Alnylam Pharmaceuticals and The Medicines Company Announce that New ALN-PCSsc Results from Late-Breaking Presentation at American Heart Association Meeting Confirm Potential for Bi-Annual Hypercholesterolemia Dose Regimen

11 Nov 2015

Alnylam Pharmaceuticals, Inc. (Nasdaq:ALNY), the leading RNAi therapeutics company, and The Medicines Company (Nasdaq:MDCO), a leading biopharmaceutical development and cardiovascular product company, today reported positive results from their ongoing Phase 1 clinical trial with ALN-PCSsc in a late-breaking oral presentation at the American Heart Association (AHA) Scientific Sessions 2015.

ALN-PCSsc is an investigational RNAi therapeutic targeting PCSK9 – a genetically validated protein regulator of LDL receptor metabolism – being developed for the treatment of hypercholesterolemia. In contrast to anti-PCSK9 monoclonal antibodies (MAbs) that bind to PCSK9 in blood, ALN-PCSsc is a first-in-class investigational medicine that acts by turning off PCSK9 synthesis in the liver. As reported previously, subcutaneous administration of ALN-PCSsc resulted in an up to 83 percent lowering of LDL-C, with an up to 64 ± 5 percent mean maximum reduction, comparable to published results for anti-PCSK9 MAbs (Zhang XL., et al., BMC Med, 2015). In new results, the effects of ALN-PCSsc were found to be highly durable, with clinically significant and clamped reductions in LDL-C, supportive of a potential bi-annual subcutaneous dose regimen. Specifically, an up to 53 percent maximal and 47 percent least squares mean reduction in LDL-C was achieved at day 180 after just a single, low volume injection. In addition, ALN-PCSsc was shown to reduce a number of atherogenic lipids, including lipoprotein (a) – or “Lp(a)” – and total cholesterol, which are associated with increased risk of cardiovascular disease. ALN-PCSsc was generally well tolerated with no clinically significant drug-related adverse events. The development leadership of ALN-PCSsc has now transferred from Alnylam to The Medicines Company, who expects to initiate the ORION-1 Phase 2 study by the end of 2015.

Our study results continue to show a highly durable PCSK9 knockdown and LDL-C reduction with just a single dose of ALN-PCSsc, a first-in-class investigational PCSK9 synthesis inhibitor. Remarkably, these data show that significant and clamped lowering of LDL-C is achieved for over 180 days, with associated decreases in other atherogenic lipids including Lp(a) and total cholesterol. Importantly, ALN-PCSsc continues to be generally well tolerated with no clinically significant drug-related adverse events,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D, and Chief Medical Officer of Alnylam. “We very much look forward to our continued partnership with The Medicines Company as they now take the lead in the ORION ALN-PCSsc development program.”

“We believe that ALN-PCSsc has significant potential given its highly competitive profile as compared with anti-PCSK9 MAbs, a recently approved class of LDL-C lowering drugs. Indeed, in our view, the potential for management of hypercholesterolemia with two injections per year could be a transformative option for patients, physicians, and payers in the treatment of atherosclerotic cardiovascular disease (ASCVD),” said David Kallend, MBBS, Vice President and Global Medical Director at The Medicines Company. “In close collaboration with our colleagues at Alnylam, we’re on track to start our initial ORION-1 Phase 2 study by the end of this year, and plan to initiate Phase 3 registration studies in 2017. In addition, we plan on conducting studies directly comparing ALN-PCSsc with anti-PCSK9 MAbs, as well as studies in homozygous familial hypercholesterolemia, to confirm the important features and potential benefits of this first-in-class investigational PCSK9 synthesis inhibitor.”

An efficacious and well tolerated bi-annual, low volume, subcutaneous dosing regimen could address the unmet needs for hypercholesterolemia management in a large, at-risk, often non-adherent population worldwide,” John J.P. Kastelein, M.D., Ph.D., Professor of Medicine and Chairman of the Department of Vascular Medicine at the Academic Medical Center (AMC) of the University of Amsterdam. “By harnessing the natural pathway of RNAi, ALN-PCSsc has the potential to offer a genetically validated approach for treating ASCVD patients with elevated LDL-C, a cardiovascular disease risk factor, to get to LDL target.”

All data reported today were as of data transfer September 24, 2015. Specifically, results from the single ascending dose cohorts (n=24) showed:

  • Maximal PCSK9 knockdown of 89 percent with mean maximum knockdown of up to 82.3 ± 2.0 percent;
  • Maximal LDL-C reduction of 78 percent with mean maximum lowering of up to 59.3 ± 5.0 percent;
  • Maximum reductions of Lp(a) of 77 percent, total cholesterol of 48 percent, apolipoprotein B of 72 percent, and non-HDL cholesterol of 68 percent, with no significant change in HDL cholesterol;
  • At day 180, an up to 53 percent reduction in LDL-C, with a least squares mean percent lowering of 47.0 percent in the 300 mg dose cohort.

Results from the multiple dose cohorts (n=45) showed:

  • Maximal PCSK9 knockdown of 94 percent with mean maximum knockdown of up to 88.5 ± 1.6 percent;
  • Maximal LDL-C reduction of 83 percent with mean maximum lowering of up to 64.4 ± 5.4 percent;
  • Maximum reductions of Lp(a) of 76 percent, total cholesterol of 55 percent, apolipoprotein B of 68 percent, and non-HDL cholesterol of 73 percent, with no significant change in HDL cholesterol;
  • At day 208 – approximately 6 months after the last dose – an up to 60 percent reduction in LDL-C, with a least squares mean percent lowering of 44.4 percent in the 300 mg dose cohort;
  • Similar effects were observed in subjects with and without concomitant statin therapy.

