Alnylam Presents Final Results from a Phase I Clinical Trial of ALN-TTR01, an RNAi Therapeutic Targeting Transthyretin (TTR) for the Treatment of Transthyretin-Mediated Amyloidosis

CAMBRIDGE, Mass.--May. 10, 2012-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today final results from its completed Phase I clinical trial with ALN-TTR01, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR). The data were presented at the XIII International Symposium on Amyloidosis held May 6-10, 2012 in Groningen, The Netherlands. Data from this study show that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels, including both wild-type and mutant TTR protein, in ATTR patients. Knockdown of TTR, the disease-causing protein, was found to be dose dependent, rapid, and durable after just a single dose. The full time course for TTR knockdown reveals the potential for once monthly or possibly once every other monthly dose regimens in further studies. ALN-TTR was found to be generally safe and well tolerated in this study.

"These Phase I data from our ALN-TTR01 clinical study demonstrate rapid, dose-dependent, and durable lowering of TTR protein levels after a single dose in ATTR patients. The observed reduction of mutant and wild-type TTR in patients with the V30M mutation is important, since both contribute to amyloid deposition. Further, the full time course for TTR knockdown after a single dose confirms our expectations for a once a month or possibly even a once every two month dosing regimen in our further studies," said Jared Gollob, M.D, Senior Director, Clinical Research. "We believe these data with ALN-TTR01 provide key human proof of concept as we advance ALN-TTR02 as our 'go-to-market' RNAi therapeutic for the treatment of ATTR, a debilitating orphan genetic disease. ALN-TTR02 uses our proprietary second-generation LNP formulation which has demonstrated markedly improved potency in human clinical studies, and we look forward to presenting results from an ongoing Phase I clinical study in the third quarter of 2012. Alnylam is committed to bringing this high impact medicine to patients afflicted with ATTR."

This Phase I study was designed as a randomized, placebo-controlled, single-dose escalation study in patients with ATTR. Patients were enrolled in seven sequential cohorts of increasing doses ranging from 0.01 to 1.0 mg/kg. There were four patients per cohort, with patients randomized to receive drug or placebo in a 3:1 ratio. Following the completion of dose escalation, additional patients were enrolled at 1.0 mg/kg. Data were presented from 32 patients, including eight who received placebo and 24 who received drug.

ALN-TTR01 clinical activity was assessed based on measurements of serum TTR protein levels. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean reduction of 38% at approximately day 7 to 10 in the 1.0 mg/kg group (geometric mean relative to placebo, p=0.01). The rapid onset and durable effect of ALN-TTR01 after a single dose was exemplified by one patient dosed at 1.0 mg/kg who showed 63% TTR lowering at 48 hours, peak TTR knockdown of 81% at day 10, approximately 50% lowering at 30 days post dose, and full recovery only at 60 days. In addition, analysis of serum samples by a liquid chromatography-mass spectrometry method revealed that both mutant and wild-type TTR were knocked down to the same extent in V30M patients; both wild-type and mutant TTR have been shown to cause amyloid plaques in ATTR patients.

ALN-TTR01 was found to be generally safe and well tolerated in ATTR patients. Mild-to-moderate acute infusion reactions were observed in 5 of 24 (20.8%) patients receiving ALN-TTR01 and were readily managed by slowing of the infusion rate where necessary. There were no significant increases in liver function test parameters. All patients on study drug completed the study; there were no discontinuations except for one patient in the placebo group who underwent elective hospitalization for a liver transplant, and was scored as a serious adverse event unrelated to study drug.

"RNAi therapeutics represent a novel and exciting approach for ATTR patients and have great potential to make a meaningful impact in the treatment of this devastating disease. The completed results of this study with ALN-TTR01 are promising, particularly the durable decreases in TTR levels after a single dose as well as the knockdown of both mutant and wild-type TTR in patients with the V30M mutation, since we believe that TTR protein suppression has the potential to lead to a reversal of amyloid plaques and clinical benefit," said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose. "Moreover, the emerging clinical data with second generation delivery technology are very encouraging for the ongoing development of ALN-TTR02. I look forward to the continued advancement of RNAi therapeutics in clinical trials for the treatment of ATTR, as there are currently few options for patients suffering from this orphan genetic disease."

Alnylam is developing ALN-TTR02 as its lead RNAi therapeutic for the treatment of ATTR. ALN-TTR02 uses the identical siRNA as ALN-TTR01 but employs a proprietary second-generation LNP formulation that has demonstrated improved potency and tolerability based on pre-clinical and clinical studies. ALN-TTR02 is currently being tested in a Phase I clinical study in normal healthy volunteers with results expected in the third quarter of 2012. Further, the company expects to start a Phase II study of ALN-TTR02 in ATTR patients in the second half of 2012 and expects to start pivotal studies in 2013.

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 options for early stage disease are liver transplantation and tafamidis; 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-TTR01 is a systemically delivered RNAi therapeutic being developed for the treatment of ATTR, including FAP and FAC. ALN-TTR01 uses first-generation lipid nanoparticle technology from Tekmira Pharmaceuticals Corporation. Alnylam is advancing ALN-TTR02, which uses the same siRNA as ALN-TTR01, but is formulated in a more potent, proprietary second-generation lipid nanoparticle (LNP) technology using the "MC3" lipid. Alnylam has initiated a Phase I trial with ALN-TTR02 aimed at evaluating safety, tolerability, and clinical activity of ALN-TTR02 in healthy volunteers. Alnylam expects to present data from this study in the third quarter of 2012. In addition, Alnylam plans to start a Phase II multi-dose study of ALN-TTR02 in ATTR patients in the second half of 2012 and, assuming positive results, expects to start a pivotal trial for ALN-TTR02 in 2013. Alnylam also plans to advance ALN-TTRsc, which utilizes a GalNAc-conjugate delivery approach and subcutaneous dose administration.

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 5x15™" 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-TTR01, ALN-TTR02 and ALN-TTRsc, its expectations with respect to the timing and success of its clinical trials for ALN-TTR02, its expectations regarding the reporting of data from its ALN-TTR02 clinical trial, 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-TTR01, ALN-TTR02 and ALN-TTRsc, the pre-clinical and clinical results for these product candidates, which may not support further development of such product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, 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 quarterly report on Form 10-Q 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.