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Alnylam and Collaborators Publish Clinical Trial Results with ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia, in The Lancet

<p class='bwalignc'> <i>– Results from Phase I Trial of ALN-PCS Demonstrate Rapid, Dose-Dependent, and Durable Reduction of Plasma PCSK9 of up to 84% and Serum LDL Cholesterol of up to 57% –</i> </p> <p class='bwalignc'> <i>– New Paper Documents First Human Proof of Concept for an RNAi Therapeutic Toward a Clinically Validated Endpoint –</i> </p>

Thursday, October 03, 2013

Alnylam and Collaborators Publish Clinical Trial Results with ALN-PCS, an RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia, in The Lancet

08:00 EDT Thursday, October 03, 2013

CAMBRIDGE, Mass. (Business Wire) -- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, announced today the publication in The Lancet of complete study results from a Phase I trial with ALN-PCS, a systemically administered RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia. The paper, titled “Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial,” (Fitzgerald, et al., The Lancet, doi:10.1016/S0140-6736(13)61914-5) reports the results of a study evaluating single intravenous dose administration of ALN-PCS, in the absence of concomitant lipid-lowering agents such as statins. Specifically, ALN-PCS administration resulted in a rapid, dose-dependent reduction in plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of low-density lipoprotein cholesterol (LDL-C) – a clinically validated endpoint – of up to 57% relative to baseline and placebo. The knockdown of PCSK9 and lowering of LDL-C were also found to be durable, with effects lasting for weeks after a single dose. This new paper documents the first human proof of concept for an RNAi therapeutic impacting a clinically validated endpoint.

“Our data with ALN-PCS demonstrate that inhibition of PCSK9 synthesis by an RNAi therapeutic may be a potentially safe and novel approach to reduce LDL-C. The study also documents the first human proof of concept for an RNAi therapeutic toward a clinically validated endpoint, namely LDL-C,” said Kevin Fitzgerald, Ph.D., Senior Director of Research at Alnylam and lead author on the paper. “We believe that the unique mechanism of action for ALN-PCS, which inhibits the synthesis of PCSK9 inside liver cells – thereby reducing both its intracellular and extracellular functions – provides a differentiated strategy for PCSK9 antagonism. This mechanism of action results in consistent clinical activity across a wide range of baseline PCSK9 plasma levels, including in individuals with very high PCSK9 levels. Together with The Medicines Company, we are now advancing ALN-PCSsc, a GalNAc-siRNA targeting PCSK9, which we believe will enable subcutaneous dose administration with a wide therapeutic index, and expect to designate our development candidate by the end of this year.”

“Cardiovascular disease remains the leading cause of mortality worldwide, with elevated LDL-C a well validated and modifiable risk factor. A substantial number of patients, especially those at high risk for cardiovascular disease, are unable to 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., professor of Medicine and chief, Division of Translational Medicine and Human Genetics, at the Perelman School of Medicine at the University of Pennsylvania. Dr. Rader also serves on Alnylam's Scientific Advisory Board. “As a key regulator of LDL receptor levels, liver-expressed PCSK9 is one of the most important and best validated novel 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 having the potential to reproduce the beneficial effects observed in individuals with loss-of-function PCSK9 mutations. I am very encouraged by the ALN-PCS Phase I safety and efficacy data generated to date and look forward to continued clinical advancement of RNAi therapeutics toward this important disease target.”

ALN-PCS is a systemically delivered RNAi therapeutic targeting PCSK9, a target validated by human genetics that is involved in the metabolism of LDL-C, or “bad” cholesterol. ALN-PCS inhibits the synthesis of PCSK9, thereby reducing intracellular and extracellular levels of PCSK9, resulting in lowered levels of LDL-C.

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 ALN-PCS on plasma PCSK9 protein levels and evaluation of clinical activity 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.

Results of the Phase I study showed that single dose administration of ALN-PCS achieved 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 70% (p<0.0001) in the highest dose group of 0.400 mg/kg. In addition, ALN-PCS administration resulted in rapid, dose-dependent, and durable reductions in LDL-C of up to 57% relative to baseline and placebo, with a statistically significant mean reduction of 40% (p<0.0001) at the 0.400 mg/kg dose level. Importantly, ALN-PCS demonstrated consistent clinical activity toward both PCSK9 and LDL-C in a manner that was independent of baseline levels of PCSK9, highlighting the unique mechanism of action for a PCSK9 synthesis inhibitor. In other words, subjects with high levels of PCSK9 at baseline achieved a comparable degree of knockdown of plasma PCSK9 and reductions in LDL-C as those with low levels of baseline PCSK9. Furthermore, there was no significant change in plasma levels of transthyretin (TTR), a liver-secreted protein that is not expected to change upon silencing PCSK9, thus confirming that the effects of ALN-PCS on plasma PCSK9 levels were specific to the target gene. In addition, data from pre-clinical studies in non-human primates were shown to be highly predictive of the clinical results, demonstrating that non-human primate data from studies with RNAi therapeutics translate to human data on a roughly equivalent mg/kg basis.

