– Patient dosing commenced –
– Comprehensive Phase III clinical program to assess LDL-C
lowering and safety in a wide range of patients –
– Efficient, focused and rapid program designed to support US
and EU regulatory filings –
The Medicines Company (NASDAQ: MDCO) and Alnylam
Pharmaceuticals, Inc. (NASDAQ: ALNY) today announced the initiation
of the Phase III clinical program for inclisiran, with the
commencement of patient dosing on November 1, 2017 in the ORION-11
trial, a Phase III study of inclisiran versus placebo in patients
with atherosclerotic cardiovascular disease (ASCVD), or ASCVD-risk
equivalents (e.g., type 2 diabetes and familial
hypercholesterolemia), and elevated LDL-cholesterol (LDL-C) despite
maximum tolerated doses of LDL-C lowering therapies.
The ORION-11 trial is a double-blind study in which 1,500
eligible patients will be randomized 1:1 to receive either
inclisiran or placebo. The primary objective of the study is to
evaluate the effect of inclisiran treatment on percent change in
LDL-C levels from baseline at Day-510 and time-adjusted percent
change in LDL-C levels from baseline between Day-90 and
Day-540.
Building on the highly-successful ORION-1 Phase II trial, which
defined the optimal dosing of inclisiran for the Phase III clinical
program, in ORION-11, the starting dose of inclisiran is 300 mg
given subcutaneously on Day-1 and Day-90, followed by maintenance
doses of 300 mg of inclisiran given subcutaneously on Day-270 and
Day-450. The treatment and observation duration of ORION-11 is 18
months. Approximately 100 clinical sites in seven European
countries and South Africa are participating in the study, which is
being performed in partnership with Pharmaceutical Product
Development, LLC (PPD), a leading global contract research
organization.
Principal Investigator for ORION-11, Professor Kausik Ray,
Professor of Public Health, Imperial College London, United
Kingdom, and Honorary Consultant Cardiologist, Imperial College NHS
Trust, said, “We are very excited to have commenced the inclisiran
Phase III clinical program with the ORION-11 trial. The ease of
dosing – small volume, subcutaneous injections twice a year, most
likely given by healthcare professionals – promises to improve
patient adherence to lipid therapy, which has been a significant
problem with all other approaches. Data from the ORION-1 Phase II
trial gives us considerable confidence in inclisiran’s potential
effectiveness, dosage regimen and safety profile, underscoring the
remarkable potential for inclisiran to become a best-in-class
therapeutic for millions of patients.”
The ORION-11 trial is one of four Phase III pivotal trials for
inclisiran, which also include the ORION-10 trial in approximately
1,500 ASCVD patients treated in North America; the ORION-9 trial in
approximately 400 patients with heterozygous familial
hypercholesterolemia (FH) treated in North America, Europe, Israel
and South Africa; and the ORION-5 trial in approximately 60
patients with homozygous FH treated in Europe, the Middle East and
North America. The Company continues to expect that all of these
trials will commence before the end of 2017 and, subject to the
progress and results of the Phase III clinical program for
inclisiran, that data from the four trials that comprise the
program will support the submission of a New Drug Application (NDA)
in the United States and a Marketing Authorization Application
(MAA) in the European Union at or around the end of 2019.
David Kallend, MBBS, Senior Vice President and Global Medical
Director of The Medicines Company, stated, “We expect a rolling
start for all four pivotal trials, and we believe the entire LDL-C
lowering program will be completed in the second half of 2019 in
anticipation of regulatory submissions in United States and the
European Union. The trials cover the entire spectrum of today’s
subjects who need LDL-C lowering beyond established treatments for
atherosclerotic cardiovascular disease, including secondary
prevention for those with prior heart attacks, strokes and
peripheral artery disease, and primary prevention for those with
familial hypercholesterolemia or other risk factors, such as type 2
diabetes and 20% or greater risk of a major cardiovascular
event.”
Kevin Fitzgerald, Ph.D., Senior Vice President of Research at
Alnylam, said, “We are delighted by the progress that investigators
and our partner, The Medicines Company, have made with inclisiran,
and we look forward to watching its progress in this comprehensive
Phase III program in thousands of patients. In addition, these
studies will provide substantial safety data that we expect will
support the overall safety profile of our RNAi therapeutics
platform.”
Anshul Thakral, Senior Vice President and Global Head of Biotech
at PPD, said, “We are pleased to partner with The Medicines Company
to conduct the ORION Phase III trials using our innovative approach
to chronic disease studies, which includes a closed-loop site
network and patient enrollment solution. We believe that these
trials can rapidly accumulate pivotal data to support NDA and MAA
submissions for inclisiran and we’re excited to contribute to the
development of this potentially important new therapy.”
