Alnylam and The Medicines Company Announce Initiation of Phase 1 Clinical Trial for ALN-PCSsc, a Subcutaneously Administered Investigational RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia

11 Dec 2014

Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), a leading RNAi therapeutics company, and The Medicines Company (Nasdaq: MDCO), a global biopharmaceutical company focused on hospital care, announced today that Alnylam has initiated a Phase 1 clinical trial with ALN-PCSsc, an investigational agent for the treatment of hypercholesterolemia. The initiation of this trial has triggered a $10 million milestone from The Medicines Company to Alnylam. ALN-PCSsc is a subcutaneously administered 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). The Phase 1 trial of ALN-PCSsc is being conducted in the U.K. as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose study, enrolling up to 76 volunteer subjects with elevated baseline LDL-C (? 100 mg/dL). As previously guided, the companies expect to report initial clinical data from the trial in mid-2015.

“As a first-in-class PCSK9 synthesis inhibitor, we believe that ALN-PCSsc represents an innovative, differentiated, and well-validated approach for the treatment of hypercholesterolemia. First, recent pre-clinical studies in non-human primates have confirmed the potential for a once-monthly, and possibly once-quarterly, low volume subcutaneous dose regimen. Further, the mechanism of action for ALN-PCSsc enables LDL-C lowering independent of baseline PCSK9 plasma levels, which we believe could result in additive or even synergistic activity in combination with statins,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “We are very excited to be advancing this investigational RNAi therapeutic – notably, our third that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform, and the second that utilizes our optimized ESC-GalNAc technology – into a Phase 1 trial. Together with The Medicines Company, we look forward to the continued advancement of ALN-PCSsc, including the expected presentation of initial clinical results in mid-2015.”

“The field of LDL research generally – and this project in particular – are moving fast. The recent IMPROVE-IT study results demonstrated the importance of LDL-C as a major risk factor for coronary artery disease and the benefit of further LDL-C reductions on top of statin therapy. In addition there is a clear need for new therapies for patients who are refractory or intolerant to current approaches for management of their LDL-C levels,” said David Kallend, MB.BS (Lon), Vice President and Global Medical Director for the lipid programs at The Medicines Company. “Together with recent progress in our other efforts, ALN-PCSsc is a key program in our pipeline of innovative medicines for hypercholesterolemia and atherosclerosis. Based on its mechanism of action and pre-clinical results, we believe that ALN-PCSsc has a highly competitive profile as compared with anti-PCSK9 monoclonal antibodies and a potential for a less frequent, small volume dosing regimen, and we look forward to confirming this potential in the clinic. Assuming positive results, The Medicines Company will lead the collaborative effort in subsequent stages of development and commercialization.”

The Phase 1 trial of ALN-PCSsc is being conducted as a randomized, single-blind, placebo-controlled, single ascending- and multi-dose, subcutaneous dose-escalation study. The study is designed to enroll up to 76 volunteer subjects with elevated baseline LDL-C (? 100 mg/dL), with subjects randomized 3:1, drug:placebo. The study will be performed in two phases: a single ascending dose (SAD) phase and a multiple dose (MD) phase. In the MD phase, subjects will receive two subcutaneous doses of either ALN-PCSsc or placebo administered four weeks apart. The MD phase will also include subjects both on and off statin co-medication. The primary objective of the Phase 1 study is to evaluate the safety and tolerability of ALN-PCSsc. Secondary objectives include assessment of clinical activity as determined by knockdown of plasma PCSK9 levels and serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc. In support of the Clinical Trial Application (CTA) to begin the Phase 1 trial, Alnylam completed toxicology studies in rodents and non-human primates (NHPs). In both species, the no observed adverse effect level (NOAEL) was determined to exceed 250 mg/kg, the top dose in both studies, with no adverse findings in clinical, hematology, laboratory chemistry, and histopathology assessments.

ALN-PCSsc is a subcutaneously administered investigational RNAi therapeutic that utilizes Alnylam’s proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-siRNA conjugate delivery platform. ESC-GalNAc-siRNA conjugates are designed to achieve targeted delivery of RNAi therapeutics to hepatocytes through uptake by the asialoglycoprotein receptor, and enable subcutaneous dosing with increased potency and durability and a wide therapeutic index. At the American Heart Association Scientific Sessions 2014 in November, the company presented pre-clinical data in NHPs showing that monthly subcutaneous administration of ALN-PCSsc resulted in PCSK9 knockdown of up to 92% and LDL-C lowering, in the absence of statin co-administration, of up to 77%; mean maximum knockdown of PCSK9 was 83.2% +/- 7.2%, and mean maximum LDL-C reduction was 59.0% +/- 13.3%. As a PCSK9 synthesis inhibitor, ALN-PCSsc showed rapid, durable, and clamped knockdown of PCSK9 and reduction of LDL-C, which contrasts with the cyclical variation in LDL-C observed with monthly dose regimens of anti-PCSK9 monoclonal antibodies (Stein, Curr Opin Lipidol 2013, 24:510–517). Based on current human translational data with ESC-GalNAC-conjugates, the projected human dose levels are expected to be less than 1 mg/kg at a subcutaneous injection volume of less than 1 mL administered once-monthly. In aggregate, these pre-clinical data are supportive of a once-monthly, and possibly once-quarterly, dosing regimen for ALN-PCSsc, which the company believes could represent a highly competitive target product profile.

