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

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

– PCSK9 Synthesis Inhibitor Achieves up to 84% Knockdown of PCSK9 and 50% Lowering of LDL Cholesterol in Single Dose, Statin-Free Phase I Trial –

– New Results Highlight Continued Improved Efficacy and Safety for Alnylam Second-Generation Lipid Nanoparticles (LNP) –

April 20, 2012

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today positive results from its Phase I clinical trial of ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of severe hypercholesterolemia. ALN-PCS is a PCSK9 synthesis inhibitor that reduces intracellular and extracellular levels of PCSK9 resulting in lowered plasma levels of low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol. The new data were presented at the American Heart Association's Arteriosclerosis, Thrombosis and Vascular Biology 2012 Scientific Sessions held in Chicago. Results showed that administration of a single dose of ALN-PCS, in the absence of concomitant lipid-lowering agents such as statins, resulted in statistically significant and durable reductions of PCSK9 plasma levels of up to 84% and lowering of LDL-C of up to 50%. The new data also highlight continued improved efficacy and tolerability for Alnylam's second-generation lipid nanoparticle (LNP) delivery technology.

"We are very excited by these new ALN-PCS data that demonstrate robust clinical efficacy for this PCSK9 synthesis inhibitor. Indeed, we believe the unique mechanism of action for ALN-PCS, which inhibits the synthesis of PCSK9 in liver cells thereby reducing both its intracellular and extracellular functions, provides a differentiated strategy for PCSK9 antagonism. This mechanism of action for ALN-PCS results in potent and durable LDL-C reductions and consistent clinical activity across a wide range of baseline PCSK9 plasma levels, including individuals with very high PCSK9 levels," said Akshay K. Vaishnaw, M.D., Ph.D., Senior Vice President and Chief Medical Officer of Alnylam. "These new results show very robust, statistically significant, and dose-dependent lowering of both PCSK9 and LDL-C levels in a single dose study performed in the absence of statin co-administration. In addition, ALN-PCS treatment was well tolerated at all dose levels studied to date indicating the potential to even further dose escalate in future studies."

"Cardiovascular disease remains the leading cause of mortality worldwide, with elevated LDL-C a major modifiable risk factor. A substantial number of patients cannot achieve target LDL levels with current drugs, such as statins, and it is clear that new therapeutic options are needed," said Daniel J. Rader, M.D., Director of Preventive Cardiovascular and Associate Director of the Institute for Translational Medicine and Therapeutics at University of Pennsylvania. "As a key regulator of the LDL receptor, liver-expressed PCSK9 is one of the most important and best validated new targets in molecular medicine for the treatment of hypercholesterolemia. An RNAi therapeutic targeting PCSK9 expression in the liver has the potential to rapidly and durably lower LDL cholesterol, thereby reproducing the effects observed in loss-of-function human mutations that are associated with significant clinical benefit. I am very encouraged by the ALN-PCS data generated to date and look forward to continued studies that highlight the unique mechanistic approach of PCSK9 synthesis inhibitors, including the potential magnitude and durability of LDL-C response when ALN-PCS is co-administered with statins."

The Phase I study was conducted as a randomized, single-blind, placebo-controlled, single-ascending dose study in healthy volunteer subjects with elevated baseline LDL-C (greater than 116mg/dL). The primary objective of the study was to evaluate the safety and tolerability of a single dose of ALN-PCS. Secondary objectives of the study included assessment of pharmacodynamic effects of the drug on plasma PCSK9 protein levels and evaluation of clinical efficacy as measured by LDL-C levels. A total of 32 subjects were enrolled into six sequential dose cohorts ranging from 0.015 to 0.400 mg/kg in a 3:1 randomization of drug to placebo.

In this study, administration of ALN-PCS resulted in rapid, dose-dependent, and durable reductions in LDL-C of up to 50% relative to baseline and placebo, with a statistically significant mean reduction of 41% (p<0.01) at the 0.400 mg/kg dose level. In addition, ALN-PCS administration resulted in rapid, dose-dependent, and durable knockdown of PCSK9 protein levels in plasma of up to 84% relative to baseline and placebo, with a statistically significant mean reduction of 68% in the highest dose group of 0.400 mg/kg (p<0.0001). 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). The effects of a single dose of ALN-PCS support a once-monthly dose administration regimen for future studies. Importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor.

ALN-PCS was shown to be safe and well tolerated in this study and there were no serious adverse events related to study drug administration. There were no drug-related discontinuations and no liver enzyme elevations. There was also no significant change compared to baseline in levels of high-density lipoprotein (HDL), or "good" cholesterol, consistent with the phenotype observed in human PCSK9 loss-of-function mutations.

"These data mark yet another important milestone in our overall 'Alnylam 5x15' efforts, as they demonstrate continued safety, tolerability, and robust clinical efficacy of an RNAi therapeutic targeting a liver-expressed disease gene utilizing our second generation lipid nanoparticle delivery technology," said Barry Greene, President and Chief Operating Officer of Alnylam. "In particular, these new data strongly support continued advancement of ALN-TTR02, an RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR), which employs the same second generation LNP delivery formulation as ALN-PCS. Dosing in our ALN-TTR02 clinical study has recently been initiated and we are on track to report data in the third quarter of this year."

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 ALN-TTR02 program, an RNAi therapeutic targeting TTR for the treatment of ATTR.

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

Dr. Rader serves as a consultant on Alnylam's ALN-PCS program, and Alnylam and Dr. Rader collaborate on research for which Alnylam provides materials.

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. patients with coronary artery disease, 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 (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 is a PCSK9 synthesis inhibitor that lowers levels of 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). PCSK9 synthesis inhibition through an RNAi mechanism 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 in the blood stream. Lower LDL-C is associated with a decreased risk of cardiovascular disease, including myocardial infarction and stroke. Alnylam plans to partner its ALN-PCS program prior to initiating a Phase II clinical study.

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-PCS and ALN-TTR02, its expectations with respect to the timing and success of its clinical trials, its plans to partner its ALN-PCS program, 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-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 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.

Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
Amanda Sellers, 202-955-6222 x2597 (Media)