ALN-PCSsc was generally well tolerated following single and multiple subcutaneous dose administration, with no serious adverse events (SAEs) or discontinuations due to AEs. All observed adverse events (AEs) were mild or moderate in severity, and were generally similar in subjects with and without concomitant statin administration. At the higher drug exposures, four subjects experienced mild, localized, and self-limiting injection site reactions (ISRs). One subject developed an approximately four times upper limit of normal increase in alanine transaminase (ALT), without increase in bilirubin that was attributed to concomitant statin therapy; ALT levels resolved upon statin discontinuation and were found to be elevated a second time after re-challenge with a lower dose of the same statin.

Alnylam and The Medicines Company confirm that the ORION-1 Phase 2 study of ALN-PCSsc is expected to be initiated by the end of 2015. ORION-1 will be a global, randomized, double blind, placebo-controlled study that will enroll approximately 480 patients with confirmed ASCVD and elevated LDL-C on maximally tolerated lipid lowering therapy. Patients will be randomized (3:1) to receive ALN-PCSsc or placebo at subcutaneous doses ranging from 100 mg to 500 mg administered either once on day 0 or twice on days 0 and 90. The primary endpoint for the study is the difference in LDL-C levels from baseline to day 180 in patients receiving ALN-PCSsc or placebo. Secondary endpoints include safety and tolerability, LDL-C lowering at day 90, PCSK9 knockdown at days 90 and 180, proportion of patients reaching global lipid guidelines, and changes in other atherogenic lipids. Upon completion of the study, all patients will be eligible to enroll into an open-label extension (OLE) study to receive ALN-PCSsc with the same dose and dose regimen as selected for further evaluation in the planned Phase 3 trial.

About the ALN-PCSsc Phase 1 Study
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, subcutaneous dose-escalation study. Enrollment in the study has been completed, but the study is ongoing with continued data collection and subject follow up. The study was 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 was performed in two phases: a single ascending dose (SAD) phase and a multiple dose (MD) phase. The MD phase also includes 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 lowering of serum LDL-C levels, as well as pharmacokinetics of ALN-PCSsc.

Conference Call Information
Alnylam and The Medicines Company will host a conference call today, Wednesday, November 11, at 4:30 p.m. ET to discuss these results with ALN-PCSsc and the ORION development program. A slide presentation will be available on the Investors page of the Alnylam website, www.alnylam.com, and on The Medicines Company website, www.themedicinescompany.com, to accompany the conference call. To access the call, please dial 877-312-7507 (domestic) or 631-813-4828 (international) five minutes prior to the start time and refer to conference ID 76033533. A replay of the call will be available beginning at 7:30 p.m. ET. To access the replay, please dial 855-859-2056 (domestic) or 404-537-3406 (international), and refer to conference ID 76033533.

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 such as statins, including genetic familial hypercholesterolemia (FH) patients, acute coronary syndrome patients, high-risk patient populations (e.g., patients with coronary artery disease, diabetes, 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 and durability, and a wide therapeutic index. This ESC-GalNAc-conjugate delivery platform is being employed in nearly all of Alnylam's pipeline programs, including ALN-PCSsc and several other 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. Alnylam's pipeline of investigational RNAi therapeutics is focused in 3 Strategic Therapeutic Areas (STArs): Genetic Medicines, with a broad pipeline of RNAi therapeutics for the treatment of rare diseases; Cardio-Metabolic Disease, with a pipeline of RNAi therapeutics toward genetically validated, liver-expressed disease targets for unmet needs in cardiovascular and metabolic diseases; and Hepatic Infectious Disease, with a pipeline of RNAi therapeutics that address the major global health challenges of hepatic infectious diseases. In early 2015, Alnylam launched its "Alnylam 2020" guidance for the advancement and commercialization of RNAi therapeutics as a whole new class of innovative medicines. Specifically, by the end of 2020, Alnylam expects to achieve a company profile with 3 marketed products, 10 RNAi therapeutic clinical programs - including 4 in late stages of development - across its 3 STArs. The company's demonstrated commitment to RNAi therapeutics has enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen, Roche, Takeda, Kyowa Hakko Kirin, Cubist, GlaxoSmithKline, Ascletis, Monsanto, The Medicines Company, and Genzyme, a Sanofi company. 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 about Alnylam's pipeline of investigational RNAi therapeutics, please visit www.alnylam.com.

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, and the potential clinical activity and durability of ALN-PCSsc, its expectations regarding the initiation of clinical studies, including studies as part of the ORION development program, expectations regarding the continued development of ALN-PCSsc by The Medicines Company, expectations regarding Alnylam's STAr pipeline growth 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 be replicated or continue to occur in other subjects or in additional studies or otherwise 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, including The Medicines Company, for development, manufacture, marketing, sales and/or 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," "hopes" 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 ALN-PCSsc will advance in the clinical trials process on a timely basis or at all, whether physicians, patients and other key decision makers will accept clinical trial results, whether the Company will make regulatory submissions for ALN-PCSsc on a timely basis or at all, whether its regulatory submissions will receive approvals from regulatory agencies on a timely basis or at all, the Company's ability to successfully compete with potential competitors which may discover, develop or commercialize competing products more successfully than we do, 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 9, 2015, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.


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Alnylam Pharmaceuticals, Inc.
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or
Josh Brodsky, 617-551-8276
Senior Manager, Investor Relations and Corporate Communications
or
The Medicines Company
Krishna Gorti, M.D., 973-290-6122
Vice President, Investor Relations
krishna.gorti@themedco.com
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Bob Laverty, 609-558-5570
Vice President, Communications
robert.laverty@themedco.com

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