Alnylam and collaborators previously published complete study results from a Phase 1 trial with ALN-PCS02 in The Lancet (Fitzgerald, et al., The Lancet, doi:10.1016/S0140-6736(13)61914-5). ALN-PCS02 is an intravenously administered investigational RNAi therapeutic targeting PCSK9. The paper showed that ALN-PCS02 administration resulted in rapid, dose-dependent knockdown of plasma PCSK9 of up to 84% relative to baseline and placebo, with a corresponding reduction in serum levels of LDL-C 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. ALN-PCS02 was shown to be well tolerated in this Phase 1 study and there were no serious adverse events related to study drug administration.

Alnylam and The Medicines Company are collaborating in the advancement of ALN-PCSsc per the companies’ agreement formed in early 2013. Under the terms of the agreement, Alnylam will complete certain pre-clinical studies and a Phase 1 clinical study of ALN-PCSsc and The Medicines Company is responsible for leading and funding development from Phase 2 forward as well as potential commercialization.

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 adequate LDL-C levels with currently available therapies including statins, including genetic familial hypercholesterolemia (FH) 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 GalNAc Conjugates and Enhanced Stabilization Chemistry (ESC) 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. Alnylam’s Enhanced Stabilization Chemistry (ESC) GalNAc-conjugate technology enables subcutaneous dosing with increased potency, durability, and a wide therapeutic index, and is being employed in several of Alnylam’s genetic medicine programs, including programs in clinical development.

About 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 as genetic medicines, including programs as part of the company’s “Alnylam 5x15™” product strategy. Alnylam’s genetic medicine programs are investigational RNAi therapeutics directed toward genetically defined targets for the treatment of serious, life-threatening diseases with limited treatment options for patients and their caregivers. These include: patisiran (ALN-TTR02) targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR) in patients with familial amyloidotic polyneuropathy (FAP); revusiran (ALN-TTRsc) targeting TTR for the treatment of ATTR in patients with TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3 targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5 targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1 targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCSsc targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3 targeting apolipoprotein C-3 (apoC3) for the treatment of hypertriglyceridemia; ALN-AGT targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1 targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); ALN-HDV targeting the hepatitis delta virus (HDV) genome for the treatment of HDV infection; ALN-PDL targeting programmed death ligand 1 (PD-L1) for the treatment of chronic liver infections; and other programs yet to be disclosed. As part of its “Alnylam 5x15” strategy, as updated in early 2014, the company expects to have six to seven genetic medicine product candidates in clinical development – including at least two programs in Phase 3 and five to six programs with human proof of concept – by the end of 2015. The company’s demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, and The Medicines Company. In early 2014, Alnylam and Genzyme, a Sanofi company, formed a multi-product geographic alliance on Alnylam's genetic medicine programs in the rare disease field. Specifically, Alnylam will lead development and commercialization of programs in North America and Europe, while Genzyme will develop and commercialize products in the rest of world. In addition, Alnylam and Genzyme will co-develop and co-commercialize revusiran in North America and Europe. In March 2014, Alnylam acquired Sirna Therapeutics, a wholly owned subsidiary of Merck. In addition, Alnylam holds an equity position in Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 200 peer-reviewed papers, including many in the world’s top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, Cell, New England Journal of Medicine, and The Lancet. 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, Alnylam’s views with respect to the potential for RNAi therapeutics, including ALN-PCSsc for the treatment of hypercholesterolemia, the timing for reporting of data from the ALN-PSCsc Phase 1 clinical study, the potential therapeutic opportunities for ALN-PCSsc, as well as its expectations regarding its “Alnylam 5x15” product strategy, and its plans regarding commercialization of RNAi therapeutics, including ALN-PCSsc, 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, 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 manage operating expenses, 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 most recent Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) 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.

About The Medicines Company
The Medicines Company's purpose is to save lives, alleviate suffering and contribute to the economics of healthcare by focusing on 3000 leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: serious infectious disease care, acute cardiovascular care, and surgery and perioperative care. The company operates in the Americas, Europe and the Middle East, and Asia Pacific regions with global centers today in Parsippany, NJ, USA and Zurich, Switzerland.

The Medicines Company Forward-Looking Statements
Statements contained in this press release about The Medicines Company that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates" "expects" and “potential” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether the Company's products will advance in the clinical trials process on a timely basis or at all, whether the Company will make regulatory submissions for product candidates on a timely basis, whether its regulatory submissions will receive approvals from regulatory agencies on a timely basis or at all, whether physicians, patients and other key decision makers will accept clinical trial results and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the SEC on November 7, 2014, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.


Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and Corporate Communications
Liz Bryan, 202-955-6222 x2526
The Medicines Company
Robert F. Laverty, 973-290-6162 (office)
609-558-5570 (mobile)
Vice President, Global Communications

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