About ORION-11
ORION-11 is a Phase III, placebo-controlled, double-blind,
randomized study in 1,500 patients with ASCVD (coronary heart
disease, cerebrovascular disease and peripheral arterial disease),
or ASCVD-risk equivalents (e.g., type 2 diabetes, FH and 20% or
greater risk of a cardiovascular event as assessed by Framingham
risk score or equivalent), and elevated LDL-C despite maximum
tolerated doses of LDL-C lowering therapies, designed to evaluate
the efficacy, safety, and tolerability of subcutaneous inclisiran
injection(s).
Patients may be included if they are ≥18 years of age with serum
LDL-C ≥1.8 mmol/L (≥70 mg/dL) for ASCVD patients or ≥2.6 mmol/L
(≥100 mg/dL) for ASCVD-risk equivalent patients, and fasting
triglyceride <4.52 mmol/L (<400 mg/dL) at screening.
Patients on statins should be receiving a maximally-tolerated
dose, which means the maximum dose of statin that can be taken on a
regular basis without intolerable adverse events. Patients not
receiving statins must have documented evidence of intolerance to
all doses of at least two different statins. Lipid-lowering
therapies (such as a statin and/or ezetimibe) should be stable for
≥30 days before screening with no planned medication or dose change
during study participation. Patients on monoclonal antibodies
directed towards PCSK9 within 90 days of screening are excluded.
Other exclusion criteria comprise standard clauses commonly used in
pivotal licensing trials for lipid-lowering therapies.
Lipids and lipoproteins will be measured at various visits,
including LDL-C, total cholesterol, triglycerides, HDL-cholesterol
(HDL-C), non-HDL-C, very low-density lipoprotein cholesterol and
apolipoprotein, as well as PCSK9 and high-sensitivity C-reactive
protein.
Safety assessments, including adverse events, serious adverse
events, electrocardiograms, concomitant medications and safety
laboratory parameters, will also be collected during the study. An
independent Data Monitoring Committee will review safety data on a
regular basis.
About inclisiran
Inclisiran (formerly known as PCSK9si or 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 that bind to PCSK9 in blood, inclisiran is a
first-in-class investigational medicine that acts by turning off
PCSK9 synthesis in the liver.
The Medicines Company and Alnylam Pharmaceuticals, Inc. are
collaborating in the advancement of inclisiran pursuant to the
terms of their 2013 agreement. Under the terms of that 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.
About ASCVD and risk equivalent disease
Despite advances in treatment, cardiovascular disease (CVD) is
the leading cause of death worldwide, resulting in over 17 million
deaths annually. Eighty percent of all CVD deaths are due to
coronary heart disease (CHD) or strokes. Elevated LDL-C is a major
risk factor for the development of CVD and has recently been
described as causative. Lowering LDL-C has been shown to reduce the
risk of cardiovascular death or heart attack, and within the range
of effects achieved so far, the clinical risk reduction is
linearly-proportional to absolute LDL-C reduction.
Approximately 100 million people worldwide are treated with
lipid lowering therapies, predominantly statins, to reduce LDL-C
and the associated risk of death, nonfatal myocardial infarction
(MI) and nonfatal stroke or associated events. However, residual
risk for cardiovascular events remains and statins are associated
with well-known limitations. First, not all subjects reach LDL-C
levels associated with optimal protection against clinical events.
Second, not all subjects tolerate statins or are able to take
statins at sufficiently-intensive doses. Third, observational
studies have demonstrated that >50% of patients do not adhere to
statin therapy for more than six months.
There is an unmet need for additional treatment options beyond
currently-available treatments for lowering of the LDL-C level to
reduce cardiovascular risk.
Despite statins alone or in combination with other lipid
lowering medications, current therapies for the management of
elevated LDL-C remain insufficient in some subjects. This is
particularly true in patients with pre-existing CHD and/or diabetes
or a history of FH, who are at the highest risk and require the
most intensive management.
About PCSK9 and PCSK9 inhibition
Proprotein convertase subtilisin/kexin type 9 (PCSK9), a member
of the serine protease family, plays a key role in controlling the
levels of low-density lipoprotein receptors (LDLR) on the surface
of hepatocytes. PCSK9 is expressed and secreted into the
bloodstream predominantly by the liver, binds LDLR both
intracellularly and extracellularly and promotes the lysosomal
degradation of these receptors in hepatocytes, thereby increasing
the circulating LDL-C levels. Loss of function mutations in PCSK9
have been found to lead to increased LDLR in the liver, reduced
serum LDL-C, and a lower risk for CHD, with no apparent negative
health consequences.
