– Up to 53 percent Maximal and 47 percent Least
Squares Mean Reduction in LDL-C Achieved at 6 Months after Single,
Low-Volume, Subcutaneous Injection –
– ALN-PCSsc Also Achieves Major Reductions in
Other Atherogenic Lipids, Including Lowering of Lp(a) and Total
Cholesterol of up to 77 percent and 55 percent, Respectively –
– Companies On Track to Initiate ORION-1 Phase
2 Trial by End-2015 –
– Companies to Host Conference Call Today at
4:30 p.m. –
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 StudyThe 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 InformationAlnylam 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 HypercholesterolemiaHypercholesterolemia 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)-GalNAcConjugatesGalNAc-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 RNAiRNAi (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 PharmaceuticalsAlnylam 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 StatementsVarious 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 CompanyThe 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
StatementsStatements 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.
View source
version on businesswire.com: http://www.businesswire.com/news/home/20151111005815/en/
Alnylam Pharmaceuticals, Inc.Christine Regan Lindenboom,
617-682-4340Vice President, Investor Relations and Corporate
CommunicationsorJosh Brodsky, 617-551-8276Senior Manager, Investor
Relations and Corporate CommunicationsorThe Medicines
CompanyKrishna Gorti, M.D., 973-290-6122Vice President,
Investor Relationskrishna.gorti@themedco.comorBob Laverty,
609-558-5570Vice President,
Communicationsrobert.laverty@themedco.com
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