Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Seve

Alnylam Reports Positive Preliminary Clinical Results for ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Severe Hypercholesterolemia
-- RNAi Therapeutic Achieves Robust Silencing of PCKS9 and Reductions of Over 50% in LDL Cholesterol, a Validated Clinical Endpoint --

CAMBRIDGE, Mass., Jan 04, 2012 (BUSINESS WIRE) -- -- Results Highlight Major Potency Improvements of Second-Generation Lipid Nanoparticle Platform in Man --

-- Alnylam to Host Conference Call Today, January 4 @ 8:30 a.m. ET to Discuss Results --

Alnylam Pharmaceuticals, Inc. ALNY +5.66% , a leading RNAi therapeutics company, announced today the achievement of positive preliminary results from its ongoing clinical trial of ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia. ALN-PCS demonstrated statistically significant RNAi silencing of PCSK9 of up to 66% and reductions of up to over 50% in levels of low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol, a clinically validated endpoint. Alnylam believes that the preliminary results of this study, presented today at the Brigham and Women's Hospital in Boston, also document for the first time major advances in delivery of RNAi therapeutics with second generation lipid nanoparticles (LNPs) in human studies. This Phase I study continues with planned dose escalation, given the favorable safety profile and positive efficacy achieved to date. Additional results of the study are expected to be reported in the first half of 2012.

"We are extremely pleased with these data from our ALN-PCS trial which represent what we believe is the first ever demonstration of efficacy for an RNAi therapeutic toward a clinically validated endpoint, namely LDL-C, a defined risk factor for coronary artery disease and acute myocardial infarction. Indeed, preliminary results from our ongoing study show robust, statistically significant, and dose-dependent lowering of both PCSK9 and LDL-C levels," said Akshay Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "The RNAi effects were rapid and durable after a single dose, exemplifying a compelling profile for RNAi therapeutics that we have now established in man for two disease programs."

This Phase I ALN-PCS study is being conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (>116mg/dL). The primary objective of the study is to evaluate the safety and tolerability of a single dose of ALN-PCS, with subjects being enrolled into sequential cohorts of increasing doses. Secondary objectives of the study include characterization of plasma and urine pharmacokinetics of ALN-PCS, assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels, and evaluation of clinical efficacy as measured by LDL-C levels. This trial is being performed in the absence of statins or other lipid lowering therapy. The findings presented today describe results from the initial 20 subjects enrolled in five sequential dose cohorts ranging from 0.015 to 0.250 mg/kg in a 3:1 randomization of drug to placebo.

In this study, administration of ALN-PCS resulted in a rapid, dose-dependent, and durable silencing of PCSK9 protein levels in plasma of up to 66% relative to baseline, with a statistically significant mean reduction of 60% at day four in the current high dose group of 0.250 mg/kg (p<0.001). In addition, administration of ALN-PCS resulted in dose-dependent reductions in LDL-C of up to 50% relative to baseline, with a statistically significant mean reduction of 39% at day four (p<0.05) at the 0.250 mg/kg dose level. Nadir effects on PCSK9 and LDL-C were achieved rapidly and occurred approximately four days after administration of a single dose. There was also a dose-dependent increase in the proportion of subjects who achieved "target" levels of LDL-C of less than 100 mg/dL (p<0.05), with 100% (6/6) of subjects in the two highest dose groups achieving target and a mean LDL-C of 84.0 mg/dL, as compared with 21.4% (3/14) of subjects achieving target in any other group. Moreover, the effects of a single dose were durable, supporting a once-monthly dose administration regimen expected in future studies. Further, there was no significant decrease in high-density lipoprotein (HDL), or "good" cholesterol levels, consistent with the phenotype observed in human loss-of-function mutations in PCSK9.

To date, ALN-PCS has been shown to be safe and well tolerated in this study and there have been no serious adverse events related to study drug administration. There have been no drug-related discontinuations from the study and no liver enzyme elevations. A mild, transient rash was observed in five subjects, including two who received placebo. The study is ongoing; based on the favorable safety profile and positive clinical activity to date, the company plans to continue dose escalation.

"Cardiovascular disease remains the leading cause of mortality worldwide, with elevated LDL-C defining the major risk factor. It is clear that new therapeutic options are needed for patients who cannot achieve target LDL levels with current drugs," said Christopher Cannon, M.D., Professor of Medicine, Harvard Medical School. "As a key regulator of the LDL receptor, PCSK9 is one of the most important targets in molecular medicine for the treatment of hypercholesterolemia. An RNAi therapeutic targeting this genetically validated gene has the potential to rapidly and durably lower LDL cholesterol, thereby reproducing the effects observed in loss-of-function human mutations associated with significant clinical benefit."

ALN-PCS is an RNAi therapeutic that utilizes proprietary second-generation LNP technology with the MC3 lipid; this study represents the first human results with this delivery platform. The same RNAi delivery formulation is being used for Alnylam's program on ALN-TTR02, an RNAi therapeutic for the treatment of transthyretin (TTR)-mediated amyloidosis (ATTR).