Recently-developed and approved PCSK9-blocking monoclonal
antibodies reduce circulating PCSK9 levels and lower LDL-C levels.
Preliminary reports indicate that treatment with such antibodies
can lead to the reduction of cardiovascular events compared with
placebo. Results from the first completed large cardiovascular
outcomes trial (FOURIER) were reported in March 2017. Repatha®
(evolocumab) significantly reduced the risk of cardiovascular
events. The study in approximately 27,000 subjects with clinically
evident ASCVD met its primary composite endpoint (cardiovascular
death, nonfatal MI, nonfatal stroke, hospitalization for unstable
angina or coronary revascularization) and the key secondary
composite endpoint (cardiovascular death, nonfatal MI or nonfatal
stroke).
About RNAi
RNAi (RNA interference) is a natural cellular process of gene
silencing that represents one of the most promising and rapidly
advancing frontiers in biology and drug development today. Its
discovery has been heralded as "a major scientific breakthrough
that happens once every decade or so," and was recognized with the
award of the 2006 Nobel Prize for Physiology or Medicine. By
harnessing the natural biological process of RNAi occurring in our
cells, 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,
and which yielded inclisiran (licensed to The Medicines Company),
function upstream of today’s medicines by potently silencing
messenger RNA (mRNA) – the genetic precursors – that encode for
disease-causing proteins, thus preventing them from being made.
This is a revolutionary approach with the potential to transform
the care of patients with genetic and other diseases.
About The Medicines Company
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
serious infectious disease care and cardiovascular care. The
Company is headquartered in Parsippany, New Jersey, with a global
innovation center in California.
About Alnylam Pharmaceuticals
Alnylam (NASDAQ: ALNY) is leading the translation of RNA
interference (RNAi) into a whole new class of innovative medicines
with the potential to transform the lives of people afflicted with
rare genetic, cardio-metabolic, and hepatic infectious diseases.
Based on Nobel Prize-winning science, RNAi therapeutics represent a
powerful, clinically validated approach for the treatment of a wide
range of severe and debilitating diseases. Founded in 2002, Alnylam
is delivering on a bold vision to turn scientific possibility into
reality, with a robust discovery platform and deep pipeline of
investigational medicines, including four product candidates that
are in late-stage development. Looking forward, Alnylam will
continue to execute on its "Alnylam 2020" strategy of building a
multi-product, commercial-stage biopharmaceutical company with a
sustainable pipeline of RNAi-based medicines to address the needs
of patients who have limited or inadequate treatment options.
Alnylam employs over 600 people in the U.S. and Europe and is
headquartered in Cambridge, MA. For more information about our
people, science and pipeline, please visit www.alnylam.com and
engage with us on Twitter at @Alnylam or on LinkedIn.
The Medicines Company Forward Looking Statements
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 the timing and success of a
commercial launch of inclisiran in the United States; the Company’s
broader commercial strategy for and competition for inclisiran;
whether clinical trials for inclisiran will advance 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 physicians will
prescribe and patients will use inclisiran, if it becomes
available; whether the Company will make additional regulatory
submissions for inclisiran on a timely basis, or at all; whether
the Company’s 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 August 9, 2017, which are incorporated
herein by reference. The Company specifically disclaims any
obligation to update these forward-looking statements.
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 inclisiran to be
a safe and effective treatment for hypercholesterolemia, the timing
of clinical studies and potential regulatory filings for approval
of inclisiran and the expected safety database to be generated
through the Phase III studies of inclisiran, its expectations
regarding the development and potential commercialization of
inclisiran by its partner The Medicines Company, and expectations
regarding 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
its 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 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, except to the
extent required by law, to update any forward-looking
statements.
Inclisiran has not been approved by the U.S. Food and Drug
Administration, the European Medicines Agency or any other
regulatory authority and no conclusions can or should be drawn
regarding the safety or effectiveness of this investigational
therapeutic.
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version on businesswire.com: http://www.businesswire.com/news/home/20171106005453/en/
The Medicines
CompanyMediaMeg Langan, 973-290-6319Vice
Presidentmargaret.langan@themedco.comorInvestorsKrishna
Gorti, M.D., 973-290-6122Vice President, Investor
Relationskrishna.gorti@themedco.comorAlnylam PharmaceuticalsInvestors and
MediaChristine Regan Lindenboom, 617-682-4340Vice
Presidentclindenboom@alnylam.comorInvestorsJosh Brodsky,
617-551-8276Associate Directorjbrodsky@alnylam.com
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