Alnylam Presents Positive Preliminary Clinical Results for ALN-TTR01, an RNAi Therapeutic for the Treatment of Transthyretin-Med

Alnylam Presents Positive Preliminary Clinical Results for ALN-TTR01, an RNAi Therapeutic for the Treatment of Transthyretin-Mediated Amyloidosis

- Results Demonstrate Human Proof of Concept for RNAi Therapeutics with Rapid, Dose-Dependent, and Durable Lowering of Serum Transthyretin (TTR) Protein Levels -

- ALN-TTR01 Shown to be Safe and Well Tolerated in Patients -


CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY - News), a leading RNAi therapeutics company, announced today positive preliminary results from its 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 VIIIth International Symposium on Familial Amyloidotic Polyneuropathy being held November 20 - 22, 2011 in Kumamoto, Japan. Data from this study show that administration of ALN-TTR01 resulted in statistically significant reductions in serum TTR protein levels in ATTR patients. Lowering of TTR was found to be dose dependent, rapid, and durable after just a single dose. To date, ALN-TTR01 has been generally safe and well tolerated in this study.

"We are very pleased with these Phase I data from our ongoing ALN-TTR01 clinical study. Importantly, we demonstrated rapid, dose-dependent, and durable lowering of serum TTR protein levels after a single dose in ATTR patients. These pharmacodynamic effects confirm our expectation for once-monthly dosing in humans with systemically delivered RNAi therapeutics. Further, we demonstrated that ALN-TTR01 was safe and well tolerated," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "We look forward to the continued advancement of our ALN-TTR program, including our upcoming ALN-TTR02 regulatory filing, and are committed to bringing this important medicine to ATTR patients in need."

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. The study was designed to enroll up to 36 patients. Data available to date were presented from 31 patients, including eight who received placebo and 23 who received drug.

Assessment of ALN-TTR01 clinical activity based on measurements of serum levels of circulating TTR protein was performed to demonstrate human proof of concept for the ALN-TTR program. ALN-TTR01 demonstrated a dose-dependent reduction in serum TTR levels with a statistically significant mean 41% reduction at the 1.0 mg/kg dose level (geometric mean relative to placebo, p=0.02). All five patients receiving drug in the 1.0 mg/kg group showed lowering of serum TTR protein which ranged from 25 to 81%. Nadir levels were achieved approximately 7 days after dosing and serum TTR levels remained decreased through at least 24 days. These effects were exemplified by one patient dosed at 1.0 mg/kg who showed 63% lowering at 48 hours, peak suppression of 81% at 7 days, and approximately 50% lowering of serum TTR protein at 28 days post dose. As expected, serum TTR reductions were well correlated with parallel changes in retinol binding protein and vitamin A levels.

To date, ALN-TTR01 has been found to be well tolerated and there were no serious adverse events related to study drug administration. Mild-to-moderate acute infusion reactions were observed in three of 23 (13%) patients receiving ALN-TTR01 and were readily managed by slowing of the infusion rate where necessary. There were no drug-related discontinuations from the study and there were no significant increases in liver function test (LFT) parameters. Further, pharmacokinetic studies showed that ALN-TTR01 administration was associated with approximately dose-proportional plasma exposure.

"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," said Teresa Coelho, M.D., Director, Unidade Clinica de Paramiloidose. "The results of this ongoing study are encouraging, particularly the evidence for dose-dependent decreases in TTR serum levels since we believe that TTR protein suppression has the potential to lead to a reversal of amyloid plaques and clinical benefit. Accordingly, 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 devastating disease."

ATTR is caused by mutations in the TTR gene, which is expressed predominantly in the liver and results in the accumulation of pathogenic deposits of mutant and wild-type TTR protein in multiple extra-hepatic tissues, including the peripheral nervous system, heart, and the gastrointestinal tract. ALN-TTR01 is a systemically delivered RNAi therapeutic that targets the TTR gene; it comprises an siRNA formulated in a first generation lipid nanoparticle (LNP). In addition, Alnylam is developing ALN-TTR02 which utilizes the company's second generation LNP technology and demonstrates an over 10-fold improvement in potency in animal models. The company plans to file an investigational new drug (IND) application, or IND equivalent, for ALN-TTR02 at or around year's end.

"These results represent a key milestone in the advancement of RNAi therapeutics as a new class of innovative medicines. Indeed, we believe that the lowering of serum TTR protein levels observed in this study demonstrates additional human proof of concept with a systemically delivered RNAi therapeutic. Moreover, we believe this result marks the first time RNAi has been shown to silence a disease-causing gene in humans," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "In the coming weeks, we expect to report data from our ALN-PCS program which targets PCSK9 for the treatment of severe hypercholesterolemia and utilizes our second generation LNP technology. Collectively, we believe current data from our ALN-TTR01 study and pending data from our ALN-PCS study will strengthen our overall confidence in our ‘Alnylam 5x15' product strategy, where we aim to advance RNAi therapeutics for the treatment of genetically defined targets and diseases."

The presentation of these data made at the VIIIth International Symposium on Familial Amyloidotic Polyneuropathy can be found on our website at

Conference Call Information

Alnylam will host a conference call on Monday, November 21 at 8:30 a.m. ET to discuss the preliminary Phase I results of its ALN-TTR01 clinical trial. To access the call, please dial 866-783-2146 (domestic) or 857-350-1605 (international) five minutes prior to the start time and provide the passcode 40291676. A replay of the call will be available beginning at 11:30 a.m. ET on November 21, 2011. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the passcode 13561687.

A live audio webcast of the call will also be available on the News & Investors page of the company's website, An archived webcast will be available on the Alnylam website approximately two hours after the event.

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 approximately 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-TTR01 is a systemically delivered RNAi therapeutic being developed for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR), including familial amyloidotic polyneuropathy (FAP) and familial amyloidotic cardiomyopathy (FAC). Pre-clinical studies have shown that treatment with ALN-TTR01 results 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 addition, ALN-TTR01 administration in pre-clinical animal models was found to result in dose-dependent and durable, yet reversible silencing of the TTR gene and serum levels of TTR. Preliminary results from Alnylam's Phase I clinical trial with ALN-TTR showed the product candidate to be well tolerated. Administration of ALN-TTR in patients demonstrated rapid, durable, and dose dependent lowering of serum TTR protein. ALN-TTR01 uses first generation lipid nanoparticle technology from Tekmira Pharmaceuticals Corporation. Alnylam is also advancing ALN-TTR02, which utilizes second-generation delivery technology. The ALN-TTR02 program is on track for an investigational new drug (IND) or IND equivalent application filing at or around year's end 2011. In 2012, following results from both ALN-TTR01 and ALN-TTR02 studies, Alnylam expects to advance this program into Phase II clinical studies.

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 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, and ALN-APC for the treatment of hemophilia. As part of its "Alnylam 5x15TM" strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in advanced stages of clinical development 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 application in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam's VaxiRNATM 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-PCS, 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 and initiate clinical trials for ALN-TTR02, its expectations regarding the reporting of data from its ALN-PCS clinical trial and potentially additional data from its ALN-TTR01 trial as well as 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-PCS, 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 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.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Senior Director, Investor Relations and
Corporate Communications
Amanda Sellers, 202-955-6222 x2597