"These data mark an important milestone in our overall 'Alnylam 5x15' efforts, as they are the first to demonstrate safety, tolerability, and clinical efficacy of an RNAi therapeutic utilizing our second generation lipid nanoparticle delivery technology. In this regard, these data strongly support advancement of our ALN-TTR02 program for the treatment of transthyretin-mediated amyloidosis, where we expect to start clinical studies shortly," said John Maraganore, Ph.D., Chief Executive Officer of Alnylam. "It is also notable that these new data round out a remarkable year of clinical achievement, where we demonstrated RNAi proof of mechanism in biopsy samples from our ALN-VSP liver cancer program, showed human proof of concept with robust TTR lowering in our ALN-TTR01 Phase I study, and now demonstrated human clinical efficacy with LDL-C reductions with ALN-PCS. To say the least, we believe these data provide very strong support for our future efforts in developing RNAi therapeutics as a new class of innovative medicines."

The presentation of these data can be found on Alnylam's website at .

Conference Call Information

Alnylam will host a conference call on Wednesday, January 4 at 8:30 a.m. ET to discuss the preliminary Phase I results of its ALN-PCS clinical trial. To access the call, please dial 800-901-5217 (domestic) or 617-786-2964 (international) five minutes prior to the start time and provide the passcode 78688967. A replay of the call will be available beginning at 10:30 a.m. ET on January 4, 2012. To access the replay, please dial 888-286-8010 (domestic) or 617-801-6888 (international), and provide the passcode 52686639. 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 Severe Hypercholesterolemia

Severe hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood which is known to increase the risk of coronary artery disease, the leading cause of death in the U.S. Most forms of hypercholesterolemia can be treated through dietary restrictions, lifestyle modifications (e.g., exercise and smoking cessation) and medicines such as statins. However, a large proportion of patients with hypercholesterolemia are not achieving target LDL-C goals with statin therapy, including genetic familial hypercholesterolemia patients, acute coronary syndrome patients, high-risk patient populations (e.g. diabetics, symptomatic carotid artery disease, etc.) and other patients that are statin intolerant. Severe hypercholesterolemia is estimated to affect more than 500,000 patients worldwide, and as a result, there is a significant need for novel therapeutics to treat patients with severe hypercholesterolemia whose disease is inadequately managed by existing therapies.


ALN-PCS is a systemically delivered RNAi therapeutic targeting the gene proprotein convertase subtilisin/kexin type 9, or PCSK9, a target validated by human genetics that is involved in the metabolism of low-density lipoprotein cholesterol (LDL-C, or "bad" cholesterol). ALN-PCS targets both intracellular and extracellular PCSK9, thereby phenocopying the human genetics observed in loss of function or null human PCSK9 mutations (N. Engl. J. Med. (2006) 354:1264-1272; Am. J. Hum. Genet. (2006) 79: 514-523), without any adverse effects on high-density lipoprotein (HDL, or "good" cholesterol) levels. An RNAi therapeutic targeting PCSK9 has the potential to lower tissue and circulating plasma PCSK9 protein levels resulting in higher LDL receptor levels in the liver, and subsequently lower LDL-C levels. Lower LDL-C is associated with a decreased risk of cardiovascular disease, including myocardial infarction and stroke. Pre-clinical data from the ALN-PCS program have shown specific silencing of PCSK9 messenger RNA (mRNA) in the liver, and plasma PCSK9 protein levels of up to 90%, with an ED50 (the dose that provides a 50% silencing effect) of approximately 0.06 mg/kg for both mRNA and protein reduction. These studies have also demonstrated a greater than 50% reduction in levels of LDL-C, which is rapid and durable, lasting for several weeks after a single dose.

About "Alnylam 5x15(TM)"

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. This strategy leverages Alnylam's clinical progress on siRNA delivery, including definitive human proof-of-concept data for systemic delivery. By the end of 2015, the company expects to have five such RNAi therapeutic programs in advanced clinical development. These include 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 one additional program from the company's ongoing discovery efforts that will be designated at or around the end of 2011. Alnylam intends to focus on developing and commercializing certain products arising under the "Alnylam 5x15" strategy itself in the United States and potentially certain other countries; the company will seek development and commercial partners for other core products both in the United States and in other global territories.

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 5x15(TM)" 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 VaxiRNA(TM) 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-PCS and ALN-TTR02, the therapeutic potential for its second-generation lipid nanoparticle delivery technology, the expected timing of regulatory filings and clinical trial initiation, including for ALN-TTR02, its expectations with respect to the timing and success of its clinical and pre-clinical trials, its expectation for a once-monthly dose administration regimen in future clinical trials, its expectations regarding the reporting of additional data from its ALN-PCS 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 those formulated in its second-generation lipid nanoparticle delivery technology, including ALN-PCS and ALN-TTR02, 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.