Alnylam and The Medicines Company Announce Filing of a Clinical Trial Application to Initiate a Phase 1 Study for ALN-PCSsc, an Investigational, Subcutaneously Administered RNAi Therapeutic Targeting PCSK9 for the Treatment of Hypercholesterolemia

Companies Expect to Initiate Phase 1 Study in Late 2014 or Early 2015, with Initial Clinical Results Mid-2015

CAMBRIDGE, MA & PARSIPPANY, NJ, USA I OCtober 28, 2014 I Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), a leading RNAi therapeutics company, and The Medicines Company (Nasdaq:MDCO), a global biopharmaceutical company focusing on saving lives, alleviating suffering and contributing to the economics of healthcare by focusing on the world’s leading acute/intensive care hospitals, announced today that Alnylam has filed a Clinical Trial Application (CTA) with the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to initiate a Phase 1 clinical trial with ALN-PCSsc, an investigational agent for the treatment of hypercholesterolemia. 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). Per the filed CTA, the Phase 1 trial of ALN-PCSsc will be 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). Following approval of the CTA, the companies expect to initiate dosing in the Phase 1 trial in late 2014 or early 2015, with initial data expected to be reported 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, pre-clinical, non-human primate studies have demonstrated 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. Accordingly, we’re very excited to advance this investigational RNAi therapeutic to clinical stages with this CTA filing,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President and Chief Medical Officer of Alnylam. “ALN-PCSsc now becomes our third RNAi therapeutic that utilizes our proprietary, clinically validated GalNAc conjugate delivery platform to enter a clinical development stage, and the second that utilizes our optimized ESC-GalNAc technology. Together with The Medicines Company, we look forward to the continued advancement of ALN-PCSsc, including the start of our Phase 1 clinical trial in the coming months, with initial data expected in mid-2015.”

“Elevated LDL-C remains a major risk factor for coronary artery disease, and new therapies are needed for patients who are refractory or intolerant to current approaches for management of their LDL-C levels. 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,” said David Kallend, MB.BS (Lon), Vice President and Global Medical Director for the lipid programs at The Medicines Company. “This new CTA filing is an important milestone in our collaboration with Alnylam, and we very much look forward to the start of Phase 1. Assuming positive results, The Medicines Company will lead the collaborative effort in subsequent stages of development and commercialization.”

ALN-PCSsc is a subcutaneously administered 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. Recent pre-clinical results in non-human primate (NHP) studies demonstrated that a single dose of ALN-PCSsc significantly reduced plasma PCSK9 protein by up to 96%, with mean PCSK9 knockdown at nadir of 88% at the top dose. Results also showed lowering of LDL-C of up to 77%, with a mean reduction of 69% at the top dose; these results were observed in the absence of statin co-administration. Knockdown of PCSK9 and lowering of LDL-C were rapid and durable, with maximal effects lasting greater than 90 days and returning to baseline at approximately 160 days. At the top dose of 10 mg/kg, an over 50% reduction in LDL-C was maintained for over 90 days. Moreover, there was sustained and clamped knockdown of PCSK9 and reduction of LDL-C across this entire time period, 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). All together, these pre-clinical data are supportive of a once-monthly, and possibly once-quarterly, dosing regimen, which could represent a highly competitive target product profile. In addition, four-week GLP toxicology studies evaluating doses administered every other week confirmed that ALN-PCSsc has a wide therapeutic index, with a No Observed Adverse Effect Level (NOAEL) of greater than 250 mg/kg in rats and NHP.

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 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.

As per the filed CTA, the Phase 1 trial of ALN-PCSsc will be 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 multi-dose phase. In the multi-dose phase, subjects will receive two subcutaneous doses of either ALN-PCSsc or placebo administered four weeks apart; the multi-dose 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.

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 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), 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 TTR cardiac amyloidosis, including familial amyloidotic cardiomyopathy (FAC) and senile systemic amyloidosis (SSA); ALN-AT3, an RNAi therapeutic targeting antithrombin (AT) for the treatment of hemophilia and rare bleeding disorders (RBD); ALN-CC5, an RNAi therapeutic targeting complement component C5 for the treatment of complement-mediated diseases; ALN-AS1, an RNAi therapeutic targeting aminolevulinic acid synthase-1 (ALAS-1) for the treatment of hepatic porphyrias including acute intermittent porphyria (AIP); ALN-PCS, an RNAi therapeutic targeting PCSK9 for the treatment of hypercholesterolemia; ALN-AAT, an RNAi therapeutic targeting alpha-1 antitrypsin (AAT) for the treatment of AAT deficiency-associated liver disease; ALN-HBV, an RNAi therapeutic targeting the hepatitis B virus (HBV) genome for the treatment of HBV infection; ALN-TMP, an RNAi therapeutic targeting TMPRSS6 for the treatment of beta-thalassemia and iron-overload disorders; ALN-ANG, an RNAi therapeutic targeting angiopoietin-like 3 (ANGPTL3) for the treatment of genetic forms of mixed hyperlipidemia and severe hypertriglyceridemia; ALN-AC3, an RNAi therapeutic targeting apolipoprotein C-III (apoCIII) for the treatment of hypertriglyceridemia; ALN-AGT, an RNAi therapeutic targeting angiotensinogen (AGT) for the treatment of hypertensive disorders of pregnancy (HDP), including preeclampsia; ALN-GO1, an RNAi therapeutic targeting glycolate oxidase (GO) for the treatment of primary hyperoxaluria type 1 (PH1); 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 ALN-TTRsc 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

SOURCE: Alnylam Pharmaceuticals

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