The Medicines Company and Alnylam Pharmaceuticals Report Positive Final Results from ORION-1 Phase II Study of Inclisiran

17 Mar 2017

The Medicines Company (NASDAQ: MDCO) and Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) today announced positive final results from the ORION-1 Phase II study of inclisiran, an investigational, first-in-class PCSK9 synthesis inhibitor being developed for the treatment of hypercholesterolemia. The results are being presented today in the “Late-Breaking Clinical Trials - Featured Clinical Research 1” session at the American College of Cardiology’s 66th Annual Scientific Session, ACC.17, and have been published in the March 17, 2017 online issue of The New England Journal of Medicine.

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<p>
  The detailed data from ORION-1 showed that inclisiran delivered 
  significant and sustained reductions of LDL-C and high standards of 
  safety and tolerability. Remarkably, every patient who received the two 
  dose starting regimen displayed a significant response and the mean 
  LDL-C reductions over time were practically constant. Inclisiran was 
  well tolerated and no material safety issue was observed, including no 
  investigational drug-related elevation of liver enzymes and no 
  neuropathy, change in renal function, thrombocytopenia, or anti-drug 
  antibodies.
</p>
<p>
  “The groundbreaking results from ORION-1 are compelling and affirm 
  inclisiran’s unique and highly-differentiated attributes, and its 
  game-changing potential to address the unmet needs of millions of 
  at-risk, often non-adherent, patients worldwide who continue to struggle 
  with high cholesterol given the limitations of available therapies,” 
  said Clive Meanwell, M.D., Ph.D., Chief Executive Officer of 
  The&nbsp;Medicines Company. “We are singularly focused on thoughtfully and 
  aggressively advancing inclisiran into Phase III development, including 
  the initiation of ORION-4, which we expect to include cardiovascular 
  outcomes in high-risk primary and secondary prevention patients with an 
  average baseline LDL-C of approximately 130 mg/dL.”
</p>
<p>
  John J.P. Kastelein, M.D., Ph.D., Professor of Medicine and Chairman of 
  the&nbsp;Department of Vascular Medicine&nbsp;at the&nbsp;Academic Medical Center&nbsp;of 
  the&nbsp;University of&nbsp;Amsterdam, continued, “We are pleased to see the 
  complete results from this comprehensive 497 patient Phase II study. 
  Inclisiran’s universal and practically constant effect is unprecedented 
  in my experience of over 30 years of dyslipidemia clinical trials. The 
  unique dosing regimen virtually eliminates variability in LDL-C levels 
  over time and inclisiran may, therefore, solve one of the most vexing 
  challenges of cardiovascular medicine – namely, how to make sure 
  everyone responds to treatment.”
</p>
<p>
  David Kallend, MBBS, Vice President and Global Medical Director of&nbsp;The 
  Medicines Company, added, “The results from ORION-1 have the potential 
  to significantly advance the treatment paradigm with robust and durable 
  knockdown of LDL-C and a convincing and highly-reassuring safety and 
  tolerability profile. The data support the selection of 300 mg as the 
  optimal dose, as well as our conclusion that a two dose starting 
  regimen, followed by dosing two times per year, constitutes a 
  highly-differentiated and competitive treatment for patients with 
  hypercholesterolemia. We believe the strength of the data will enable a 
  quick and efficient transition to Phase III development.”
</p>
<p>
  John Maraganore, Ph.D., Chief Executive Officer of Alnylam, added, “We 
  are delighted with these final data from the ORION-1 study and impressed 
  by the progress made by investigators and our partner, The Medicines 
  Company. Importantly, as the largest study yet to be performed for an 
  RNAi therapeutic, we believe the results provide compelling support for 
  the positive safety and tolerability profile of our investigational 
  medicines.”
</p>
<p>
  In ORION-1, the mean baseline LDL-C was approximately 130 mg/dL among 
  497 randomized and treated patients. The optimal starting dose regimen 
  (300 mg injection administered on Day-1 and Day-90) achieved a mean 
  LDL-C reduction of 52.6% and up to 81% at Day-180, and a time-adjusted 
  mean of &gt;50% for the six month period from Day-90 through Day-270. For 
  all dose groups, at all time points, differences in the primary (LDL-C) 
  and secondary (PCSK9) endpoints between inclisiran and placebo were 
  statistically significant (p &lt;0.0001).
</p>
<p>
  The overall incidence of treatment emergent adverse events was 76% in 
  both patients randomized to placebo and patients randomized to 
  inclisiran, with no significant difference between inclisiran doses. 
  Injection site reactions associated with inclisiran were infrequent 
  (observed in 6.5% of patients given the two dose starting regimen and 
  3.8% of patients given the one dose starting regimen), mild or moderate, 
  and transient.
</p>
<p>
  The results from the Phase II study of inclisiran, published in today’s 
  online issue of <i>The New England Journal of Medicine</i>, can be found <a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.nejm.org%2Fdoi%2Ffull%2F10.1056%2FNEJMoa1615758&amp;esheet=51527621&amp;newsitemid=20170317005437&amp;lan=en-US&amp;anchor=here&amp;index=1&amp;md5=b4d009d2d4ce51967b853f98d804f836" rel="nofollow">here</a>.
</p>
<p>
  <b>Webcast Information for Late-Breaking Clinical Trial Presentations</b>
</p>
<p>
  Live audio and video of the “Late-Breaking Clinical Trials - Featured 