ALN-PCS was shown to be generally safe and well tolerated in this Phase I study and there were no serious adverse events related to study drug administration. There were no drug-related discontinuations and no liver enzyme elevations. In addition, there were no clinically significant, dose-dependent changes in any laboratory indices – including liver function tests, creatine phosphokinase, C-reactive protein, and hematological parameters – or cytokines. There was also no statistically 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.

Alnylam is currently advancing ALN-PCSsc, an RNAi therapeutic targeting PCSK9 that utilizes the company's proprietary GalNAc conjugate delivery platform enabling subcutaneous dose administration with a wide therapeutic index. At its R&D Day in July 2013, the company presented pre-clinical data from non-human primate studies performed in the absence of concomitant statin therapy, showing that subcutaneous administration of ALN-PCSsc resulted in greater than 80% knockdown of plasma PCSK9 with greater than 50% reductions in LDL-C. The company expects to nominate a development candidate for ALN-PCSsc in late 2013.

In February 2013, Alnylam formed an exclusive global alliance with The Medicines Company for the development and commercialization of the ALN-PCS program. Alnylam will lead the program through the completion of Phase I. The Medicines Company is responsible for leading and funding development from Phase II forward and commercializing the ALN-PCS program if successful.

“We are very excited by the pre-clinical and early clinical data that our partner Alnylam has generated to date with ALN-PCS as reported in The Lancet, in addition to the more recent progress with ALN-PCSsc, which we believe has the potential to deliver a highly competitive profile with subcutaneous dose administration. We have seen that inhibition of PCSK9 by various therapeutic approaches, such as monoclonal antibodies and gene silencing, can substantially reduce LDL-C in patients. Epidemiological and disease mechanism studies suggest this reduction in LDL-C can further reduce the risks of the world's number one killer, coronary artery disease,” said David Kallend MB.BS (Lon), Vice President and Global Medical Director for the lipid programs at The Medicines Company. “Our focus on acute and intensive care medicine has led us to a leadership position in the management of patients who are at extreme risk as a consequence of the rupture of their vulnerable coronary artery plaque at and around the time of acute coronary syndromes. We look forward to working with Alnylam in advancing ALN-PCSsc to patients.”

About Hypercholesterolemia

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. Some 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 forms of hypercholesterolemia are 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 hypercholesterolemia whose disease is inadequately managed by existing therapies.

About ALN-PCS

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 therapies are PCSK9 synthesis inhibitors that lower 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.

About LNP Technology

Alnylam has licenses to Tekmira LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About GalNAc Conjugates

GalNAc-siRNA conjugates are a proprietary Alnylam delivery platform and are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor. Research findings demonstrate potent and durable target gene silencing, as well as a wide therapeutic index, with subcutaneously administered GalNAc-siRNAs from multiple “Alnylam 5x15” programs.

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 RNA (siRNA), 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 toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: ALN-TTR02, an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases, amongst other programs. 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 partnered programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection and ALN-VSP for the treatment of liver cancers. 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, Cubist, Ascletis, Monsanto, Genzyme, and The Medicines Company. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. 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, Cell, the New England Journal of Medicine, and The Lancet. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit www.alnylam.com.

About “Alnylam 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics toward genetically defined targets for the treatment of 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-TTR02, an intravenously delivered RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); ALN-TTRsc, a subcutaneously delivered RNAi therapeutic targeting TTR for the treatment of ATTR in patients with familial amyloidotic cardiomyopathy (FAC); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-AS1, an RNAi therapeutic targeting aminolevulinate synthase-1 (ALAS-1) for the treatment of porphyria including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-AAT, an RNAi therapeutic targeting alpha-1-antitrypsin (AAT) for the treatment of AAT deficiency liver disease; and ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases, amongst other programs. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in North and South America, Europe, and other parts of the world; these include ALN-TTR, ALN-AT3, ALN-AS1, and ALN-CC5, amongst other programs.

Alnylam Forward-Looking Statements

Various statements in this press release concerning Alnylam's future expectations, plans and prospects, including without limitation, Alnylam's expectations regarding its “Alnylam 5x15” product strategy, Alnylam's views with respect to the potential for RNAi therapeutics, including ALN-PCS, its views regarding the predictive nature of non-human primate data with RNAi therapeutics towards human data, its expectations regarding the timing of nomination of an ALN-PCSsc development candidate, its expectations with respect to the timing and success of its clinical trials for the ALN-PCS program, including trials with ALN-PCSsc, and its plans with respect to commercialization of the ALN-PCS program, 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 and delivery approaches, successfully demonstrate the efficacy and safety of its drug candidates, including ALN-PCS and ALN-PCSsc, 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, Alnylam's ability to enforce its patents against infringers and defend its patent portfolio against challenges from third parties, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, Alnylam's ability to obtain additional funding to support its business activities and establish and maintain strategic business alliances and new business initiatives, Alnylam's dependence on third parties for development, manufacture, marketing, sales and distribution of products, the outcome of litigation, and unexpected expenditures, as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam's Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on August 9, 2013 and in other filings that Alnylam makes with the SEC. 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 explicitly disclaims any obligation to update any forward-looking statements.

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

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