Alnylam Pharmaceuticals and The Medicines Company Announce Publication of Phase 1 Clinical Data with Inclisiran (ALN- PCSsc) in the New England Journal of Medicine

13 Nov 2016

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 announced that results from the Phase 1 study of inclisiran (in-CLEE-si-ran), the recommended International Nonproprietary Name (INN) for ALN-PCSsc, were published in The New England Journal of Medicine (NEJM). Inclisiran is an investigational RNAi therapeutic targeting PCSK9 – a genetically validated protein regulator of LDL receptor metabolism – being developed for the treatment of hypercholesterolemia. The paper can be found online here.

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  Results from the study showed doses ?300 mg (single or multiple doses) 
  significantly reduced PCSK9 and LDL cholesterol for at least 6 months. 
  Moreover, inclisiran was found to be generally well tolerated.
  "The published findings from our Phase 1 trial with inclisiran add to 
  the clinical evidence supporting PCSK9 as a therapeutic target for 
  significantly lowering LDL cholesterol, as well as the ability of RNAi 
  therapeutic candidates to inhibit synthesis of liver-derived target 
  proteins in a potent and durable manner,” said Akshay Vaishnaw, M.D., 
  Ph.D., Executive Vice President of R&amp;D and Chief Medical Officer of 
  Alnylam. “We believe that inclisiran represents an innovative and 
  differentiated approach for the treatment of hypercholesterolemia.”
  Inclisiran is currently being studied in the ORION-1 Phase 2 study by 
  The Medicines Company. With more than 500 patients enrolled, ORION-1 is 
  the largest study of a GalNAc-siRNA conjugate to date. The Medicines 
  Company recently announced positive top-line results from the day 90 
  interim analysis of the Phase 2 study demonstrating significant and 
  durable LDL-C reduction that validates the potential for a triannual or 
  biannual dosing regimen. Top-line results also showed that inclisiran 
  was generally well tolerated, with no evidence of drug-related 
  elevations of liver enzymes, neuropathy adverse events, or changes in 
  renal function. The Medicines Company plans to present complete interim 
  results from the ongoing study in a Late-Breaking Clinical Trial Session 
  at the American Heart Association (AHA) Scientific Sessions on November 
  15, 2016.
  “We look forward to presenting the interim results of the ORION-1 Phase 
  2 data at AHA this week including Day 90 follow-up results for all 501 
  patients and a preliminary analysis of Day 180 follow-up for up to 200 
  patients,” said David Kallend, MBBS, Vice President and Global Medical 
  Director at The Medicines Company. “Based on the strong results from the 
  Phase 1 study, we hope to further elucidate the hypothesis of triannual 
  or biannual dosing of inclisiran with the ORION-1 results.”
  The NEJM publication highlights key results from the Phase 1 clinical 
  trial of inclisiran, including safety and pharmacodynamic measures 
  (PCSK9, LDL cholesterol, exploratory lipid parameters).
  In the single-ascending-dose (SAD) phase, pharmacodynamic measures 
  <li class="bwlistitemmargb">
    Doses ?300 mg reduced PCSK9 at day 84 (up to a least-squares mean 
    (LSM) reduction of 74.5%);
  <li class="bwlistitemmargb">
    Doses ?100 mg reduced LDL cholesterol at day 84 (up to a LSM reduction 
    of 50.6%);
  <li class="bwlistitemmargb">
    Reductions in PCSK9 and LDL cholesterol were maintained at day 180 
    with little variation over the 6-month period for doses ?300 mg.
  In the multiple-dose (MD) phase, pharmacodynamic measures showed:
  <li class="bwlistitemmargb">
    Reduced PCSK9 (up to a LSM reduction of 83.8%) and LDL cholesterol (up 
    to a LSM reduction of 59.7%) at day 84;
  <li class="bwlistitemmargb">
    Levels of PCSK9 and LDL cholesterol remained reduced in all the 
    inclisiran cohorts at day 196.
  Safety and side effect profile evaluations showed:
  <li class="bwlistitemmargb">
    Inclisiran was generally well tolerated following single and multiple 
    subcutaneous dose administration;
  <li class="bwlistitemmargb">
    No serious adverse events (SAEs) or discontinuations due to AEs were 
  <li class="bwlistitemmargb">
    All observed adverse events (AEs) were mild or moderate in severity;
  <li class="bwlistitemmargb">
    There was one Grade 3 GGT elevation considered related to statin 
  The lead development responsibility for inclisiran transitioned from 
  Alnylam to The Medicines Company in August 2015. The two companies are 
  now working to advance inclisiran in the ORION development program, a 
  comprehensive global clinical development plan designed to support 
  regulatory approval and market access worldwide.
  <b>About the Inclisiran Phase 1 Study</b>
  The Phase 1 trial of inclisiran was conducted in the U.K. as a 
  randomized, single-blind, placebo-controlled, single ascending- and 
  multi-dose, subcutaneous dose-escalation study. The study enrolled 69 
  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 included subjects both on and off stable doses 
  of statin co-medication. The primary objective of the Phase 1 study was 
  to evaluate the safety, side effect profile, and pharmacodynamics 
  effects of inclisiran.
  <b>About Hypercholesterolemia</b>
  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.