  Clinical Research 1” presentation by ORION-1’s principal investigator, 
  Kausik K. Ray, M.D., MPhil (Cantab), FRCP, Professor of Public Health, 
  Imperial College London, will be webcast over the internet at 1:30 p.m., 
  Eastern Time, today. The live webcast may be accessed from the 
  “Investors-Events/Presentations” section of <a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.themedicinescompany.com%2Finvestors%2Fevents&amp;esheet=51527621&amp;newsitemid=20170317005437&amp;lan=en-US&amp;anchor=The+Medicines+Company&amp;index=2&amp;md5=dd6a1bfaa8eb453ad47a5dad3f18ebb3" rel="nofollow">The 
  Medicines Company</a> website.
</p>
<p>
  <b>Conference Call and Webcast Details</b>
</p>
<p>
  The Medicines Company will host a conference call and webcast today at 
  4:30 p.m., Eastern Time. The conference call may be accessed as follows:
</p>
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<p>
  The live webcast may be accessed in the “Investors-Events/Presentations” 
  section of <a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.themedicinescompany.com%2Finvestors%2Fevents&amp;esheet=51527621&amp;newsitemid=20170317005437&amp;lan=en-US&amp;anchor=The+Medicines+Company&amp;index=3&amp;md5=cbe75a1d3b71abcaceb466c413da9e78" rel="nofollow">The 
  Medicines Company</a> website.
</p>
<p>
  A taped replay of the conference call will be archived and available for 
  approximately one week. The replay may be accessed as follows:
</p>
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      (855) 859-2056
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<p>
  A replay of the webcast will also be archived and available after the 
  conference call.
</p>
<p>
  <b>About ORION-1</b>
</p>
<p>
  ORION-1 is a placebo-controlled, double-blind, randomized Phase II study 
  of single or multiple subcutaneous injections of inclisiran in a total 
  of 501 patients with atherosclerotic cardiovascular disease (ASCVD) or 
  ASCVD-risk equivalents (<span class="bwuline">e.g</span>., diabetes and 
  familial hypercholesterolemia) and elevated LDL-C despite maximum 
  tolerated doses of LDL-C lowering therapies. The study compares the 
  effect of different doses of inclisiran and evaluates the potential for 
  an infrequent dosing regimen. The primary endpoint of the study is the 
  percentage change in LDL-C from baseline at Day-180.
</p>
<p>
  <b>About Inclisiran</b>
</p>
<p>
  Inclisiran (formerly known as PCSK9si and ALN-PCSsc) is an 
  investigational GalNAc-conjugated 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, 
  inclisiran is a first-in-class investigational medicine that acts by 
  turning off PCSK9 synthesis in the liver.
</p>
<p>
  The Medicines Company and Alnylam Pharmaceuticals, Inc. are 
  collaborating in the advancement of inclisiran pursuant to their 2013 
  agreement. Under the terms of the agreement, Alnylam completed certain 
  pre-clinical studies and the Phase I clinical study, with The Medicines 
  Company leading and funding the development of inclisiran from Phase II 
  forward, as well as potential commercialization.
</p>
<p>
  <b>About The&nbsp;Medicines Company</b>
</p>
<p>
  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.
</p>
<p>
  <b>About Alnylam Pharmaceuticals</b>
</p>
<p>
  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&nbsp;<i>Nature, Nature 
  Medicine, Nature Biotechnology, Cell, New England Journal of Medicine,</i>&nbsp;and&nbsp;<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&nbsp;<a href="http://cts.businesswire.com/ct/CT?id=smartlink&amp;url=http%3A%2F%2Fwww.alnylam.com&amp;esheet=51527621&amp;newsitemid=20170317005437&amp;lan=en-US&amp;anchor=www.alnylam.com&amp;index=4&amp;md5=2fb5cd0a4a5c4b202986cc186ca6c1ee" rel="nofollow">www.alnylam.com</a>.
</p>
<p>
  <b>The Medicines Company Forward-Looking Statements</b>
</p>
<p>
  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&nbsp;Securities and Exchange Commission,&nbsp;including, without limitation, 
  the risk factors detailed in the Company's Annual Report on Form 10-K 
  filed with the&nbsp;Securities and Exchange Commission&nbsp;on&nbsp;March 1, 2017, 
  which are incorporated herein by reference. The Company specifically 
  disclaims any obligation to update these forward-looking statements.
</p>
<p>
  <b>Alnylam Forward-Looking Statements</b>
</p>
<p>
  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 inclisiran, its expectations regarding the timing of clinical 
  studies, its expectations regarding scientific and regulatory support 
  for inclisiran, 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 Annual Report on Form 10-K 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.
</p>
<p>
  The scientific information referenced 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 its safety or effectiveness.
</p>


Contacts

The Medicines Company
Media:
Meg Langan, 973-290-6319
Vice President
margaret.langan@themedco.com
Investors:
Krishna Gorti, M.D., 973-290-6122
Vice President, Investor Relations
krishna.gorti@themedco.com
or
Alnylam Pharmaceuticals
Investors and Media:
Christine Regan Lindenboom, 617-682-4340
Vice President
clindenboom@alnylam.com
Investors:
Josh Brodsky, 617-551-8276
Associate Director
jbrodsky@alnylam.com

Contact Us

The Medicines Company
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Tel 973 290 6000
Toll-free 800 388 1183
Global Medical Information

Human Resources
Verification of employment
Tel 973 290 6361
Fax 862 207 6361

Investors Relations

Krishna Gorti, MD
Tel 973 290 6122
krishna.gorti@themedco.com

Media Inquiries

Michael Blash
Tel 973 290 6100
michael.blash@themedco.com