 40,000 people worldwide. ATTR patients with FAP have a mean life expectancy of five to 15 years from symptom onset and the only treatment option is liver transplantation; as a result there is a significant need for novel therapeutics to treat patients who have inherited mutations in the TTR gene.

About ALN-TTR Program

ALN-TTR is a systemically delivered RNAi therapeutic being developed for the treatment of ATTR. Pre-clinical studies have shown that treatment with Alnylam's first-generation product candidate, ALN-TTR01, resulted in both prevention and regression of pathogenic TTR deposits in peripheral tissues including dorsal root ganglia, sciatic nerve, stomach, and intestines in animal models. In November 2011, Alnylam reported positive preliminary clinical results from its ALN-TTR01 Phase I, multinational clinical trial showing that ALN-TTR01 was generally safe and well tolerated and resulted in statistically significant lowering of TTR serum levels in ATTR patients. Alnylam has completed enrollment in the ALN-TTR01 Phase I trial and expects to present final data in the first half of 2012. In March 2012, Alnylam initiated a Phase I clinical trial with ALN-TTR02, its second-generation ATTR therapeutic candidate which utilizes an improved second-generation LNP formulation with the "MC3" lipid. In pre-clinical studies, this second-generation LNP technology demonstrated an over 10-fold improvement in potency. Data from the ALN-TTR02 Phase I trial are expected in the third quarter of 2012. In addition, Alnylam plans to start a Phase II multi-dose clinical study of ALN-TTR02 in ATTR patients in the second half of 2012 and, assuming positive results, expects to initiate a pivotal trial with ALN-TTR02 in 2013. Alnylam is also advancing ALN-TTRsc, which utilizes a GalNAc-conjugate delivery approach and subcutaneous dose administration. Alnylam plans to file an investigational new drug (IND) application or IND equivalent for ALN-TTRsc in the second half of 2012, with data expected in the first half of 2013. ALN-TTRsc has the potential to provide product differentiation and expansion in the ATTR indication.

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 RNAs (siRNAs), 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 5x15™"

The "Alnylam 5x15" strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined 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 5x15" programs include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-APC for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in the United States and potentially certain other countries; the company will seek development and commercial alliances for other core programs both in the United States and in other global territories.

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 for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, ALN-APC for the treatment of hemophilia, and ALN-TMP for the treatment of hemoglobinopathies. As part of its "Alnylam 5x15TM" 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 partner-based programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington's disease. 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, and Cubist. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. 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

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, statements regarding Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-TTR02 and ALN-TTRsc, its expectations with respect to the timing and success of its clinical and pre-clinical trials, the expected timing of regulatory filings, including its plan to file an IND or IND equivalent application for ALN-TTRsc and to initiate clinical trials for ALN-TTR02 and ALN-TTRsc, its expectations regarding the reporting of data from its ALN-TTR01, ALN-TTR02 and ALN-TTRsc clinical trials, and Alnylam's expectations regarding its "Alnylam 5x15" 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, successfully demonstrate the efficacy and safety of its drug candidates, including ALN-TTR02 and 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, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, and Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, as well as those risks more fully discussed in the "Risk Factors" section of its most recent annual report on Form 10-K on file with the Securities and Exchange Commission. 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 does not assume any obligation to update any forward-looking statements.