  <b>About GalNAc Conjugates and Enhanced Stabilization Chemistry 
  (ESC)-GalNAc Conjugates</b>
  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 
  inclisiran and several other programs in clinical development.
  <b>About RNAi</b>
  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.
  <b>About Alnylam Pharmaceuticals</b>
  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 Ionis, Novartis, Roche, Takeda, Merck, Monsanto, The 
  Medicines Company, and Sanofi Genzyme. 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 <i>Nature, Nature Medicine, 
  Nature Biotechnology, Cell, New England Journal of Medicine,</i> and <i>The 
  Lancet</i>. Founded in 2002, Alnylam maintains headquarters in 
  Cambridge, Massachusetts. For more information about Alnylam's pipeline 
  of investigational RNAi therapeutics, please visit <a href=";;esheet=51459699&amp;newsitemid=20161113005052&amp;lan=en-US&amp;;index=3&amp;md5=f0ad88e59be6886e2f2dca99ac131846" rel="nofollow"></a>.
  <b>Alnylam Forward Looking Statements</b>
  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 inclisiran, including 
  the potential dosing regimen, the timing of clinical studies and the 
  presentation of clinical data, its expectations regarding its STAr 
  pipeline growth strategy, and its “Alnylam 2020” guidance for the 
  advancement and commercialization of RNAi therapeutics, constitute 
  forward-looking statements for the purposes of the safe harbor 
  provisions under The Private Securities Litigation Reform Act of 1995. 
  Actual results and future plans may differ materially from those 
  indicated by these forward-looking statements as a result of various 
  important risks, uncertainties and other 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 product 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 for a 
  specified indication or at all, actions or advice of regulatory 
  agencies, which may affect the design, initiation, timing, continuation 
  and/or progress of clinical trials or result in the need for additional 
  pre-clinical and/or clinical testing, delays, interruptions or failures 
  in the manufacture and supply of our product candidates, obtaining, 
  maintaining and protecting intellectual property, Alnylam's ability to 
  enforce its intellectual property rights against third parties and 
  defend its patent portfolio against challenges from third parties, 
  obtaining and maintaining regulatory approval, pricing and reimbursement 
  for products, progress in establishing a commercial and ex-United States 
  infrastructure, competition from others using technology similar to 
  Alnylam's and others developing products for similar uses, Alnylam's 
  ability to manage its growth and operating expenses, 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 and 
  distribution of products, the outcome of litigation, the risk of 
  government investigations, 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&nbsp;Securities and 
  Exchange Commission&nbsp;(SEC) and in other filings that Alnylam makes with 
  the&nbsp;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, except to the extent required by law, to update any 
  forward-looking statements.
  The scientific information discussed in this news release relating to 
  inclisiran is preliminary and investigative. Inclisiran has not been 
  approved by the U.S. Food and Drug Administration, European Medicines 
  Agency, or any other regulatory authority and no conclusions can or 
  should be drawn regarding the safety or effectiveness of this 
  <b>About The&nbsp;Medicines Company</b>
  The Medicines Company is a biopharmaceutical company driven by an 
  overriding purpose—to save lives, alleviate suffering and contribute to 
  the economics of healthcare. The Company’s mission is to create 
  transformational solutions to address the most pressing healthcare needs 
  facing patients, physicians and providers in three critical therapeutic 
  areas: serious infectious disease care, cardiovascular care and surgery 
  and perioperative care. The Company is headquartered in Parsippany, New 
  Jersey, with global innovation centers in California and Switzerland.
  <b>Forward Looking Statements</b>
  Statements contained in this press release 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," “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 clinical trials for inclisiran, will advance in the 
  clinical process on a timely basis, or at all, or succeed in achieving 
  their specified endpoints; whether physicians, patients and other key 
  decision makers will accept clinical trial results; whether the Company 
  will make regulatory submissions for inclisiran on a timely basis, or at 
  all; whether its regulatory submissions will receive approvals from 
  regulatory agencies on a timely basis, or at all; 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 Securities and Exchange Commission on October 27, 2016, 
  which are incorporated herein by reference. The Company specifically 
  disclaims any obligation to update these forward-looking statements.


Alnylam Pharmaceuticals, Inc.
Christine Regan Lindenboom, 617-682-4340
(Investors and Media)
Josh Brodsky, 617-551-8276
The Medicines Company
Meg Langan, 973-290-6319
Vice President
Krishna Gorti, M.D., 973-290-6122
Vice President, Investor Relations

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